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listlengths 0
18
|
|---|---|---|---|---|---|---|
test-101
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[] |
test-102
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Dermatology
|
DERM
|
[] |
test-103
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Pregnancy
|
Pregnancy
|
[
"She was born after a normal pregnancy and delivery."
] |
test-104
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Lymphatic-System
|
LYMPH
|
[] |
test-105
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"27 - year - old"
] |
test-106
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Age-of-Onset
|
Age (of onset)
|
[] |
test-107
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"MELAS syndrome"
] |
test-108
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-109
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[
"blood pressure of 111/59 mm Hg, pulse rate of 109 beats / min, respiratory rate of 20 / min, and body temperature of 36.0 ℃.",
"blood pressure of 209/147 mm Hg, pulse rate of 140 beats / min, respiratory rate of 25 / min, and body temperature of 36.5 ℃"
] |
test-110
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Gastrointestinal-System
|
GI
|
[] |
test-111
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Patient-History
|
History
|
[
"frequent and insidious onset of seizure - like episodes, dysarthria, gait disturbance and a right - sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia."
] |
test-112
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Neurology
|
Neuro
|
[
"seizure - like episode lasting for approximately five minutes and subsiding spontaneously",
"frequent and insidious onset of seizure - like episodes, dysarthria, gait disturbance and a right - sided visual field defect that had started four years ago",
"Laboratory results were raised cerebrospinal fluid ( CSF ) lactate of 5.2 mmol / L.",
"Electroencephalography ( EEG ) showed diffuse cerebral dysfunction",
"Electromyography revealed sensorimotor polyneuropathy and chronic myopathy",
"Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ).",
"Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria",
"Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly",
"stuporous",
"recovered consciousness"
] |
test-113
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"Laboratory results were raised cerebrospinal fluid ( CSF ) lactate of 5.2 mmol / L.",
"Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ).",
"Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity ( E ' velocity ) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy"
] |
test-114
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Cardiovascular-System
|
CVS
|
[
"electrocardiography ( ECG ) showed supraventricular tachycardia",
"follow - up ECG showed sinus rhythm with pre - excitation",
"Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity ( E ' velocity ) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy",
"followed up without tachycardia attack."
] |
test-115
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Endocrinology
|
ENDO
|
[] |
test-116
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Genitourinary-System
|
GU
|
[] |
test-117
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Respiratory-System
|
RESP
|
[] |
test-118
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Musculoskeletal-System
|
MSK
|
[
"Electromyography revealed sensorimotor polyneuropathy and chronic myopathy",
"Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria"
] |
test-119
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[] |
test-120
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Dermatology
|
DERM
|
[] |
test-121
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Pregnancy
|
Pregnancy
|
[] |
test-122
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Lymphatic-System
|
LYMPH
|
[] |
test-123
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"21 - year - old"
] |
test-124
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Age-of-Onset
|
Age (of onset)
|
[] |
test-125
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"MELAS syndrome"
] |
test-126
|
3242024
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
{'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-127
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-128
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Gastrointestinal-System
|
GI
|
[] |
test-129
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Patient-History
|
History
|
[
"diagnosed with mitochondrial myopathy, encephalopathy and stroke - like episodes ( MELAS ) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure.",
"Her family history is significant for a 12 - year - old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss"
] |
test-130
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Neurology
|
Neuro
|
[
"a fall at her job that was thought to be secondary to a seizure",
"she was no longer able to be employed and her husband became her primary caretaker",
"sensorineural hearing loss",
"bilateral ophthalmoplegia, ptosis, seizures and stroke - like episodes with concern for dementia",
"Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes ( R > L ), and moderate cerebellar atrophy with extensive white matter disease."
] |
test-131
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"positive results for the A - to - G transition at nucleotide 3243 ( m.3243A > G ) of the mitochondrial genome, with 25 % heteroplasmic deleterious mutation in MT - TL1, a mitochondrial leucine transfer RNA gene",
"an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub - epicardium of approximately 25–50 % in thickness in the inferior segment at the base, inferior to lateral segments at the mid - ventricle and lateral segment of the apex, with sparing of the endocardium and septum",
"Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes ( R > L ), and moderate cerebellar atrophy with extensive white matter disease",
"Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 ( normal < 200 ng / L ). Her liver and kidney functions were normal and there was no hyperglycemia."
