A rare inherited subacute encephalopathy characterized by the variable association of basal ganglia calcification, leukodystrophy, cerebrospinal fluid (CSF) lymphocytosis and evidence of enhanced type I interferon signaling in blood and CSF.

Summary:
Epidemiology
More than 500 cases of Aicardi-Goutières syndrome (AGS) have been reported in the literature to date.
Clinical description
The majority of affected infants are born at full term with normal growth parameters. In its classic form, onset occurs within the first few days or months of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy, chilblain skin lesions on the extremities and episodes of aseptic febrile illness. These features can continue over several weeks/months (with the development of microcephaly and pyramidal signs) before the disease apparently stabilizes. Less severe forms have been described with onset after 1 year of age, and relative preservation of communication skills, cognitive function and head circumference. The phenotype can manifest with marked inter- and intrafamilial variation. Less frequently still, mutations in AGS-related genes can be associated with other distinct phenotypes, including bilateral striatal necrosis, non-syndromic spastic paraparesis of the lower limbs with normal intellect and neuroradiology, cerebrovascular disease similar to Moyamoya, and even complete clinical non-penetrance.
Etiology
Since 2006, causative mutations have been identified in nine genes encoding: (i) the 3'->5' exonuclease TREX1; (ii) the three components of the RNase H2 endonuclease complex (RNASEH2A, RNASEH2B and RNASEH2C), (iii) SAMHD1, which functions as a deoxynucleoside triphosphate triphosphohydrolase; (iv) ADAR1, which catalyzes the hydrolytic deamination of adenosine to inosine in RNA; (v) MDA5, (encoded by IFIH1) a cytosolic double stranded RNA sensor; and (vi) two components of the histone pre-mRNA processing complex (RNU7-1 and LSM11). Mutations in TREX1, RNASEH2C and RNASEH2A are more often associated with severe neurological problems, whereas mutations in RNASEH2B, SAMHD1, IFIH1 and ADAR1 can be associated with a relative preservation of skills. The phenotype associated with mutations in LSM11 and RNU7-1 have yet to be fully determined.
Diagnostic methods
Calcification (involving the basal ganglia and white matter), cystic leukodystrophy (predominantly frontotemporal in very early onset cases) and cortical-subcortical atrophy are cardinal features of typical AGS, sometimes associated with atrophy of the corpus callosum, the brain stem and cerebellum. Elevated IFN-alpha activity and lymphocytosis in the CSF are frequent but not constant findings in the initial stage of the disease, but tend to normalize or resolve within a few years. The expression of interferon stimulated genes (ISGs)—a so-called interferon signature—can be recorded in the blood of the majority of cases, except in patients carrying RNASEH2B variants (where ~ 20% of patients have normal ISG expression after age 4 years). The diagnosis is confirmed by detection of mutations in one of the nine disease-associated genes.
Differential diagnosis
The principle differential diagnoses are TORCH congenital infections (toxoplasma, rubella, cytomegalovirus, HSV1 and HSV2), and other diseases associated with white matter abnormalities and/or intracranial calcification.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Disease due to mutations in TREX1, RNASEH2A/B/C, SAMHD1, ADAR, LSM11 and RNU7-1 are almost always inherited as an autosomal recessive trait, although rare dominant mutations in TREX1 and ADAR —affecting highly specific residues— are well recognized. In contrast, mutations in IFIH1 are always inherited as an autosomal dominant trait.
Management and treatment
To date, treatment has been mostly symptomatic (management of feeding problems, tone, epilepsy etc.). However, JAK1 inhibition (JAKi) is a therapeutic option for the systemic features of AGS, such as recurrent fevers and chilblains. The efficacy of JAKi on the neurological features of the disease is less evident. Side effects of such targeted therapies should be considered.
Prognosis
Around 10% of patients die within the first 5 years of life, but prolonged survival into the third and fourth decades of life is well recognized.

                            Last update:
                            May 2024

                            - Expert reviewer(s):
                            Pr Yanick CROW | RITA* - Pr Marie-Louise FRÉMOND | RITA* - Pr Bénédicte NEVEN

                                * European Reference Network


A rare condition associated with acquired immunodeficiency syndrome (AIDS) and characterized by unwanted weight loss (involving both fat and muscle) of more than ten percent of body weight, with either diarrhea or weakness and fever which have lasted at least 30 days and are not related to an infection.


A rare benign vascular tumor characterized by rapid growth after birth (followed by spontaneous partial regression over the course of years), potentially leading to life-threatening airway obstruction due to the subglottic location. Patients present with respiratory symptoms including biphasic stridor, recurrent croup, cyanosis, apnea, and sternal and intercostal retractions. The tumor may be accompanied by cutaneous hemangiomata, especially in the lower facial ("beard") distribution.


AKT2-related familial partial lipodystrophy

A rare familial partial lipodystrophy characterized by adult onset of distal lipoatrophy and severe insulin resistance in the liver and peripheral tissues, hyperinsulinemia, and diabetes mellitus. Acanthosis nigricans and hypertension have been reported in association.


A clonal B-cell disorder characterized by the aggregation and deposition of insoluble amyloid fibrils derived from misfolding of monoclonal immunoglobulin light chains. It usually presents as systemic AL amyloidosis with involvement of one or more parenchymal organ(s) and, less frequently, as localized amyloidosis with usually nodular deposits restricted to a single organ and/or system.

Summary:
Epidemiology
It represents the most common type of systemic amyloidosis in western countries; in Europe and the USA the incidence ranges from 1/80,000-330,000 and prevalence between 1/17,000-50,000. AL amyloidosis affects men slightly more often than women.
Clinical description
The average age of diagnosed patients is 63 years. The clinical manifestations depend on organ involvement and general symptoms, such as fatigue and weight loss, can also occur. The heart (approximately 80%) and the kidneys (65%) are the most commonly involved organs, followed by soft tissues, liver, peripheral and autonomic nervous system, and gastrointestinal tract. This can result in fluid retention, dyspnea, arrhythmias, liver enlargement, macroglossia, swelling if the submandibular glands, carpal tunnel syndrome, peripheral neuropathy, hypotension, diarrhea or constipation. Localized AL amyloidosis can affect the skin, the respiratory, gastrointestinal and urinary tract, and the eye.
Etiology
AL amyloidosis results from conformational changes of monoclonal immunoglobulin light chains produced by a usually small B-cell (most commonly plasma cell) clone. These light chains misfold, aggregate, and deposit in tissue in the form of fibrils. Organ dysfunction and damage is dependent on a direct toxic effect of monoclonal light chains, particularly in the heart, and on the mechanical effect of deposits.
Diagnostic methods
Diagnosis of systemic AL amyloidosis is established by demonstrating amyloid deposits (red-green birefringence with Congo red staining under cross-polarized light) in the affected organ by biopsy or other less invasive alternatives (e.g. subcutaneous fat aspirate) and by demonstrating that amyloid fibrils are formed by immunoglobulin light chains (amyloid typing). Amyloid typing can be achieved by immunohistochemical staining, immunofluorescence on renal biopsies in patients with kidney involvement, and mass spectrometry. A B-cell clone producing a light chain of the same isotype as that documented in the deposits should be searched for and demonstrated. The presence and severity of organ involvement should be assessed (by echocardiography, cardiac magnetic resonance imaging, measurement of proteinuria and renal and liver function parameters) and graded. Cardiac and renal staging systems based on natriuretic peptide type-B or its N-terminal pro-hormone, troponin, free light chain proteinuria, and glomerular filtration rate accurately predict the risk of death and progression to dialysis. Localized AL amyloidosis is diagnosed by biopsy of the deposits.
Differential diagnosis
Systemic AL amyloidosis should be distinguished from other forms of systemic amyloidosis and from non-amyloid light chain deposition disease.
Management and treatment
Treatment of systemic AL amyloidosis is based on therapies targeting the underlying plasma clone aiming at reducing the supply of the amyloid-forming light chain. Successful treatment can improve organ involvement and extend survival. The only licensed therapy is the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD). Other effective regimens are bortezomib, melphalan, dexamethasone (BMDex) and CyBorD. Autologous stem cell transplant is effective and induces long term survival in responders, but only a minority of patients (approximately 20%) are fit enough to safely undergo this procedure. Relapsed and refractory patients are usually rescued with immunomodulatory drugs, such as lenalidomide and pomalidomide. Patients in whom the disease is not caused by a plasma cell clone are treated with regimens used in the corresponding B cell malignancy. Localized AL amyloidosis is treated by surgical removal of the amyloid deposits when this is necessary and possible.
Prognosis
The prognosis of systemic AL amyloidosis depends on the presence and severity of heart involvement and on response to therapy. Patients who are diagnosed when advanced heart involvement is already established are at high risk of early death (within a few months), whereas patients who attain rapid and deep response to therapy can enjoy a prolonged survival. Localized AL amyloidosis has a largely better outcome and only exceptionally is it life threatening.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Giovanni PALLADINI | EuroBloodNet*

                                * European Reference Network


A rare, genetic, inborn error of metabolism disorder characterized by global developmental delay, hypotonia, choreoathetosis, hypo-/alacrimia, and liver dysfunction which manifests with elevated liver transaminases and hepatocyte cytoplasmic storage material or vacuolization on liver biopsy. Additional features reported include acquired microcephaly, hypo-/areflexia, seizures, peripheral neuropathy, intellectual and language/speech disability, additional ocular anomalies and EEG and brain imaging abnomalities.


A rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxonterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys.

Summary:
Epidemiology
The prevalence is approximately 1/70,000.
Clinical description
The disease may manifest in newborns by prolonged jaundice due to conjugated hyperbilirubinemia, and/or cardiac signs and symptoms. Cardiac abnormalities include pulmonary atresia or stenosis, atrial and/or ventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus (see these terms). Cholestasis manifests by conjugated hyperbilirubinemia, hepatosplenomegaly, hypercholesterolemia, hypertriglyceridemia, and coagulopathy. Pruritus and xanthomas may occur. Minor skeletal abnormalities include butterfly hemivertebrae (around 50% of cases), and shortening of the radius, ulna, and phalanges. Characteristic facial features, if present, are usually apparent from childhood and include prominent forehead, deep-set eyes, upslanting palpebral fissures, hypertelorism, flat nasal root, and pointed chin. Ophthalmic anomalies include posterior embryotoxon (75% of cases), Axenfeld anomaly (see this term), pigmentary retinopathy, papillary and optic disc anomalies. Growth delay, fat malabsorption (rickets may occur), and sometimes developmental delay occur. Small and dysplastic kidneys (common in AGS type 2), and hypothyroidism may be present.
Etiology
AGS is most commonly due to JAG1 (20p12) gene mutations (AGS type 1), encoding a Notch signaling pathway ligand. AGS type 2 is due to NOTCH2 gene mutations (1p12).
Diagnostic methods
The diagnosis is based on the clinical picture and liver biopsy revealing chronic cholestasis and paucity of interlobular bile ducts. Imaging (abdominal ultrasonography, cholangiography) helps to identify biliary anatomy. Screening for ophthalmic, skeletal, vascular and endocrine (thyroid) abnormalities should be performed. DNA sequencing may confirm the diagnosis.
Differential diagnosis
Differential diagnoses include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia (see these terms).
Antenatal diagnosis
If a pathogenic mutation has been identified, prenatal genetic diagnosis is possible on DNA from chorionic villous tissue or cultured amniocytes. Otherwise, detailed fetal ultrasonography may identify cardiac and/or renal anomalies if present.
Genetic counseling
Transmission is autosomal dominant, but reduced penetrance (up to 50% of cases) and somatic mosaicism (~8%) are common.
Management and treatment
Treatment is non-specific and includes high-carbohydrates and high-medium chain triglyceride diets and vitamin supplementation. Pruritus may be reduced by cholestyramine or rifampin. Liver transplantation may be necessary for patients with refractory disease. Cardiac or vascular procedures may be required for significant symptomatic lesions.
Prognosis
The prognosis is usually favorable, but complications such as cirrhosis, variceal hemorrhage, refractory ascites, and spontaneous bacterial peritonitis may occur. The disease usually stabilizes between ages 4 and 10 years. When hepatic failure and/or cardiac lesions are present, mortality risk is increased.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Peter TURNPENNY


Alar cartilages hypoplasia-coloboma-telecanthus syndrome

A very rare dysmorphic disorder characterized by hypoplasia and coloboma of the alar cartilages and telecanthus described in 2 sisters. No new cases with similar features have been reported since 1976.


A rare form of primordial dwarfism, often microcephalic, characterized by short stature, global developmental delay, variable intellectual disability and recognizable dysmorphic facial features (triangular face, prominent forehead, deeply set eyes, low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, and widely spaced teeth).

Summary:
Epidemiology
To date, less than 30 affected individuals reported worldwide, about half of which belong to a few consanguineous families.
Clinical description
Alazami syndrome is a genetic developmental defect characterized by mild to severe short stature, head circumference below the 50th centile, microcephaly in half of the individuals, and global developmental delay with moderate to severe intellectual disability. Speech can be absent or delayed (mainly expressive rather than receptive language delay in milder cases). Short stature and reduced head circumference are progressive, but usually already apparent at birth; endocrinological testing is normal in the majority of examined patients, with only a slight reduction of IGF-1 in some. Most individuals have distinctive facial features: triangular face, prominent forehead, deeply set eyes (often with narrow palpebral fissures), low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, widely spaced teeth. Scoliosis and strabismus are reported in one third of affected individuals. Several patients display autistic and/or maladaptive behaviors, including stereotypies similar to hand-washing. All features show inter- and intrafamilial variability. Additional, variable features may also include congenital heart defects such as pulmonary artery stenosis or atrial septal defect, seizures, aplasia/hypoplasia of the corpus callosum or other brain MRI anomalies, and accelerated skeletal maturation. Features more rarely reported include cleft palate, brachydactyly, prominent interphalangeal joints, 2-3 toe syndactyly, metaphyseal dysplasia, hydronephrosis due ureteropelvic junction stenosis, and hypospadias.
Etiology
The syndrome is caused by biallelic loss-of-function variants in the LARP7 gene (4q25), which encodes a protein involved in the regulation of RNA transcription and splicing. At least one variant retaining partial protein function has been described, but no specific genotype-phenotype correlation could be established.
Diagnostic methods
Diagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date.
Differential diagnosis
Differential diagnosis includes other syndromes characterized by intellectual disability and short stature.
Antenatal diagnosis
Prenatal diagnosis is available for at-risk pregnancies, if a pathogenic variant has been identified in a member of the affected family.
Genetic counseling
Alazami syndrome is an autosomal recessive disorder, with homozygous and compound heterozygous variants described. It is expected to have increased frequency in populations where consanguineous couples are frequent. Genetic counseling should be offered to at-risk couples (both carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is multidisciplinary, based on the clinical manifestations, with lifelong follow-up. Most patients will require various degrees of assistance with day-to-day activities. Neuropsychiatric assistance, speech therapy and educational support may be effective.
Prognosis
Life expectancy is currently unknown. Affected individuals have been reported to live into early adulthood, and only a few of the known associated clinical features can pose a life-threatening risk. There is only one report indicating a possible increase in tumor susceptibility. The level of autonomy is dependent on the severity of intellectual disability and language delay.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Stefano Giuseppe CARAFFI | ITHACA* - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network


A sclerosing disorder of the skeleton characterized by increased bone density that classically displays the radiographic sign of ''sandwich vertebrae'' (dense bands of sclerosis parallel to the vertebral endplates).

Summary:
Epidemiology
The prevalence is estimated to be 1/20,000.
Clinical description
Onset of the disease is typically in late childhood or adolescence. The main manifestations are confined to the skeleton, including fractures, scoliosis, hip osteoarthritis and osteomyelitis, particularly affecting the mandible in association with dental abscess or caries. Cranial nerve compression is a rare but important complication, with hearing and visual loss affecting around 5% of individuals. Moderate bone marrow failure is described occasionally.
Etiology
The disease is caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene (16p13).
Diagnostic methods
Diagnosis is based on clinical findings and largely depends on the radiographic appearance of the skeleton. Genetic testing is available and can be used to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes other subtypes of osteopetrosis, fluorosis, beryllium, lead and bismuth poisoning, myelofibrosis, Paget's disease (sclerosing form) and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible if the mutation causing the condition in the family is known.
Genetic counseling
Albers-Schönberg osteopetrosis is transmitted in an autosomal dominant manner. Genetic counseling should be offered to families. Each child of an affected individual has 50% risk of being affected. The parents of the proband should be carefully evaluated for signs of osteopetrosis, including radiographic studies of the skeleton.
Management and treatment
At present, there is no effective medical treatment for osteopetrosis. Management is supportive and aims at providing multidisciplinary surveillance and symptomatic treatment.
Prognosis
Clinical manifestations may worsen over time but life expectancy is usually normal.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK


A rare disorder characterised by congenital nerve deafness and piebaldness with no ocular albinism. It has been described in one large pedigree. Transmission is X-linked with affected males presenting with profound sensorineural deafness and severe pigmentary abnormalities of the skin, and carrier females presenting with variable hearing impairment without any pigmentary changes. The causative gene has been mapped to Xq26.3-q27.1.


A rare, genetic, neurometabolic disease characterized by prenatal and postnatal growth retardation, hypotonia, failure to thrive, large and late-closing fontanel, development delay, cutis laxa, joint laxity, progeroid appearance, and dysmorphic facial features. In addition, corneal opacities, cataracts, myopia, seizures, hyperreflexia and athetoid movements have also been associated.


A rare, systemic amyloidosis characterized by slowly progressive renal disease presenting with proteinuria, hypertension and decreased glomerular filtration rate leading to progressive renal failure. Histology reveals amyloid deposits of leukocyte chemotactic factor-2 protein in the renal cortical interstitium, tubular basement membranes, glomeruli and the vessel walls. Extra-renal deposits can be seen in the liver, lungs, spleen and adrenal glands.


An astrogliopathy and the most severe and common form of Alexander disease (AxD), presenting before the age of 4 and characterized by seizures, megalencephaly and developmental delay with progressive deterioration.

