An autosomal dominant cerebellar ataxia type I that is characterized by very slowly progressive or non-progressive ataxia, dysarthria, oculomotor abnormalities and intellectual disability.

Summary:
Epidemiology
Spinocerebellar ataxia type 29 (SCA29) prevalence is unknown. More than 50 cases have been reported in the literature to date.
Clinical description
SCA29 presents at birth, or shortly after, with manifestations including very slowly progressive or non-progressive gait and limb ataxia causing delayed walking and frequent falling in children. Mild developmental delay, learning difficulties, and language dysfunction are frequently reported. Other manifestations include nystagmus, dysarthria, dysmetria, and dysdiadochokinesia. Affected patients occasionally present with intention tremor, dystonia, and migraine headaches. Although the disease course is not well established, it appears to range from non-progressive or very slowly progressive ataxia (that does not affect ambulation) to progressively disabling ataxia. A slight improvement in cerebellar signs has been reported in some cases over time.
Etiology
SCA29 is due to mutations in the ITPR1 gene (3p26.1), which is also the causal gene of SCA15.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA29 are not specific, diagnosis is only confirmed with the finding of a mutation in the ITPR1 gene.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
SCA29 is inherited autosomal dominantly, occasionally autosomal recessively, and genetic counseling is possible.
Management and treatment
There is no cure for SCA29 and treatment is supportive. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease progression is very slow, but precise prognosis is unknown.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1; see this term), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations.

Summary:
Epidemiology
Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence in North America, Australia and India. Accurate estimates of prevalence are not available. However, SCA3 is the most common form of ADCA1 in most genetically characterized populations and accounts for up to 72 % of families with ataxia. Based on an English language literature review about 600 cases have been published.
Clinical description
SCA3 is divided into 3 forms. SCA3 type 1 (MJD Type 1, see this term) is associated with ataxia, ophthalmoparesis, pyramidal signs such as spasticity and hyperreflexia, and extrapyramidal signs including dystonia and other movement disorders presenting in adolescence. SCA3 type 2 (MJD Type 2, see this term) presents in middle adulthood with ataxia, spasticity, and dystonia. SCA3 type 3 (MJD Type 3, see this term) occurs after the age of 40 and includes ophthalmoparesis and anterior horn cell disease, i.e. fasciculations, atrophy, and weakness. Parkinsonism can also be a feature of SCA3. A likely overlooked but common feature is impairment of temperature sensation involving the entire body.
Etiology
The disease is associated with a CAG repeat expansion mutation in the ATXN3 gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56.
Diagnostic methods
Diagnosis is based on the clinical picture, familial history and ultimately on genetic testing.
Differential diagnosis
Differential diagnosis is broad and includes other types of SCA which may have similar features.
Antenatal diagnosis
Prenatal diagnosis and pre-manifestation diagnosis in patients with a family history of SCA can be offered.
Genetic counseling
SCA3 follows an autosomal dominant pattern of inheritance with full penetrance and anticipation phenomenon. Genetic counseling is recommended in symptomatic patients or those with a family history of the disorder due to known SCA mutation, and pre-symptomatic testing should be discussed in adults.
Management and treatment
In the absence of specific treatments to slow or stop disease progression, care is supportive. For example, parkinsonism, restless legs syndrome, spasticity, sleep disorders and depression can be treated pharmacologically. Dystonia and spasticity can be managed with local botulinum toxin injections. Occupational and physical therapy are essential. Speech therapy may also be of benefit for managing dysarthria.
Prognosis
Prognosis is poor but patients have been reported to survive for decades after onset of symptoms.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type III that is characterized by a slowly progressive and relatively pure ataxia.

Summary:
Epidemiology
Spinocerebellar ataxia type 30 (SCA30) has only been described in 6 patients from one Australian family to date.
Clinical description
The age of onset ranges from 45 to 76 years with a mean age of onset of 52 years. It presents with oculomotor dysfunction, moderate dysarthria, and ataxia that progresses slowly and eventually leads to mobility impairment. Some patients have also reported mild hyperreflexia in the lower limbs. Rarer manifestations include gaze-evoked nystagmus and dystonia. Head MRI shows atrophy of cerebellum with preservation of nodulus/uvula and brainstem.
Etiology
The causal gene has not yet been identified but it has been linked to chromosome 4q34.3-q35.1.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and family history of SCA30.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia.
Antenatal diagnosis
Antenatal diagnosis is not possible, since a causative gene has not yet been identified for SCA30.
Genetic counseling
SCA30 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA30 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease progression is very slow, but precise prognosis is unknown.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type III that is characterized by the late-onset of ataxia, dysarthria and horizontal gaze nystagmus, and that is occasionally accompanied by pyramidal signs, tremor, decreased vibration sense and hearing difficulties.