] |
test-132
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Cardiovascular-System
|
CVS
|
[
"progressive left ventricular hypertrophy ( LVH ) on echocardiogram",
"cardiac work - up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non - sustained atrial tachycardia",
"an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub - epicardium of approximately 25–50 % in thickness in the inferior segment at the base, inferior to lateral segments at the mid - ventricle and lateral segment of the apex, with sparing of the endocardium and septum",
"slightly elevated brain natriuretic peptide of 305 ( normal < 200 ng / L )."
] |
test-133
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Endocrinology
|
ENDO
|
[
"no hyperglycemia."
] |
test-134
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Genitourinary-System
|
GU
|
[] |
test-135
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Respiratory-System
|
RESP
|
[] |
test-136
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Musculoskeletal-System
|
MSK
|
[
"myopathy",
"bilateral ophthalmoplegia, ptosis"
] |
test-137
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"sensorineural hearing loss,",
"bilateral ophthalmoplegia, ptosis,"
] |
test-138
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Dermatology
|
DERM
|
[] |
test-139
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Pregnancy
|
Pregnancy
|
[] |
test-140
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-141
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"44 - year - old"
] |
test-142
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Age-of-Onset
|
Age (of onset)
|
[
"age 32"
] |
test-143
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"mitochondrial myopathy , encephalopathy and stroke - like episodes ( MELAS )"
] |
test-144
|
4750557
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
{'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-145
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-146
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Gastrointestinal-System
|
GI
|
[
"vomiting.",
"anorexia"
] |
test-147
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Patient-History
|
History
|
[
"previously healthy",
"generalized tonic - clonic seizures",
"In 1989, hearing impairment was first documented and ascribed to the previous encephalitis",
"recurrent admissions for seizures,",
"In 1999, he was diagnosed with diabetes mellitus",
"The patient 's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness ( MIDD ). The 3243A > G mutation in the MT - TL1 gene of the mitochondrial DNA ( mtDNA ) was subsequently demonstrated in blood leucocytes, confirming the diagnosis",
"The patient now lives in a nursing home"
] |
test-148
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Neurology
|
Neuro
|
[
"headache",
"Meningism, but no focal neurological signs, was noted on examination",
"slight elevation of protein in the cerebrospinal fluid ( CSF ) but no increased cell count",
"right - sided weakness developed",
"Electroencephalogram demonstrated left parieto - occipital focal slowing",
"Results of T1 / T2 - weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area",
"generalized tonic - clonic seizures",
"No residual neurological deficits persisted",
"recurrent admissions for seizures",
"patient 's functional status deteriorated progressively",
"In the initial CSF analysis, no lactate levels had been checked.",
"CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto - occipital hypodensity, likely representing a previous stroke - like event",
"Cerebral computed tomography of a 40 - year - old man showing generalized cerebral atrophy, bilateral basal ganglia calcification ( asterisks ) and a left parieto - occipital hypodensity ( arrow )"
] |
test-149
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"slight elevation of protein in the cerebrospinal fluid ( CSF ) but no increased cell count",
"Results of T1 / T2 - weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area.",
"herpes serology came back negative",
"In the initial CSF analysis, no lactate levels had been checked",
"CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto - occipital hypodensity, likely representing a previous stroke - like event",
"demonstration of the 3243A > G transition in blood and urine. The heteroplasmy rate ( the mixture of normal and mutated mitochondrial DNA ) was 50 and 90 %, respectively",
"Cerebral computed tomography of a 40 - year - old man showing generalized cerebral atrophy, bilateral basal ganglia calcification ( asterisks ) and a left parieto - occipital hypodensity ( arrow"
] |
test-150
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Cardiovascular-System
|
CVS
|
[
"Electrocardiogram showed Wolff – Parkinson – White syndrome"
] |
test-151
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Endocrinology
|
ENDO
|
[
"diagnosed with diabetes mellitus, requiring insulin straightaway."