Summary:
Epidemiology
The prevalence is unknown. This form accounts for approximately 60% of AxD cases.
Clinical description
AxD type I typically presents between birth and the age of 4. Those with a neonatal onset (within the first 30 days) usually have a more severe disease course presenting with symptoms of generalized, frequent, and often intractable seizures, aqueductal stenosis (leading to hydrocephalus with raised intracranial pressure) and severe motor and intellectual disability. In infantile-onset cases, ataxia, hyperreflexia and pyramidal signs are seen along with seizures. Megalencephaly and frontal bossing are further manifestations of the disease. In all infants there is a loss of developmental milestones with progressive psychomotor retardation. The disease course is severe with death usually, but not always, occurring in the first two decades after diagnosis. In the neonatal form the disease progresses even faster with severe disability or death occurring within the first years of life.
Etiology
AxD is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.
Diagnostic methods
MRI shows characteristic leukodystrophy with frontal, basal ganglia signal abnormality, brainstem signal abnormality and contrast enhancement. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. The presence of Rosenthal fibers in astrocytes can also be seen in other diseases and is therefore not diagnostic.
Differential diagnosis
Differential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, Aicardi-Goutières syndrome, the frontal variant of adrenoleukodystrophy and megalencephalic leukoencephalopathy with subcortical cysts (see these terms).
Antenatal diagnosis
Although most cases of AxD type I are sporadic, antenatal diagnosis is possible if a disease causing mutation has been identified in an affected family member.
Genetic counseling
AxD type I typically occurs sporadically and is associated with the occurrence of de novo  mutations. Most patients do not reproduce. Gonadal mosaicism should be considered in advising families of the risk of recurrence when a de novo mutation is identified. Genetic counseling can be proposed to families with a history of the disease and family members can be tested for the disease-causing mutation. Penetrance is complete.
Management and treatment
There is no cure for AxD type I. Treatment is symptomatic and focuses on seizure control, maintenance of pulmonary function and nutrition. Those with severe feeding difficulties and recurrent vomiting may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Antibiotics can be given to treat intercurrent infections and antiepileptic drugs are given to control seizures. Orthopedic complications should be prevented, in particular scoliosis, and the management of spasticity by a multidisciplinary team is an important component of care. Psychological counseling can also be proposed to families of infants with the disease.
Prognosis
The prognosis is poor but with supportive therapies some patients have lived into adolescence and adulthood.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Dr Albee MESSING  - Dr Adeline VANDERVER


An astrogliopathy and a form of Alexander disease (AxD) characterized by ataxia, bulbar symptoms, spastic paraparesis, palatal myoclonus, and autonomic symptoms.

Summary:
Epidemiology
Prevalence is unknown. It accounts for approximately 40% of AxD cases.
Clinical description
AxD type II can present throughout life, most commonly in late adolescence or adulthood (over the age of 12) and more rarely in childhood, with the age of onset ranging from 4-62 in published cases. It presents most commonly with bulbar symptoms (dysarthria, dysphonia, dysphagia), pyramidal signs and gait difficulties due to ataxia and/or spastic paraparesis. Unlike AxD type I (see this term), seizures are rarely seen and cognitive impairment is sometimes absent. Abnormalities of ocular movements are common and include saccadic pursuit, nystagmus, mild upper lid ptosis or diplopia. Sleep disorders (apneas and snoring) due to brainstem involvement are common as are urinary disturbances. Palatal myoclonus is also common. Other manifestations may include hypothermia episodes, sweating disturbances, constipation, pupillary abnormalities, impotence, kyphosis and scoliosis. Progression is slow and disease course is less severe than AxD type I but eventually muscle wasting and weakness often lead to motor impairment and dysphagia. Death is often due to aspiration pneumonia and respiratory insufficiency.
Etiology
AxD type II is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). Both sporadic cases with de novo mutations and familial cases have been reported. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.
Diagnostic methods
MRI is the most useful diagnostic tool as AxD type II characteristically shows a predominance of hindbrain lesions with mild to severe atrophy of the medulla oblongata and upper spinal cord. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. Pathological findings of Rosenthal fibers do not determine diagnosis as they are present in other conditions.
Differential diagnosis
Differential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, megalencephalic leukoencephalopathy with subcortical cysts as well as other leukodystrophies such as Canavan disease, X-linked adrenoleukodystrophy and Krabbe disease (see these terms). AxD type II can also be misdiagnosed as primary lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and amyotrophic lateral sclerosis (see these terms) or one of numerous types of neoplasms (ex. spinal cord lesions, focal brain stem glioma, focal posterior fossa lesions).
Antenatal diagnosis
Antenatal diagnosis is possible if a disease causing mutation has been identified in a family member.
Genetic counseling
The disease is transmitted autosomal dominantly. Both de novo and familial cases have been reported. Genetic counseling can be offered to those with a family member with a mutation in the GFAP gene but is difficult as penetrance is sometimes incomplete.
Management and treatment
There is no cure for AxD type II. Treatment is symptomatic and supportive. Monitoring and assessment of speech and swallowing difficulties is necessary. Evaluation and management of sleep apnea can greatly improve quality of life. Early recognition of scoliosis can prevent long term complications. As the disease progresses most patients require walking aids and/or wheelchairs. Patients with dysphagia may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Psychological assessment of patients along with counseling for patients and their families can be offered.
Prognosis
The prognosis is quite poor with median survival time after disease onset being 25 years.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Dr Albee MESSING  - Dr Adeline VANDERVER


A rare neurodegenerative disorder of the astrocytes comprised of two clinical forms: Alexander disease (AxD) type I and type II manifesting with various degrees of macrocephaly, spasticity, ataxia and seizures and leading to psychomotor regression and death.

Summary:
Epidemiology
The prevalence is unknown. One population based study in Japan estimated an annual incidence of 1/ 2.7 million.
Clinical description
The clinical presentation depends on the subtype. Previously, AxD was classified either as infantile, juvenile or adult, based simply on age of onset. The currently used classification system is based on a constellation of clinical and radiologic features and includes AxD type I and AxD type II (see these terms). AxD type I is more likely to be of early onset (mean 1.74 years) and shorter survival (median 14 years) whereas type II exhibits onset throughout the lifespan (mean 21.64 years, but can occur in early childhood) and has longer survival (median 25 years). The two types also differ in their clinical symptoms. AxD type I manifests with symptoms of encephalopathy, epilepsy and failure to thrive and has an infantile presentation, while patients with AxD type II manifest with bulbar, autonomic and motor signs such as dysarthria, dysphonia, dysphagia, ataxia, spastic paraparesis and palatal myoclonus. AxD type II also has a slower progression and cognitive impairment can be completely absent.
Etiology
In the vast majority (95%) of patients, AxD is caused by gain-of-function de novo mutations in the glial fibrillary acidic protein (GFAP) gene. Several familial cases have also been reported with autosomal dominant transmission. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the central nervous system (CNS). It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Dr Albee MESSING  - Dr Adeline VANDERVER


A severe form of congenital disorders of N-linked glycosylation characterized by severe developmental and psychomotor delay, muscular hypotonia, intractable early-onset seizures, and microcephaly. Additional features include altered blood coagulation with a high probability of hemorrhages or thromboses, nephrotic syndrome, ascites, hepatomegaly, cardiomyopathy, ocular manifestations (strabismus, nystagmus), and immunodeficiency. The disease is caused by loss-of-function mutations in the gene ALG1 (16p13.3).


A form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (microcephaly, high forehead, low posterior hairline, strabismus), hypotonia, failure to thrive, intractable seizures, developmental delay, persistent vomiting and gastric bleeding. Additional features that may be observed include fat pads anomalies, inverted nipples, and body temperature oscillation. The disease is caused by mutations in the gene ALG11 (13q14.3).


A form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (prominent forehead, large ears, thin upper lip), generalized hypotonia, feeding difficulties, moderate to severe developmental delay, progressive microcephaly, frequent upper respiratory tract infections due to impaired immunity with decreased immunoglobulin levels, and decreased coagulation factors. Additional features include hypogonadism with or without hypospadias in males, skeletal anomalies, seizures and cardiac anomalies in some cases. The disease is caused by loss of function mutations of the gene ALG12 (22q13.33).


A form of congenital disorders of N-linked glycosylation characterized by microcephaly, hepatomegaly, edema of the extremities, intractable seizures, recurrent infections and increased bleeding tendency. The disease is caused by mutations in the gene ALG13 (Xq23).


A form of congenital disorders of N-linked glycosylation characterized by iris coloboma, cataract, infantile spasms, developmental delay and abnormal coagulation factors. The disease is caused by loss-of-function mutations in the gene ALG2 (9q31.1). Transmission is autosomal recessive.


A form of congenital disorders of N-linked glycosylation characterized by severe neurological involvement, including hypotonia, developmental delay, intellectual disability, postnatal microcephaly, and progressive brain and cerebellar atrophy. Epilepsy with hypsarrythmia is frequently reported. Additional features that may be observed include failure to thrive, arthrogryposis multiplex congenita (AMC), vision impairment (optic atrophy, iris coloboma) and facial dysmorphism (hypertelorism with a broad nasal bridge, large and thick ears, thin lips, micrognathia). The disease is caused by loss of function mutations of the gene ALG3 (3q27.3).