Summary:
Epidemiology
Spinocerebellar ataxia type 31 (SCA31) is the third most common form of ADCA in Japan, where more than 20 families have been reported to date. It is rarely found in other Asian countries and is extremely rare in Western countries.
Clinical description
The mean age of disease onset is 58 years but it can present between the ages of 8 to 83 years. Ataxia, dysarthria, and horizontal gaze nystagmus are the common manifestations of SCA31, and the disease duration can be more than 10 years. Less common manifestations include pyramidal signs, tremor, decreased vibration sense, hearing difficulties, and blepharospasm
Etiology
SCA31 is due to non-coding pentanucleotide repeat expansions in the BEAN1 gene (16q21), encoding protein BEAN1.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA31 are not specific, diagnosis is only confirmed with the finding of a mutation in the BEAN1 gene
Differential diagnosis
Differential diagnosis includes other types of ADCA.
Genetic counseling
SCA31 is inherited autosomal dominantly with incomplete penetrance and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA31 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease progression is very slow. Life expectancy is not reduced but the quality of life can be significantly affected. According to recent reports, patients can become wheelchair bound at age of 79 years, and died at age of 89 years.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type 1 that is characterized by ataxia and cognitive impairment. Azoospermia is a typical feature in affected males.

Summary:
Epidemiology
Spinocerebellar ataxia type 32 (SCA32) has been reported in one Chinese family to date.
Clinical description
Disease onset occurs in adulthood with females more affected than males. Manifestations include ataxia, cognitive impairment and, in males, azoospermia. Cerebellar atrophy is visible with magnetic resonance imaging.
Etiology
The causal gene of SCA32 has not yet been identified but it is located to chromosome 7q32-q33.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and family history of the disease.
Differential diagnosis
Differential diagnosis includes other types of ADCA.
Genetic counseling
SCA32 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA32 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Precise prognosis is unknown due to limited number of patients reported. Mean age when aid walking needed is about 34 years.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type I that is characterized by papulosquamous, ichthyosiform plaques on the limbs appearing shortly after birth and later manifestations including progressive ataxia, dysarthria, nystagmus and decreased reflexes.

Summary:
Epidemiology
To date the disorder has been reported in 45 patients including 4 asymptomatic carriers, from one French-Canadian family and three Japanese families.
Clinical description
Disease onset occurs from shortly after birth to adolescence with the appearance of papulosquamous, ichthyosiform plaques on the limbs, which are often only present in the winter. After the age of 25 years they tend to disappear completely. Progressive ataxia, dysarthria, decreased reflexes, and nystagmus are further clinical signs of the disease that occur after the onset of skin manifestations, generally from the third to fifth decade of life. Patients occasionally present with autonomic dysfunction and pyramidal signs. Cerebellar and pontine atrophy is visible with magnetic resonance imaging (MRI) in individuals who develop cerebellar ataxia.
Etiology
The disorder is due to a mutation in the ELOVL4 gene (6q14).
Diagnostic methods
Diagnosis is based on characteristic clinical findings (skin lesions occurring shortly after birth and adult-onset slowly progressive cerebellar ataxia), and on the molecular genetic testing. Mutations in the ELOVL4 gene confirms diagnosis of SCA34. Magnetic resonance imaging usually shows marked atrophy of the cerebellum and pontine which is sometimes accompanied by Hot Cross Bun sign that is common in cerebellar type of multiple system atrophy.
Differential diagnosis
Differential diagnoses include other forms of autosomal dominant cerebellar ataxia. From the view point of radiological findings, multiple system atrophy is important in differential diagnosis, especially in patients who also develop autonomic dysfunction.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known ELOVL4 mutation.
Genetic counseling
The disorder is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment is only supportive. Physical activity should be maintained as much as possible with the help of prosthetic devices. Motorized chairs/scooters are eventually necessary. Speech therapy and communication devices should be offered to those with severe dysarthria.
Prognosis
Disease progression is slow; the patients require cane or walker in their late 60s, and wheelchair in their 70s.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type 1 that is characterized by the adult-onset of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor of hands, hyperreflexia and spasmodic torticollis.