] |
test-152
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Genitourinary-System
|
GU
|
[] |
test-153
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Respiratory-System
|
RESP
|
[] |
test-154
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Musculoskeletal-System
|
MSK
|
[] |
test-155
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"hearing impairment",
"Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy"
] |
test-156
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Dermatology
|
DERM
|
[] |
test-157
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Pregnancy
|
Pregnancy
|
[] |
test-158
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Lymphatic-System
|
LYMPH
|
[] |
test-159
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"18 - year - old"
] |
test-160
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Age-of-Onset
|
Age (of onset)
|
[
"18 - year - old"
] |
test-161
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"Mitochondrial encephalopathy with lactic acidosis and stroke - like episodes ( MELAS )"
] |
test-162
|
4369985
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
{'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."}
|
IEM-Treatment
|
IEM_Treatment
|
[
"treatment with coenzyme Q 10 was started"
] |
test-163
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[
"he had a short stature one standard below the mean with a BMI within normal limits."
] |
test-164
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Gastrointestinal-System
|
GI
|
[] |
test-165
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Patient-History
|
History
|
[
"A 17 - year - old Venezuelan male with a 5 - year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup ( Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non - significant.",
"5 - year past medical history of bilateral ptosis",
"His personal and family history was non - significant"
] |
test-166
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Neurology
|
Neuro
|
[
"bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions;",
"MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"His CSF protein and lactate levels were elevated",
"chronic external ophthalmoplegia",
"Bilateral ptosis"
] |
test-167
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"His CSF protein and lactate levels were elevated",
"A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests"
] |
test-168
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Cardiovascular-System
|
CVS
|
[
"echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"EKG, which unveiled complete right branch block, and a left anterior hemiblock",
"The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization",
"cardiac conduction defects",
"Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock"
] |
test-169
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Endocrinology
|
ENDO
|
[] |
test-170
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Genitourinary-System
|
GU
|
[] |
test-171
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Respiratory-System
|
RESP
|
[] |
test-172
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Musculoskeletal-System
|
MSK
|
[] |
test-173
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"He had diplopia, decreased visual acuity and nyctalopia",
"bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism.",
"On funduscopic examination, bilateral atypical pigmentary retinopathy was seen",
"audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"chronic external ophthalmoplegia",
"pigmentary retinopathy",
"Bilateral ptosis",
"Funduscopic examination showing atypical pigmentary retinitis"
] |
test-174
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Dermatology
|
DERM
|
[] |
test-175
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Pregnancy
|
Pregnancy
|
[] |
test-176
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-177
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"17 - year - old"
] |
test-178
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Age-of-Onset
|
Age (of onset)
|
[
"onset of disease before 20 years of age"
] |
test-179
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"The diagnosis of KSS was made from the following findings"
] |
test-180
|
4776051
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
{'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-181
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[
"835 g ( −0.5 SDS ),"
] |
test-182
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Gastrointestinal-System
|
GI
|
[] |
test-183
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Patient-History
|
History
|
[
"A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios",
"Aside from a spontaneously closed ventricular septal defect ( VSD ) in her own infancy, both parents were healthy",
"A maternal uncle of the mother had died postnatally of an unknown cause",
"The mother was pregnant again before exome sequencing had started",
"Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child.",
"The VSD in our patient is considered to be a separate finding ( familial trait )"
] |
test-184
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Neurology
|
Neuro
|
[
"mild dilatation of both lateral ventricles ( 11 mm ).",
"showing an enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ).",
"hypotonic infant",
"Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy.",
"Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst ( Figure S1C ), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst ( Figure S1D )",
"brain abnormalities on more detailed fetal ultrasound examination",
"hypotonia and diminished fetal movements",
"mitochondrial encephalomyopathy",
"cerebellar atrophy",
"hypotonic",
"poor condition with need for mechanical ventilation,"
] |