A form of congenital disorders of N-linked glycosylation characterized by feeding problems, mild-to-moderate neurologic involvement with hypotonia, poor head control, developmental delay, ataxia, strabismus, and seizures, ranging from febrile convulsions to epilepsy. Retinal degeneration has also been reported. A minority of patients show other manifestations, particularly intestinal (such as protein-losing enteropathy) and liver involvement. The disease is caused by loss of function mutations of the gene ALG6 (1p31.3).


A rare form of congenital disorders of N-linked glycosylation characterized by gastrointestinal symptoms (diarrhea, vomiting, feeding problems with failure to thrive, protein-losing enteropathy), edema and ascites (including hydrops fetalis), hepatomegaly, renal tubulopathy, coagulation anomalies due to thrombocytopenia, brain involvement (psychomotor delay, seizures, ataxia), facial dysmorphism (low-set ears and retrognathia), pes equinovarus, and muscular hypotonia. Cataracts may also be observed. Prognosis is usually poor. The disease is caused by loss-of-function mutations in the gene ALG8 (11q14.1), resulting in a block in the initial step of protein glycosylation.


A rare form of congenital disorders of N-linked glycosylation characterized by progressive microcephaly, hypotonia, developmental delay, drug-resistant infantile epilepsy, and hepatomegaly. Additional features that may be observed include failure to thrive, pericardial effusion, renal cysts, skeletal dysplasia, facial dysmorphism (frontal bossing, hypertelorism, depressed nasal bridge, low-seated ears, large mouth) and hydrops fetalis. The disease is caused by loss-of-function mutations in the gene ALG9 (11q23).


ALK-negative anaplastic large cell lymphoma

A type of ALCL, a rare and aggressive peripheral T-cell non-Hodgkin lymphoma affecting lymph nodes and extranodal sites, which is characterized by the lack of expression of a protein called anaplastic lymphoma kinase (ALK).

Summary:
Epidemiology
The prevalence of ALK- ALCL is unknown. This subtype is more commonly found in patients over the age of 40.
Clinical description
ALK- ALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless,enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALK- ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver. The 5-year survival for ALK-negative patients is of 33-49%.
Etiology
Etiology is unknown.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Pauline BRICE


ALK-positive anaplastic large cell lymphoma

A type of ALCL, a rare and aggressive peripheral T-cell non-Hodgkin lymphoma affecting lymph nodes and extranodal sites, which is characterized by the expression of a protein called anaplastic lymphoma kinase (ALK).

Summary:
Epidemiology
The prevalence of ALK+ ALCL is unknown. This subtype usually affects children and young adults.
Clinical description
ALK+ ALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless, enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALK+ ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver. The 5-year survival rate of ALK-positive patients is 70-80%.
Etiology
In ALK+ ALCL, the anaplastic lymphoma receptor tyrosine kinase ALK>/i> gene is overexpressed due to a t(2;5) (p23;q35) translocation.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Pauline BRICE


A very rare variant of diffuse large B-cell lymphoma (DLBCL) mainly affecting middle-aged immunocompetent men and characterized by a consistent primary involvement of lymph nodes (mainly in the cervical and mediastinum lymph nodes) and with infrequent extra nodal involvement of the bone marrow and other extra-nodal sites (head and neck region, liver, spleen, and gastrointestinal tract). It has an aggressive disease course, and is associated with a poor prognosis.


A rare genetic leukodystrophy characterized by infantile onset of stagnation and regression of motor and language development resulting in complete lack of communication and purposeful movement. Further neurological manifestations include truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy, and neurogenic bladder. Patients also present multiple contractures, late-onset relative macrocephaly, short stature, and facial dysmorphism (including coarse facial features, sloping forehead, thick eyebrows, low-set ears, prominent nose, flat philtrum, and prominent lower lip). Brain imaging at advanced stages shows diffuse abnormal white matter signal and severe atrophy. Sural nerve biopsy reveals decreased myelination.


A rare disorder of phenylalanine and tyrosine metabolism characterized by the accumulation of homogentisic acid (HGA) and its oxidized product, benzoquinone acetic acid (BQA), in various tissues (e.g. cartilage, connective tissue) and body fluids (urine, sweat), causing urine to darken when exposed to air as well as grey-blue coloration of the sclera and ear helix (ochronosis), and a disabling joint disease involving both the axial and peripheral joints (ochronotic arthropathy).

Summary:
Epidemiology
Birth prevalence is estimated at around 1/250,000 to 1/1,000,000 in most ethnic groups. The condition is more common in Slovakia and the Dominican republic where it affects up to 1 in 19,000 newborns.
Clinical description
Many affected individuals are asymptomatic and unaware of their condition until adulthood, however, homogentisic aciduria may be recognized early in infancy by dark-stained diapers. After the third decade, unusual pigmentation of the sclera and the skin overlying cartilage begins to be observed, as well as muscular-skeletal symptoms such as back pain and stiffness. Involvement of the large peripheral joints usually occurs several years after spinal changes, often leading to end-stage joint disease. Ochronotic peripheral arthropathy is generally degenerative in nature. From the fourth decade, joint mobility diminishes. Ankylosis may be present. Fractures of the vertebrae and long bones are also possible. Other features may include genitourinary (e.g. renal, bladder, prostatic stones) and cardiac (mitral valvulitis, arrhythmias) complications as well as respiratory insufficiency due to musculoskeletal involvement.
Etiology
Patients are homozygous or compound heterozygous for loss-of-function mutations (more than 200 different variants described worldwide) in the HGD gene, encoding homogentisate 1,2-dioxygenase, an enzyme of the phenylalanine and tyrosine catabolic pathway. The inability to break down HGA leads to its accumulation. Tissue damage results from the deposition of a melanin-like pigment, which is a polymerized form of BQA, that has a high affinity for connective tissue. This pigment is able to trigger numerous redox reactions and induce free radical production, causing further damage to the connective tissue.
Diagnostic methods
Diagnosis is suspected upon clinical examination and is based on the amount of HGA found in the urine using gas chromatography-mass spectroscopy. As many patients present without dark urine, it may be advisable to look for HGA in all patients with radiographic evidence of osteoarthritis. A spinal x-ray will reveal disk degeneration combined with dense calcification, particularly in the lumbar area. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes acute intermittent porphyria, rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.
Genetic counseling
Transmission is autosomal recessive, there is a 25% risk of disease transmission to offspring where both parents are unaffected carriers.
Management and treatment
Treatment is palliative. Dietary restriction (low protein diet) is beneficial, but compliance is often limited. Medical therapy (paracetamol, non-steroidal anti-inflammatory drugs) associated with physiotherapy help to minimize pain and improve the range of joint motion. Older individuals may require removal and fusion of lumbar discs. Hip or knee joint replacement may be necessary. Therapeutic strategies aimed at perturbing the altered phenylalanine-tyrosine pathway have been devised (e.g. nitisinone). Off-label usage of nitisinone has been shown to slow the rate of disease progression; however, the long-term effectiveness and safety in adult patients with alkaptonuria, as well as the most suitable age for intervention, remains to be evaluated (currently an open-label clinical trial and observation study are under way).
Prognosis
Life expectancy is not significantly reduced but pain can be constant and progressive functional decline is observed with a loss of mobility; patients often require the use of physical aids (crutches, wheelchair). Cardiac complications are often life-threatening and may worsen the prognosis.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Berardino PORFIRIO


An X-linked intellectual disability syndrome with neuromuscular involvement characterized by infantile hypotonia, muscular hypoplasia, spastic paraparesis with dystonic/athetoic movements, and severe cognitive deficiency.

Summary:
Epidemiology
At least 132 families with 320 affected individuals have been reported in the literature to date. Although the prevalence is unknown, one study identified AHDS in 1.4% of males with intellectual disability of unknown etiology. Only males are affected.
Clinical description
The disease manifests as congenital hypotonia (appearing at birth or in the first weeks/months of life) that progresses to spasticity (contractures, Babinski sign, and clonus), and is usually detectable early in life. Hyperreflexia appears later in life. Affected males also present, in infancy and early childhood, with muscle hypoplasia and generalized muscle weakness that manifests as difficulty in supporting the head and delayed motor milestones. Hypotonia and severe intellectual deficit are present in 100% of patients. Severe psychomotor delay is present from the outset (delay of motor and language milestones) and autonomy is never reached. The face has distinctive features that evolve over time: open mouth, tented upper lip, ptosis, abnormal folding of the ears, thickening of the soft tissue of the nose and ears, and upturned earlobes. Long, thin everted feet are also typical. Ocular manifestations (i.e. rotary nystagmus and disconjugate eye movements) are rare. Seizures and poor weight gain are reported in some patients. Pectus excavatum and scoliosis are sometimes present, perhaps as a result of the hypotonia and muscle hypoplasia.
Etiology
AHDS is caused by mutations in the SLC16A2 gene (Xq13.2), which encodes for monocarboxylate transporter 8 (MCT8), a specific transporter for thyroid hormone T3. Identified mutations include truncations, in-frame deletions, nonsense and missense mutations. Neurological problems may be due to an inability to transport thyroid hormone T3 into some neuronal cells.
Diagnostic methods
Diagnosis is based on clinical findings and on the presence of altered thyroid- hormone serum levels: males have abnormally high 3,3',5'-triiodothyronine (T3), low to normal free tetraiodothyronine (T4) levels, and normal to slightly elevated thyroid stimulating hormone (TSH) levels. Molecular genetic testing revealing mutations in the SLC16A2 gene confirms the diagnosis.
Differential diagnosis
Differential diagnoses include X-linked intellectual disability conditions associated with ataxia, spastic paraplegia or muscle hypoplasia such as X-linked intellectual disability-spastic paraplegia with iron deposits syndrome, X-linked progressive cerebellar ataxia, and spastic paraplegia type 2. Pelizaeus-Merzbacher disease and Snyder-Robinson syndrome should also be considered.
Antenatal diagnosis
Antenatal diagnosis of a male with AHDS is possible if the mother is a carrier of a specific SLC16A2 mutation.
Genetic counseling
Transmission is X-linked recessive. Affected families should be offered genetic counseling and informed that boys have a 50% risk of being affected if the mother is a carrier of a SLC16A2 mutation and that girls have a 50% risk of inheriting the SLC16A2 mutation if their mother is a SLC16A2 mutation carrier.
Management and treatment
At present, no treatment is available for AHDS and management consists of supportive measures. Physical, occupational, and speech therapy may be beneficial. Dystonia may be treated with certain medications, including anticholinergics, L-DOPA, carbamazepine, or lioresol. Seizures, when present, can be controlled with standard antiepileptic drugs. Treatment for hypothyroidism does not appear to be beneficial.
Prognosis
Although several patients have survived into their 60s, overall life expectancy is compromised and quality of life is severely affected as most patients are unable to sit, stand or walk independently.