Summary:
Epidemiology
Spinocerebellar ataxia type 35 (SCA35) has been reported worldwide in less than 30 cases to date.
Clinical description
Disease onset occurs in adulthood with manifestations of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses (Babinski sign), reduced proprioception, and hyperreflexia. Cognitive impairment is rare. Patients are usually wheelchair bound 10 years or more after the onset of symptoms. Head MRI shows diffuse cerebellar atrophy without involvement of the brainstem.
Etiology
SCA35 is caused by a mutation in the TGM6 gene (20p13) encoding transglutaminase 6 (TG6), a member of the transglutaminase family of enzymes. TG6 is expressed in the kidney, skin, eyes and neurons but the exact process that leads to SCA35 is unknown.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA35 are not specific, diagnosis is only confirmed with the finding of a mutation in the TGM6 gene.
Differential diagnosis
Differential diagnosis includes other types of ADCA.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
SCA35 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA35 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
SCA35 is slowly progressive disease, and most of reported patients are usually wheelchair bound 10 years or more after the onset of symptoms.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type 1 that characterized by gait and limb ataxia, lower limb spasticity, dysarthria, muscle fasiculations, tongue atrophy and hyperreflexia.

Summary:
Epidemiology
Spinocerebellar ataxia type 36 (SCA36) prevalence is unknown. SCA36 has been described in more than 100 families in Asia (Japan and China) and Europe (France, Italy, Poland, and Spain-Galicia). In a US population, SCA36 accounts for 0.7% of disease in a large undiagnosed ataxia cohort.
Clinical description
SCA36 presents in adulthood with ataxic dysarthria, truncal ataxia, limb ataxia, general hyperreflexia and variably occurring lower limb spasticity. Motor neuron involvement occurs later in the disease course and manifests with fasciculations and atrophy of the skeletal muscles and tongue. Sensorineural hearing loss may also be present in some. Oromandibular dystonia is a rare manifestation. Only mild cerebellar atrophy is reported.
Etiology
SCA36 is due to a pathogenic heterozygous GGCCTG repeat expansion in intron 1 of the NOP56 gene (20p13).
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA36 are not specific, diagnosis is only confirmed with the finding of a pathogenic heterozygous GGCCTG repeat expansion in intron 1 of the NOP56 gene.
Differential diagnosis
Differential diagnosis includes other types of ADCA (Autosomal dominant cerebellar ataxia).
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known genetic cause.
Genetic counseling
SCA36 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA36 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type 1 that is characterized by a cerebellar syndrome along with altered vertical eye movements.

Summary:
Epidemiology
Spinocerebellar ataxia type 37 (SCA37) has been reported in nine members of a Spanish kindred to date.
Clinical description
Disease onset occurs in adulthood (from the ages of 38-64). Clinical manifestations of SCA37 patients are characterized by slowly progressive cerebellar ataxia (starting with falls, dysarthria and clumsiness followed by other cerebellar signs) along with altered vertical eye movements. Generalized cerebellar atrophy is visible with magnetic resonance imaging.
Etiology
SCA37 is due to a pathogenic pentanucleotide ATTTC insertion within the 1p32 5' non-coding regulatory region of the DAB1 gene (1p32.2).
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA37 are not specific, diagnosis is only confirmed with the finding of a pathogenic mutation in the DAB1 gene.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia.
Antenatal diagnosis
Prenatal diagnosis is possible when the ATTTC insertion within the DAB1 gene has been identified in a family member.
Genetic counseling
SCA37 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA37 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Precise prognosis is unknown due to small number of patients reported, but disease progression is slow and the patients generally need wheelchair from 10 and 30 years after the disease onset.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 38 (SCA38) is a subtype of autosomal dominant cerebellar ataxia type 3 characterized by the adult-onset (average age: 40 years) of truncal ataxia, gait disturbance and gaze-evoked nystagmus. The disease is slowly progressive with dysarthria and limb ataxia following. Additional manifestations include diplopia and axonal neuropathy.


Spinocerebellar ataxia type 4 (SCA4) is a very rare progressive and untreatable subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by ataxia with sensory neuropathy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
SCA4 typically starts in middle-aged adults and presents with cerebellar ataxia, pyramidal signs, and peripheral sensory loss.
Etiology
The disease has been linked to chromosome 16q22.1 in kindreds from Utah (USA) and Germany but the mutation is yet unknown and does not appear to involve trinucleotide repeats.
Prognosis
There is insufficient clinical data to draw conclusions concerning prognosis.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 40 (SCA40) is a very rare subtype of autosomal dominant cerebellar ataxia type 1, characterized by the adult-onset of unsteady gait and dysarthria, followed by wide-based gait, gait ataxia, ocular dysmetria, intention tremor, scanning speech, hyperreflexia and dysdiadochokinesis.


Spinocerebellar ataxia type 41 is a rare autosomal dominant cerebellar ataxia type III disorder characterized by adult-onset progressive imbalance and loss of coordination associated with an ataxic gait. Mild atrophy of the cerebellar vermis has been reported on brain magnetic resonance imaging.