test-185
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"Firstâ€trimester combined test revealed a low risk for trisomies ( NT 1.1 mm ).",
"The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50.",
"More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD",
"QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 ( 11q22.1 ), including exon 1 of the contactine 5 ( CNTN5 ) gene.",
"Maternal serum infection testing ( TORCHES ) was also normal",
"Postnatal cardiac ultrasound confirmed the presence of a small VSD.",
"Cranial ultrasound on first postnatal day showed bilateral peri†and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy.",
"progressive lactate acidosis with extremely high plasma lactate : 19.1 mmol / L and high pyruvate : 269 μ mol / L. The L / P ( lactate / pyruvate ) ratio was 71, which is strongly increased ( normal < 20 ). Organic acid analysis in urine showed a strong increase of lactate ( 56540 μ mol / mmol creatinine ) and increases of 3â€OHâ€butyrate, pyruvate, fumarate, malate, and 4â€OHâ€phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very longâ€chain fatty acids in plasma were normal",
"Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra†and periventricular hemorrhage with adjacent cyst ( Figure S1C ), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst ( Figure S1D )",
"DNA analysis of the PDHA1 â€gene ( most frequent genetic cause of pyruvateâ€dehydrogenase complex deficiency ) showed no pathogenic mutations",
"Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing : c.292C > T ( p.(Arg98*))and c.1303C > T ( p.(Arg435 * ) ).",
"brain abnormalities on more detailed fetal ultrasound examination",
"persistent lactate acidosis"
] |
test-186
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Cardiovascular-System
|
CVS
|
[
"spontaneously closed ventricular septal defect ( VSD ) in her own infancy,",
"The myocardium was hypertrophic with a small perimembraneous VSD",
"Postnatal cardiac ultrasound confirmed the presence of a small VSD",
"hypotension",
"The VSD in our patient is considered to be a separate finding ( familial trait )"
] |
test-187
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Endocrinology
|
ENDO
|
[] |
test-188
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Genitourinary-System
|
GU
|
[
"Testes were not palpable in the scrotum"
] |
test-189
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Respiratory-System
|
RESP
|
[
"respiratory distress syndrome.",
"poor condition with need for mechanical ventilation"
] |
test-190
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Musculoskeletal-System
|
MSK
|
[
"He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges",
"The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels",
"mitochondrial encephalomyopathy"
] |
test-191
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[] |
test-192
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Dermatology
|
DERM
|
[
"lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus",
"small fingernails"
] |
test-193
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Pregnancy
|
Pregnancy
|
[
"First‐trimester combined test revealed a low risk for trisomies ( NT 1.1 mm ). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios ( uterine size that outpaced gestational age ) and premature contractions.",
"Ultrasound showed polyhydramnios ( MVP 9.9 cm, AFI 27.5 cm ) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles ( 11 mm ).",
"enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD",
"Two days later ( 26 + 0 ), she spontaneously delivered a boy of 835 g ( −0.5 SDS ), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively.",
"A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome.",
"the neonate died 2 days after birth",
"polyhydramnios",
"early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements",
"polyhydramnios, causing premature delivery"
] |
test-194
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-195
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"30‐year‐old"
] |
test-196
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Age-of-Onset
|
Age (of onset)
|
[] |
test-197
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"FBXL4 ‐related encephalopathy"
] |
test-198
|
4831400
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
{'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-199
|
4750615
|
{'Case report': 'The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months. Routine work-up showed significant metabolic acidosis with low serum bicarbonate concentrations. He was started on oral sodium citrate and admitted for evaluation, which revealed low serum glucose of 3.05 mmol/L (55 mg/dL) and very low plasma l -carnitine (total carnitine:7 μmol/L, reference range: 25–69). Serum creatine phosphokinase (CK) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat/L (12,086 U/L), AST at 341 U/L and ALT at 190 U/L. Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation disorders. The patient had started on carnitine and cornstarch but continued to deteriorate, with multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy (MRS) showed lactate peaks in the left basal ganglion and lateral ventricle. As this finding was suggestive of a mitochondrial disorder, treatment with coenzyme Q10, riboflavin, creatine monohydrate, alpha-lipoic acid, and medium chain triglyceride (MCT) oil was initiated, while continuing carnitine supplementation. Leucovorin was later added due to a low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate level. At age eight, he required a gastric feeding tube (G-tube) placement for malnutrition and continued weight loss. The urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3-methylglutaconate, and branched-chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4) with normal results . Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine (in vitro probe assay) showed marked elevations of long-chain species, suggestive of carnitine palmitoyltransferase II or carnitine–acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol/L (< 2.8), and a low normal level of 5-methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver (10%; control range 3.3 +/− 1.7%) and muscle (3.0%; control range 0.94 +/− 0.55). However, sequencing of PHKA1 and PHKG2 genes (GSD IX) and AGL gene (GSD III) was normal. Activities of debranching enzyme (EC 2.4.1.25 GSD III) and hepatic phosphorylase kinase (GSD IX, EC 2.7.11.19) in the liver and muscle, and glucose-6-phosphatase (GSD Ia, EC 3.1.3.9) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain (ETC) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 (mean 1461, standard deviation 473); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu-Ala-Thr (m.15319_15327delCCTAGCAAC; p.Leu192_Thr194del, Fig. 2 ) in the MT-CYB gene encoding cytochrome b subunit of complex III, with > 90% mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts. Since the diagnosis, ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal. The child dramatically improved with the start of G-tube feeding and dietary supplements, with increased energy level, improved exercise tolerance and progress in academic performance. Previously confined to a wheel chair, he started to walk independently and actively. Lactic acid, transaminases and CK levels have stabilized, although lactate showed occasional elevations as high as 11 mmol/L without symptoms of metabolic decompensation. His G-tube was removed at age 12 years and he stopped taking supplements, and he continues to do remarkably well physically.'}
|
{'Case report': 'The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months. Routine work-up showed significant metabolic acidosis with low serum bicarbonate concentrations. He was started on oral sodium citrate and admitted for evaluation, which revealed low serum glucose of 3.05 mmol/L (55 mg/dL) and very low plasma l -carnitine (total carnitine:7 μmol/L, reference range: 25–69). Serum creatine phosphokinase (CK) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat/L (12,086 U/L), AST at 341 U/L and ALT at 190 U/L. Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation disorders. The patient had started on carnitine and cornstarch but continued to deteriorate, with multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy (MRS) showed lactate peaks in the left basal ganglion and lateral ventricle. As this finding was suggestive of a mitochondrial disorder, treatment with coenzyme Q10, riboflavin, creatine monohydrate, alpha-lipoic acid, and medium chain triglyceride (MCT) oil was initiated, while continuing carnitine supplementation. Leucovorin was later added due to a low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate level. At age eight, he required a gastric feeding tube (G-tube) placement for malnutrition and continued weight loss. The urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3-methylglutaconate, and branched-chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4) with normal results . Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine (in vitro probe assay) showed marked elevations of long-chain species, suggestive of carnitine palmitoyltransferase II or carnitine–acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol/L (< 2.8), and a low normal level of 5-methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver (10%; control range 3.3 +/− 1.7%) and muscle (3.0%; control range 0.94 +/− 0.55). However, sequencing of PHKA1 and PHKG2 genes (GSD IX) and AGL gene (GSD III) was normal. Activities of debranching enzyme (EC 2.4.1.25 GSD III) and hepatic phosphorylase kinase (GSD IX, EC 2.7.11.19) in the liver and muscle, and glucose-6-phosphatase (GSD Ia, EC 3.1.3.9) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain (ETC) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 (mean 1461, standard deviation 473); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu-Ala-Thr (m.15319_15327delCCTAGCAAC; p.Leu192_Thr194del, Fig. 2 ) in the MT-CYB gene encoding cytochrome b subunit of complex III, with > 90% mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts. Since the diagnosis, ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal. The child dramatically improved with the start of G-tube feeding and dietary supplements, with increased energy level, improved exercise tolerance and progress in academic performance. Previously confined to a wheel chair, he started to walk independently and actively. Lactic acid, transaminases and CK levels have stabilized, although lactate showed occasional elevations as high as 11 mmol/L without symptoms of metabolic decompensation. His G-tube was removed at age 12 years and he stopped taking supplements, and he continues to do remarkably well physically.'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-200
|
4750615
|