                            Last update:
                            March 2017

                            - Expert reviewer(s):
                            Dr Charles SCHWARTZ


A rare immunologic pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, clinically manifesting with poorly controlled asthma and recurrent pulmonary infiltrates.

Summary:
Epidemiology
The prevalence of ABPA in the general population is unknown.
Clinical description
ABPA is most commonly diagnosed in adults although it is increasingly being diagnosed in children. Although affected individuals can occasionally be asymptomatic, most of them present with wheezing, bronchial hyperreactivity, hemoptysis, productive cough, low-grade fever, malaise, weight loss, and/or worsening symptoms of asthma and cystic fibrosis (see this term), the two underlying diseases of most of the ABPA patients (about 2% of patients with asthma and 1 to 15% of patients with cystic fibrosis develop ABPA).
Etiology
ABPA is an immunologic disorder due to a predominant T-helper 2 lymphocyte response to Aspergillus fumigatus infection without tissue invasion. The resulting lung inflammation induces mucus production, airway hyperactivity and, finally, bronchiectasis. Its increased frequency in patients with asthma or cystic fibrosis is consistent with a genetic susceptibility to ABPA.
Diagnostic methods
Diagnostic findings of ABPA include immediate cutaneous hyperreactivity to A. fumigatus antigen, elevated A. fumigatus specific IgE levels and total serum IgE levels over 1,000 IU/mL. High levels of A. fumigatus-specific IgG antibodies and eosinophils can also be observed. Chest radiographs and thoracic high-resolution computed tomography (HRCT) can reveal fleeting pulmonary parenchymal opacities, central bronchiectasis, high attenuation mucus, air trapping and centrilobular nodules. Pulmonary function tests may detect airflow obstruction. According to laboratory and imaging findings, five stages of the disease have been defined: acute, remission, recurrent exacerbation (with presence of pulmonary infiltrates, elevation of total serum IgE), corticosteroid-dependent asthma (severe wheezing resulting from discontinuation of the treatment) and fibrotic (irreversible pulmonary function abnormalities). However, the disease usually does not progress through these successive stages.
Differential diagnosis
Differential diagnosis includes severe asthma with fungal sensitization, newly diagnosed cystic fibrosis, tuberculosis, infectious pneumonia (especially during exacerbations) and other causes of eosinophilic pneumonia like Churg-Strauss syndrome (see this term), and bronchocentric granulomatosis.
Management and treatment
The best treatment approach is not currently established. Therapeutic options include oral corticosteroids (e.g: prednisolone, prednisone) and antifungal agents (like itraconazole, voriconazole or posaconazole). Other treatments that have been tried include pulse doses of methylprednisolone, and nebulized amphotericin B and omalizumab (antifungal agents). The duration of corticosteroid therapy ranges from several weeks to several months after an acute episode but corticosteroid-dependent asthma patients are very difficult to wean off steroids. The duration of the antifungal therapy has yet to be established. However, if tolerated, it can be used for years.
Prognosis
The clinical course of ABPA is variable. Many ABPA patients can be stabilized for long periods when treated. However, long-lasting remissions are seen in only 50% of patients and many patients require recurrent courses of therapy. Central bronchiectasis, high-attenuation mucus and concomitant aspergilloma at diagnosis identify a patient with a propensity for recurrent relapses and chronicity, which requires close monitoring.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Ritesh AGARWAL


A severe form of holoprosencephaly characterized by a single brain ventricle and no interhemispheric fissure. Severe craniofacial features may manifest as cyclopia, ethmocephaly or cebocephaly.


A rare primary immunodeficiency disorder characterized by the association of alopecia areata totalis and antibody deficiency (congenital agammaglobulinemia or incomplete antibody deficiency syndrome), manifesting with recurrent infections. There have been no further descriptions in the literature since 1976.


A form of alopecia areata, an inflammatory disease of the hair follicle, characterized by a complete loss of hair of the entire scalp which becomes glabrous.


A disorder of most severe form of alopecia areata, an inflammatory disease of the hair follicle, which is characterized by a complete loss of hair of the scalp and all the hair-bearing areas of the body.


A form of ectodermal dysplasia syndrome characterized by a short stature of prenatal onset, alopecia, ichthyosis, photophobia, ectrodactyly, seizures, scoliosis, multiple contractures, fusions of various bones (particularly elbows, carpals, metacarpals, and spine), intellectual disability, and facial dysmorphism (microdolichocephaly, madarosis, large ears and long nose). ACD syndrome overlaps with ichthyosis follicularis-alopecia-photophobia syndrome.


A rare genetic syndromic intellectual disability that is characterized by congenital permanent alopecia universalis, intellectual disability, psychomotor epilepsy and periodontitis (pyorrhea). Total permanent alopecia and pyorrhea are invariably concomitant while intellectual disability and psychomotor epilepsy are observed in most patients. No other abnormality of nails or skin (apart from absence of hair) has been reported. Transmission is autosomal dominant.


An extremely rare genetic syndromic intellectual disability described in less than 20 families to date and characterized by total or partial alopecia associated with intellectual deficit. The syndrome can be associated with other anomalies such as seizures, sensorineural hearing loss, delayed psychomotor development, and/or hypertonia.


Alopecia-intellectual disability-hypergonadotropic hypogonadism syndrome

A rare multiple congential anomalies syndrome characterized by association of congenital total alopecia, mild intellectual deficit and hypergonadotropic hypogonadism.


A cerebrohepatopathy and a rare and severe form of mitochondrial DNA (mtDNA) depletion syndrome characterized by the triad of progressive developmental regression, intractable seizures, and hepatic failure.

Summary:
Epidemiology
The incidence of AHS is estimated to be between 1/100,000 and 1/250,000.
Clinical description
Development is usually normal until disease onset and presentations are highly variable. The most common age of onset is between 2-4 years (ranges from 3 months to 36 years). Seizures (mainly partial, secondary generalized tonic-clonic, or myoclonic) are often the presenting feature, evolving into focal status epilepticus, epilepsia partialis continua, and/or multifocal myoclonic epilepsy. Seizures may respond to treatment initially but usually become intractable. Headaches, visual disturbances and movement disorders (e.g. myoclonus and choreoathetosis) are also common. Cerebellar ataxia develops in most patients. Peripheral neuropathy develops in many and becomes increasingly common in older children and young adults. Loss of cognitive function progresses with varying rates (rapid regression seen during infectious diseases) with manifestations including somnolence, irritability, loss of concentration, loss of language skills and memory deficits, ending in dementia and visual loss. Gastrointestinal involvement (i.e. swallowing dysfunction, intestinal dysmotility) is also noted. Liver disease may be indolent for years before the first acute exacerbation, but may be the first presenting symptom in some children. The clinical course of both brain and liver abnormalities is often episodic with acute exacerbations followed by periods of partial recovery.
Etiology
AHS is due to mutations in the polymerase gamma (POLG) gene (15q24). This gene encodes DNA polymerase subunit gamma-1, which is involved in the replication and repair of mtDNA. Ecogenetic and epigenetic stressors, including incidental infections and drugs like valproic acid, can accelerate the onset of symptoms and modify how the phenotype unfolds.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Electroencephalogram findings include explosive seizures with asymmetric occipital lobe predominance of epileptiform discharges, evolving into epilepsia partialis continua or status epilepticus. Neuroimaging may show neuronal loss/gliosis and generalized brain atrophy. Mitochondrial respiratory chain deficiencies and low levels of mtDNA are noted in the liver and muscle as the disease progresses. Molecular genetic testing revealing a POLG mutation confirms diagnosis.
Differential diagnosis
Differential diagnoses are numerous with some examples being disease phenocopies caused by mutations in the C10ORF2 gene (10q24), which can cause autosomal dominant progressive external ophthalmoplegia (adPEO) as well as recessive mutations that can lead to other phenotypes that may overlap with AHS. Others disorders include infantile neuronal ceroid-lipofuscinosis, late-infantile neuronal ceroid lipofuscinosis, MERRF and MELAS. Other POLG-related disorders include recessive mitochondrial ataxia syndrome (MIRAS), ataxia neuropathy spectrum (ANS), and autosomal recessive PEO.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
AHS is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
There is no cure for AHS and treatment is symptomatic and palliative. Anticonvulsive therapy is prescribed for the management of epileptic seizures but is not always successful. As valproic acid may trigger or worsen liver disease, it is contraindicated. Occupational, physical, and/or speech therapy may be offered to maintain neurologic function as long as possible. Tracheostomy placement, artificial ventilation and placement of a gastric feeding tube may all be necessary as the disease progresses.
Prognosis
The prognosis is severe with life-expectancy in patients ranging from 3 months to 12 years, after disease onset.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Pr Robert NAVIAUX  - Dr Russell SANETO


A rare hemorrhagic disorder due to a constitutional platelet anomaly characterized by moderate to severe deficiency in both platelet alpha-granules and dense bodies, resulting in impaired platelet function and decreased aggregation responses. Patients present increased bleeding tendency with symptoms like easy bruising, or menorrhagia.


A rare hereditary, metabolic disease characterized by serum levels of alpha-1-antitrypsin (AAT) that are well below the normal range. In the most severe form, the disease can clinically manifest with chronic liver disorders (cirrhosis, fibrosis), respiratory disorders (emphysema, bronchiectasis), and rarely panniculitis or vasculitis.

Summary:
Epidemiology
Prevalence of the genetic condition at birth is estimated between 1/1,600-5,000 in Western Europe and in the USA.
Clinical description
The severe form, caused by homozygous Z variant in the gene SERPINA1, is the most clinically relevant and referred to here as Z-AATD. Z-AATD has an extraordinary heterogeneous disease course. Some individuals remain healthy, while others develop a severe lung or liver disease, rarely both. The age of onset is variable in Z-AATD, liver disease presents typically in newborn/early childhood age or later on in adult life (typically at ≥ 40 years of age). Z-AATD can lead to neonatal cholestasis in about 10 % of the affected infants and about 30-50% of these will develop chronic progressive liver disease. About 10% of adults develop liver cirrhosis. Onset of lung disease is generally between 20 and 50 years of age. The main pulmonary manifestations include early onset panacinar emphysema, bronchiectasis, bronchial asthma or vasculitis presenting with persistent, dyspnea, cough, wheezing, and production of sputum. Smoking is a major factor affecting the course of the pulmonary manifestations, and is associated with earlier onset. Other features include weight loss, recurrent respiratory infections, and fatigue. Panniculitis of variable severity and developing at any age is a rare disease manifestation. A strongly increased risk of developing liver cirrhosis and hepatocellular carcinoma has been reported. The course may be severe in the absence of appropriate treatment and continued tobacco smoking.
Etiology
The disease is due to variants in SERPINA1 (14q32.13). Major gene sequencing efforts carried out in disease populations disclosed more than 100 rare SERPINA1 variants which may cause the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even form a modified enzyme inhibitory activity (dysfunctional alleles). The low levels of the serine protease inhibitor alpha-1-antitrypsin, involved in regulation of neutrophil elastase and proteinase 3, leads to alveolar damage. The pathophysiology of lung alveolar damage is based on the protease-antiprotease balance hypothesis.
Diagnostic methods
Manifestations are non-specific and therefore may lead to delayed diagnosis. Liver and lung diseases are investigated with imaging and biopsies. The diagnosis is based on detection of low serum concentrations of AAT and molecular genetic testing.
Differential diagnosis
The main differential diagnoses include asthma in younger patients and chronic obstructive pulmonary disease (COPD) in older individuals. Chronic viral hepatitis, hemochromatosis, Wilson disease, non-alcoholic/alcoholic fatty liver and primary biliary cirrhosis should be considered as alternative causes of liver disease.
Antenatal diagnosis
When mutations have been identified in an affected family, prenatal diagnosis is possible.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
There is currently no curative treatment. Treatment is similar to that used for COPD and emphysema and aims at reducing symptoms and slowing progression. Long-acting bronchodilators, antibiotics, corticosteroid inhalations, and long-acting beta-agonists are the mainstay of treatment. Another treatment option in severe cases involves augmentation therapy with administration of purified human AAT to reach normal physiological levels. Smoking and exposure to tobacco smoke should be avoided. Vaccines for common respiratory disorders may be beneficial. Lung transplantation may be required for end-stage lung disease. Likewise, liver transplantation can be considered for advanced liver disease. Panniculitis usually responds to treatment with intravenous augmentation of AAT. Several treatments for lung and liver disease are currently in clinical trials.
Prognosis
The prognosis is generally very good in non-smokers. Smoking is known to exacerbate the disease and leads to poorer outcomes. Obesity, diabetes, alcohol misuse, metabolic syndrome and male sex are risk factors for liver disease.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr J. [Jan] STOLK | ERN-LUNG* - Pr Pavel STRNAD | RARE-LIVER*

                                * European Reference Network


Alpha-B crystallin-related late-onset myopathy

A rare, genetic, alpha-crystallinopathy disease characterized by adult-onset myofibrillar myopathy, variably associated with cardiomyopathy and/or posterior polar cataracts. Patients typically present progressive proximal and distal muscle weakness and wasting of lower and upper limbs, often with velopharyngeal involvement including dysphagia, dysphonia and ventilatory insufficiency. Electromyography shows myopathic features and muscle biopsy reveals myofibrillar myopathy changes.


Alpha-dystroglycan-related limb-girdle muscular dystrophy R16

A form of limb-girdle muscular dystrophy characterized by slowly-progressive, mainly proximal, muscle weakness presenting in early childhood (with difficulties walking and climbing stairs) and mild to severe intellectual disability. Additional manifestations reported include microcephaly, mild increase in thigh or calf muscles, and contractures of the ankles.


A type of HCD characterized by the production of incomplete monoclonal alpha-heavy chains without associated light chains. Alpha-HCD is considered to be a subtype of immunoproliferative small intestinal disease (IPSID). The clinical presentation includes chronic diarrhea with evidence of malabsorption.

Summary:
Epidemiology
The prevalence of the disease is unknown but most cases have been from North African and Middle Eastern/Mediterranean countries and have been associated with poor sanitation. There have been more than 400 cases reported in the world literature.
Clinical description
Alpha-HCD has a predilection for young age groups (20-30 years). Patients present with symptoms of malabsorption. Diarrhea, weight loss and abdominal pain are common. Parasitic infections are often present. Infiltration of the jejunal mucosa with plasmacytoid cells is the most frequent pathologic feature. Immunoblastic lymphoma occurs as the disease progresses.
Etiology
The exact cause of alpha-HCD is unknown. The lymphoplasmacytic infiltration of the intestinal mucosa is felt to be a response of the alimentary tract immune system to prolonged luminal antigenic stimulation by intestinal organisms.
Diagnostic methods
The diagnosis of alpha-HCD is based on identification of free alpha-heavy chains without associated light chains. Truncated alpha-heavy chains can be detected in biological fluids (serum, urine, jejunal secretions) by immunoelectrophoresis, immunoselection, or immunofixation.
Differential diagnosis
Alpha-HCD disease must be differentiated from non-Hodgkin lymphoma (NHL; see this term), although this is an uncommon diagnosis in the age range typical of alpha-HCD. Other causes of small bowel malabsorption need to be considered, especially celiac disease (see this term).
Management and treatment
Initial treatment consists of eradication of any concurrent infection (e.g., parasites, viruses, Helicobacter pylori, Campylobacter jejuni) with appropriate antibiotics. For patients with symptomatic disease not responding adequately to antibiotics, chemotherapy similar to that used to treat NHL is recommended. Surgical resection is sometimes needed when bulky masses are present.
Prognosis
The disease course of alpha-HCD is variable and long-term prognosis of the disease is imprecise. Without antibiotics and chemotherapy the disease progresses rapidly and prognosis is poor.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER


An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit.

Summary:
Epidemiology
It occurs in approximately 1 in 500,000 live births.
Clinical description
Affected infants often appear normal at birth but their condition worsens progressively. However, some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial dysmorphism is marked by a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity.
Etiology
The disorder is caused by lysosomal alpha-mannosidase deficiency. It is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12).
Diagnostic methods
Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic.
Differential diagnosis
The principle differential diagnoses are other lysosomal storage diseases, such as the various forms of mucopolysaccharidosis (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible, based on both biochemical and genetic methods.
Genetic counseling
Alpha-mannosidosis is inherited in an autosomal recessive fashion. Genetic counseling should be provided to explain the nature of the disease and to detect carriers.
Management and treatment
Management should be proactive, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often needed and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary.
Prognosis
The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. However, many patients survive to over 50 years of age.

                            Last update:
                            July 2016

                            - Expert reviewer(s):
                            Pr Dag MALM  - Pr Oivind NILSSEN


Alpha-N-acetylgalactosaminidase deficiency type 1

A very rare and severe type of NAGA deficiency characterized by infantile neuroaxonal dystrophy.