{'Case report': 'The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months. Routine work-up showed significant metabolic acidosis with low serum bicarbonate concentrations. He was started on oral sodium citrate and admitted for evaluation, which revealed low serum glucose of 3.05 mmol/L (55 mg/dL) and very low plasma l -carnitine (total carnitine:7 μmol/L, reference range: 25–69). Serum creatine phosphokinase (CK) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat/L (12,086 U/L), AST at 341 U/L and ALT at 190 U/L. Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation disorders. The patient had started on carnitine and cornstarch but continued to deteriorate, with multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy (MRS) showed lactate peaks in the left basal ganglion and lateral ventricle. As this finding was suggestive of a mitochondrial disorder, treatment with coenzyme Q10, riboflavin, creatine monohydrate, alpha-lipoic acid, and medium chain triglyceride (MCT) oil was initiated, while continuing carnitine supplementation. Leucovorin was later added due to a low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate level. At age eight, he required a gastric feeding tube (G-tube) placement for malnutrition and continued weight loss. The urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3-methylglutaconate, and branched-chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4) with normal results . Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine (in vitro probe assay) showed marked elevations of long-chain species, suggestive of carnitine palmitoyltransferase II or carnitine–acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol/L (< 2.8), and a low normal level of 5-methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver (10%; control range 3.3 +/− 1.7%) and muscle (3.0%; control range 0.94 +/− 0.55). However, sequencing of PHKA1 and PHKG2 genes (GSD IX) and AGL gene (GSD III) was normal. Activities of debranching enzyme (EC 2.4.1.25 GSD III) and hepatic phosphorylase kinase (GSD IX, EC 2.7.11.19) in the liver and muscle, and glucose-6-phosphatase (GSD Ia, EC 3.1.3.9) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain (ETC) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 (mean 1461, standard deviation 473); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu-Ala-Thr (m.15319_15327delCCTAGCAAC; p.Leu192_Thr194del, Fig. 2 ) in the MT-CYB gene encoding cytochrome b subunit of complex III, with > 90% mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts. Since the diagnosis, ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal. The child dramatically improved with the start of G-tube feeding and dietary supplements, with increased energy level, improved exercise tolerance and progress in academic performance. Previously confined to a wheel chair, he started to walk independently and actively. Lactic acid, transaminases and CK levels have stabilized, although lactate showed occasional elevations as high as 11 mmol/L without symptoms of metabolic decompensation. His G-tube was removed at age 12 years and he stopped taking supplements, and he continues to do remarkably well physically.'}
|
{'Case report': 'The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months. Routine work-up showed significant metabolic acidosis with low serum bicarbonate concentrations. He was started on oral sodium citrate and admitted for evaluation, which revealed low serum glucose of 3.05 mmol/L (55 mg/dL) and very low plasma l -carnitine (total carnitine:7 μmol/L, reference range: 25–69). Serum creatine phosphokinase (CK) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat/L (12,086 U/L), AST at 341 U/L and ALT at 190 U/L. Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation disorders. The patient had started on carnitine and cornstarch but continued to deteriorate, with multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy (MRS) showed lactate peaks in the left basal ganglion and lateral ventricle. As this finding was suggestive of a mitochondrial disorder, treatment with coenzyme Q10, riboflavin, creatine monohydrate, alpha-lipoic acid, and medium chain triglyceride (MCT) oil was initiated, while continuing carnitine supplementation. Leucovorin was later added due to a low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate level. At age eight, he required a gastric feeding tube (G-tube) placement for malnutrition and continued weight loss. The urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3-methylglutaconate, and branched-chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4) with normal results . Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine (in vitro probe assay) showed marked elevations of long-chain species, suggestive of carnitine palmitoyltransferase II or carnitine–acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol/L (< 2.8), and a low normal level of 5-methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver (10%; control range 3.3 +/− 1.7%) and muscle (3.0%; control range 0.94 +/− 0.55). However, sequencing of PHKA1 and PHKG2 genes (GSD IX) and AGL gene (GSD III) was normal. Activities of debranching enzyme (EC 2.4.1.25 GSD III) and hepatic phosphorylase kinase (GSD IX, EC 2.7.11.19) in the liver and muscle, and glucose-6-phosphatase (GSD Ia, EC 3.1.3.9) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain (ETC) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 (mean 1461, standard deviation 473); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu-Ala-Thr (m.15319_15327delCCTAGCAAC; p.Leu192_Thr194del, Fig. 2 ) in the MT-CYB gene encoding cytochrome b subunit of complex III, with > 90% mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts. Since the diagnosis, ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal. The child dramatically improved with the start of G-tube feeding and dietary supplements, with increased energy level, improved exercise tolerance and progress in academic performance. Previously confined to a wheel chair, he started to walk independently and actively. Lactic acid, transaminases and CK levels have stabilized, although lactate showed occasional elevations as high as 11 mmol/L without symptoms of metabolic decompensation. His G-tube was removed at age 12 years and he stopped taking supplements, and he continues to do remarkably well physically.'}
|
Gastrointestinal-System
|
GI
|
[
"intermittent vomiting, diarrhea, constipation, weight loss"
] |
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