Summary:
Epidemiology
Prevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency
Clinical description
The disease presents with psychomotor retardation at around 9 months of age and later, at the age of 2, with developmental retrogression. Further manifestations follow between the ages of 4-10 years, including muscular hypotonia, spasticity, nystagmus, strabismus, myoclonic jerks, grand-mal seizures, cortical blindness and deafness, optic and brain atrophy, loss of environmental contact and decorticate posturing. No visceromegaly or coarsening of features has been reported.
Etiology
NAGA deficiency type 1 is caused by a homozygous NAGA gene (22q13.2) mutation resulting in a Glu325-to-Lys (E325K) substitution and the dysfunction, instability and rapid degradation of the lysosomal protein NAGA.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.

                            Last update:
                            June 2013


Alpha-N-acetylgalactosaminidase deficiency type 2

A very rare mild adult type of NAGA deficiency with the features of angiokeratoma corporis diffusum and mild sensory neuropathy.

Summary:
Epidemiology
Prevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency.
Clinical description
This disorder is clinically heterogeneous. Some patients have been reported to have, in addition to angiokeratoma, mild intellectual impairment, but no neurologic signs. Another patient had lymphedema, cardiomegaly, corneal opacity and slight facial coarsening including thick lips, a depressed nasal bridge and an enlarged tip of the nose. Other facultative features consist of tinnitus, hearing loss and vertigo (Meniere disease) (see this term). Pathological characteristics are comprised of vacuolization seen in the blood and dermal cells including the endothelial cells of blood and lymphatic vessels, pericytes, fibrocytes, fat cells, Schwann cells, axons, arrector pili smooth muscle cells, and eccrine sweat gland cells. Vacuolization is most prominent in vascular endothelial cells and the secretory portion of sweat glands.
Etiology
Different causal homozygous mutations of the NAGA gene (22q13.2) have been described in the reported patients. These mutations lead to the dysfunction, instability and rapid degradation of the lysosomal protein, NAGA. Lack of this enzyme activity leads to impaired catabolism and accumulation of undegraded glycoconjugates in the tertiary lysosomes.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.

                            Last update:
                            June 2013


Alpha-N-acetylgalactosaminidase deficiency type 3

A rare clinically heterogeneous type of NAGA deficiency with developmental, neurologic and psychiatric manifestations presenting at an intermediate age.

Summary:
Epidemiology
Prevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency
Clinical description
A very wide spectrum of signs, with a juvenile onset, has been described including asymptomatic patients at the time of diagnosis. Manifestations seen in clinically overt cases may include epilepsy of variable severity, psychomotor retardation, intellectual impairment, autism, strabismus and cataract.
Etiology
Compound heterozygous or homozygous mutations of the alpha-N-acetylgalactosaminidase gene (NAGA; 22q13.2) have been reported in affected patients but also occasionally in their healthy siblings. These mutations lead to the dysfunction, instability and rapid degradation of the lysosomal protein NAGA.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.

                            Last update:
                            June 2013


A very rare lysosomal storage disease that is clinically and pathologically heterogeneous and is characterized by deficient NAGA activity.

Summary:
Epidemiology
Exact prevalence of NAGA deficiency is unknown but fewer than 20 cases have been reported to date in patients of German, Dutch, Spanish, Japanese, French and Moroccan origin.
Clinical description
Extreme clinical variability has been reported. Cases of NAGA deficiency have been divided into 3 clinical subtypes: NAGA deficiency type 1, type 2 and type 3 (see these terms). Type 1 is characterized by infantile-onset neuroaxonal dystrophy, type 2 is described in adult patients with angiokeratoma corporis diffusum and minimal involvement of the nervous system and type 3 is an intermediate clinical form with manifestations ranging from intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays or mild autism-like symptoms.
Etiology
All individuals with NAGA deficiency have mutations in the alpha-N-acetylgalactosaminidase gene (NAGA; 22q13.2) but not all develop neurological symptoms. A number of different NAGA mutations have been identified. There is however no direct genotype-phenotype correlation in view of the clinical heterogeneity of the reported cases. It has been suggested that other factors or genes contribute to the occurrence of neurological symptoms but there is no conclusive evidence to confirm this theory.
Diagnostic methods
The currently known cases were identified through reduced activity of the NAGA enzyme assessed by enzyme tests (assays) on white blood cells (leukocytes), blood plasma or cultured lymphoblasts or fibroblasts, or through urinalysis by thin layer chromatography for oligosaccharide and glycopeptide profiles that revealed increased levels of these complex compounds. Confirmation may be sought by mutation analysis of the NAGA gene.
Differential diagnosis
Differential diagnosis depends on the type of NAGA deficiency and may include infantile neuroaxonal dystrophy, associated with mutations in the PLA2G6 gene, pantothenate kinase-associated neurodegeneration, associated with mutations in the PANK2 gene and other lysosomal diseases, including Fabry disease, due to different lysosomal enzyme defects or unknown factors (see these terms).
Antenatal diagnosis
Prenatal diagnosis is theoretically possible by mutation analysis of the NAGA gene after amniocentesis or chorionic villus sampling but as the clinically different forms of the disease have been mapped to the same gene they cannot be determined prenatally.
Genetic counseling
NAGA deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should therefore be offered to affected families.
Management and treatment
Treatment of this disorder is symptomatic and supportive. It includes the maintenance of satisfactory nutrition and hydration, management of infectious diseases (possibly by antibiotic shielding), control of seizures by anti-epileptic drugs, reduction of spasticity or pain with medication, adequate positioning, physiotherapy to prevent joint contractures or pneumonia, and aspiration prophylaxis potentially including tube feeding. Recent studies identify NAGA deficiency as a typical protein folding disorder. As such, investigational studies are examining whether it is amenable to pharmacological chaperone approaches or enzyme replacement therapy. Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders.
Prognosis
Prognosis is variable depending on the type of NAGA deficiency, with type 1 having the worst and the other types having fairer outcomes. Evidence-based mortality rates or life expectancy figures are not available due to the very small number of patients.

                            Last update:
                            June 2013


Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3

A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by childhood onset of progressive proximal weakness of the shoulder and pelvic girdle muscles, resulting in difficulty walking, scapular winging, calf hypertrophy and contractures of the Achilles tendon, which lead to a tiptoe gait pattern. Cardiac and respiratory involvement is rare.


A rare developmental defect during embryogenesis, a contiguous gene deletion syndrome, is a form of alpha-thalassemia characterized by microcytosis, hypochromia, normal hemoglobin (Hb) level or mild anemia, associated with developmental abnormalities.

Summary:
Epidemiology
Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16 (ATR-16) prevalence is unknown. More than 20 cases have been reported to date.
Clinical description
ATR-16 is a congenital disease. Patients present with either alpha-thalassemia trait or mild hemoglobin H disease (HbH disease) associated with a mild to profound (in most cases) intellectual disability and, in some cases, with mild, nonspecific dysmorphic features (mild hypertelorism, down slanted palpebral fissures, broad or prominent nasal bridge, small ears, short neck), microcephaly and short stature. Genital abnormalities (hypospadias and cryptorchidism) have been reported in males. Club foot is common.
Etiology
ATR-16 is due to large deletions on chromosome band 16p13.3 which remove the alpha-globin genes (HBA1 and HBA2), and many other flanking genes. The gene(s) responsible for intellectual deficiency and other developmental abnormalities has not been clearly identified. All cases are due to de novo deletions or segregation for parental translocations inherited in an unbalanced manner.
Diagnostic methods
Diagnosis is based on the clinical picture and confirmed by cytogenetic testing. Routine cytogenetic studies may be sufficient to identify the deletion. However, in some instances other methods such as comparative genomic hybridization (CGH) arrays are used to detect cryptic subtelomeric deletions.
Differential diagnosis
Differential diagnosis includes Alpha thalassemia - X-linked intellectual deficit syndrome, and the co-occurrence of common alpha-thalassemia trait and an intellectual deficiency of another cause.
Antenatal diagnosis
Antenatal diagnosis is indicated in cases of parental translocations but it can also be offered to parents of a patient with de novo deletions to prevent recurrence due to germline mosaicism.
Genetic counseling
Genetic counseling is possible when parents are known carriers of the chromosomal translocation.
Management and treatment
There is no treatment for ATR-16. Management is symptom-based and requires a multidisciplinary approach. Management of intellectual deficiency usually includes speech therapy and individualized educational plans. In case of anemia, specific treatment may include occasional red blood cell transfusions, iron chelation and other supportive measures.
Prognosis
The prognosis is highly variable, depending on the degree of intellectual deficiency.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Catherine BADENS


An acquired form of alpha-thalassemia characterized by a myelodysplastic syndrome (MDS) or more rarely a myeloproliferative disease (MPD) associated with hemoglobin H disease (HbH).

Summary:
Epidemiology
About 80 cases have been identified to date and most involved patients are of northern European descent. Some cases have been reported in patients from Asia and the Mediterranean area.
Clinical description
ATMDS occurs predominantly in males during the 7th decade of life (male-to-female ratio greater than 6:1). The main clinical features include anemia and other signs associated with MDS such as shortness of breath, weakness, tendency to bruise or bleed and an increased susceptibility to infections. It has occasionally been associated with MPD and in these cases, splenomegaly frequently co-occurs. MDS progresses to leukemia in about 25% of cases and HbH is usually no longer detectable at this time.
Etiology
ATMDS is due to acquired somatic mutations in the ATRX gene (Xq21.1). There is also evidence that acquired deletions of chromosome 16p may be causative. These defects result in significant down-regulation of alpha-globin gene expression.
Diagnostic methods
Typical hematological findings show hypochromic microcytic red blood cells and striking anisopoikilocytosis, and the presence of HbH inclusions in a proportion of red blood cells that varies depending on the patients. Cytological and cytogenetic analysis of bone marrow cells is required to confirm the diagnosis and to classify the underlying MDS. Direct sequencing of the ATRX gene in DNA samples from blood or bone marrow usually indicates a mosaicism, identified by a single nucleotide mutation.
Differential diagnosis
Differential diagnoses include other causes of anemia, cytopenia or microcytosis. It is especially important to exclude an inherited form of alpha-thalassemia by molecular analysis of the HBA locus.
Management and treatment
Treatment depends on the underlying MDS. Stem cell transplantation is the only curative treatment but it is rarely feasible. Other treatment options may include hypomethylant (azacitabine) therapy and lenalinomide. Supportive care includes blood transfusions, erythropoietin stimulating agents, growth factors, antibiotics (if infections are present), and iron chelation therapy in those undergoing long term transfusion therapy.
Prognosis
Prognosis depends on the sub-type of MDS according to the International scoring system (ISS). The scoring system takes into account the percentage of marrow blasts, the severity of cytopenia, and cytogenetic analysis of bone marrow cells. Death is usually due to leukemic transformation, infections due to neutropenia, bleeding related to thrombocytopenia and, in some cases, to other co-morbidities such as cardiovascular disease.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Pr Catherine BADENS  - Pr Christian ROSE


A rare inherited hemoglobinopathy characterized by impaired synthesis of two to all four alpha-globin chains leading to a variable clinical picture depending on the number of affected alleles.

Summary:
Epidemiology
Like other globin gene disorders, alpha-thalassemia is highly prevalent in all tropical and subtropical regions (around 1/10,000), particularly in the African equatorial belt. Intermediate and severe forms of alpha-thalassemia are very rare in North America and Northern Europe (about 1/1,000,000), but predominantly seen in immigrant populations from South-East Asia or Mediterranean countries.
Clinical description
Disease expression varies according to the level of alpha-globin chain deficiency. Alpha thalassemia trait (or alpha thalassemia minor) causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. Hemoglobin H disease (HbH) is characterized by moderate hemolytic anemia with variable amounts of hemoglobin H along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin chains with serious developmental implications.
Etiology
Alpha globin synthesis is regulated by four alpha-globin genes, two on each copy of chromosome 16 (16p13.3). Alpha-thalassemia most frequently results from deletion of two or more alleles (HBA1 and HBA2). More rarely, point mutations in critical regions of these genes may cause non-deletional alpha-thalassemia. Deletions of regulatory elements located upstream of the alpha-globin genes have also been found. The severity of the clinical picture is correlated with the degree of alpha-globin chain deficiency. It has been found that interactions involving non-deletional forms lead to more severe manifestations than those involving deletional forms. Deletion of 1 allele results in the silent form, 2 alleles in alpha-thalassemia trait, 3 alleles in HbH and 4 alleles in Hb Bart's hydrops fetalis.
Diagnostic methods
Diagnosis is based on hematologic testing of red blood cell (RBC) indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. Confirmation of diagnosis is based on molecular genetic testing.
Differential diagnosis
Differential diagnosis should include iron deficiency anemia and defects in heme synthesis. An acquired form known as alpha-thalassemia-myelodysplastic syndrome (ATMDS) has been described mainly in adult males and should also be considered; it is characterized by myelodysplasia (MD) associated with HbH. A syndromic form, alpha-thalassemia-intellectual deficit syndrome, is characterized by very mild to severe anemia associated with developmental abnormalities.
Antenatal diagnosis
Prenatal diagnosis is possible when Hb Bart's hydrops fetalis or a severe form of Hb H disease has previously been identified in a family member.
Genetic counseling
Carriers of a single allelic variant are asymptomatic (silent alpha-thalassemia) but pose a risk of transmission to their offspring. The pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Patients with silent alpha-thalassemia or thalassemia trait do not require treatment. Specific treatment is however required for other forms of the disease and may include occasional or regular red blood cell transfusions, iron chelation, and other supportive measures.
Prognosis
The prognosis for carriers of silent alpha-thalassemia or alpha-thalassemia trait is very good. Neonates with Hb Bart's hydrops fetalis usually die in the perinatal period. In patients with hemoglobin H disease, the prognosis is usually good, but depends on complications and care.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Corinne PONDARRE


A rare genetic gastroenterological disease characterized by severe, refractory intestinal inflammation with mucosal erosions and ulcerations potentially involving the small and large intestine. Epithelioid granulomas are typically absent. Patients present with severe diarrhea, abdominal pain, vomiting, rectal bleeding, and weight loss.


Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome

A rare constitutional hemolytic anemia that is characterised by the association of Alport syndrome, midface hypoplasia, intellectual deficit and elliptocytosis. It has been described in two families. The syndrome is transmitted as an X-linked trait is caused by a contiguous gene deletion in Xq22.3 involving several genes including COL4A5, FACL4 and AMMECR1.


A rare renal disease characterized by glomerular nephropathy with hematuria progressing to end-stage renal disease (ESRD), frequently associated with sensorineural deafness, and occasionally with ocular anomalies.

Summary:
Epidemiology
The global prevalence of Alport syndrome (AS) is unknown. The prevalence at birth in Finland is estimated at 1/53,000. In the USA, Alport syndrome reportedly accounts for up to 2% of new cases of pediatric ESRD.
Clinical description
The clinical subtypes of AS include X-linked (XL), autosomal recessive (AR) and autosomal dominant (AD) AS and count for about 80%, 15% and 5% of all AS cases, respectively. AS can present anywhere from childhood to elderly age, although it generally manifests earlier (during childhood or adolescence) in XL and AR forms. Males are severely affected in XLAS and present with microhematuria very early in life, followed by micro-albuminuria, macroproteinuria and progression to ESRD before the age of 40 years old. XLAS is highly variable in females, ranging from an asymptomatic disease to lifelong microscopic hematuria (with preserved renal function), or renal failure at a young age. Sensorineural hearing loss is common. Occasional ocular anomalies (e.g. anterior lenticonus, retinal flecks, corneal lesions) may develop in late childhood or early adulthood, males being more commonly affected than females. Rarely, leiomyomatosis (esophagus, tracheobronchial tree or female genitalia) can be associated, forming the X-linked diffuse leiomyomatosis-AS (XL-DLAS). ARAS is similar to XLAS in males, but presents without any gender differentiation in the disease course and the family history. ADAS varies from an asymptomatic disease (mostly presenting as a familial benign hematuria) to AD forms of proteinuria and focal segmental glomerulosclerosis (in cases without hematuria or not as a first line presentation). The progression to ESRD is usually slower than in XLAS, and extra-renal manifestations are less common.
Etiology
AS involves a structural defect of type IV collagen, an essential component of the glomerular basal membrane. XLAS is due to mutations in COL4A5 (Xq22.3) gene coding for the alpha 5 chain of type IV collagen. ARAS and ADAS are due to mutations in both COL4A3 (2q36.3) and COL4A4 (2q36.3) genes coding for the alpha 3 and 4 chains of type IV collagen, respectively. XL-DLAS is due to COL4A5 (Xq22.3) and COL4A6 (Xq22.3).
Diagnostic methods
The diagnosis is based on familial history, clinical signs, electron microscopy examination of renal biopsy (showing abnormalities of the glomerular basal membrane), and immunohistochemical findings on renal and cutaneous biopsy (even if it cannot establish the diagnosis in all the patients). Molecular genetic testing can confirm the diagnosis.
Differential diagnosis
The differential diagnoses include hematuria related to urologic diseases and cancer, IgA nephropathy, nephropathy related to MYH9 mutation, and familial benign hematuria.
Antenatal diagnosis
A prenatal and pre-implantation diagnosis is possible for at-risk pregnancies, if a causative mutation has been found in a member of the affected family.
Genetic counseling
Most AS cases follow an X-linked dominant mode of inheritance, but AR and AD cases have also been reported. A genetic counseling should be proposed to affected families.
Management and treatment
The management of AS is only symptomatic, mainly aiming at slowing the progression to ESRD. It includes angiotensin blockade (e.g. angiotensin converting enzyme inhibitors, angiotensin receptor blockers), diuretics, and a salt-restricted diet. The most severe cases require dialysis and renal replacement therapy. Regular hearing and ocular follow-up are recommended. Hearing aids should be prescribed when needed, and surgical intervention for ocular anomalies can be considered.
Prognosis
The prognosis of AS is poor due to the progression to ESRD (often affecting young adults). However, renal transplantation is usually successful, since the development of anti-type IV collagen antibodies is a rare event. The extra-renal features can affect the quality of life.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*

                                * European Reference Network