A rare, autosomal dominant cerebellar ataxia characterized by pure and slowly progressive cerebellar signs combining gait instability, dysarthria, nystagmus, saccadic eye movements and diplopia. Less frequent clinical signs and symptoms include spasticity, hyperreflexia, decreased distal vibration sense, urinary urgency or incontinence and postural tremor.


Spinocerebellar ataxia type 43 is a rare autosomal dominant cerebellar ataxia type I disorder characterized by late adult-onset of slowly progressive cerebellar ataxia, typically presenting with balance and gait disturbances, in association with axonal peripheral neuropathy resulting in reduced/absent deep tendon reflexes and sensory impairment. Lower limb pain and amyotrophy may be present, as well as various cerebellar signs, including dysarthria, nystagmus, hypometric saccades and tremor.


A rare autosomal dominant cerebellar ataxia characterized by slowly progressive late-onset gait and limb ataxia, dysarthria, and variable nystagmus. Brain imaging reveals cerebellar atrophy.


A rare autosomal dominant cerebellar ataxia characterized by slowly progressive late-onset cerebellar ataxia, variably combined with sensory axonal neuropathy. Patients may present gait and limb ataxia, dysarthria, abnormal oculomotor function, and distal sensory impairment. Cerebellar atrophy is typically mild or absent.


An autosomal dominant cerebellar ataxia type III that is characterized by the early-onset of cerebellar signs with eye movement abnormalities and a very slow disease progression.

Summary:
Epidemiology
Spinocerebellar ataxia type 5 (SCA5) prevalence is unknown. Five families (American, French, German, and Japanese) with SCA5 have been reported to date.
Clinical description
The mean age of onset is 33 years but it can range from 6 years to 68 years. SCA5 patients clinically present with cerebellar signs (ataxia, dysarthria, tremor), intention tremor, and eye movement abnormalities such as gaze-evoked nystagmus, down beat nystagmus, and impaired smooth pursuit. Occasionally defects of the visual field and horizontal gaze palsy can be also present. Non-cerebellar signs such as facial myokimia, resting tremor, writer's cramp, impaired vibration sense, dysphagia, and brisk deep tendon reflexes have been reported in some patients. SCA5 progresses very slowly with a disease duration of more than 30 years after symptom onset.
Etiology
SCA5 is caused by mutations in the SPTBN2 gene (11q13.2) encoding beta-III spectrin, a protein essential for the correct functioning and development of Purkinje cells.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA5 are not specific, diagnosis is only confirmed with the finding of a mutation in the SPTBN2 gene.
Differential diagnosis
Differential diagnosis includes other types of ADCA (Autosomal dominant cerebellar ataxia).
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
The disease is a rare autosomal dominant spinocerebellar ataxia. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA5 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease progression is slow, but precise prognosis is unknown.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type III that is characterized by late-onset and slowly progressive gait ataxia and other cerebellar signs such as impaired muscle coordination and nystagmus.

Summary:
Epidemiology
Spinocerebellar ataxia type 6 (SCA6) estimated worldwide prevalence is less than 1/100,000. It is most commonly seen in Japan, Korea, the Netherlands and Germany.
Clinical description
The mean age of onset is 45 years but can range from the ages of 16 to 72 years. It usually presents with the cerebellar signs of ataxia, dysarthria and dysphagia. Some patients also have episodic vertigo and diplopia. Eye movement abnormalities such as gaze evoked and downbeat nystagmus, impaired smooth pursuit and abnormal vestibulo-ocular reflex are commonly seen in SCA6 patients. Less common presentations include pyramidal tract signs and peripheral neuropathy. Parkinsonism, dystonia, myoclonus, tremor and cognitive impairment have been reported in rare cases. Depression and fatigue have been associated with SCA6. Disease severity seems to increase during pregnancy. SCA6 progresses very slowly with a disease duration that can last over 25 years.
Etiology
SCA6 is caused by small expansions of the trinucleotide (CAG) repeat in the CACNA1A gene (19p13) which encodes an alpha 1 subunit of a P/Q-type voltage-gated calcium channel, necessary for proper neural communication in the brain. The expansions in SCA6 patients are usually of 21-29 CAG repeats.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA6 are not specific, diagnosis is only confirmed with the finding of a mutation in the CACNA1A gene.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia, familial or sporadic hemiplegic migraine and episodic ataxia type 2.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
SCA6 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA6 and treatment is supportive. Acetazolamide may help with episodes of ataxia but does not halt the progression of the disease. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Life expectancy is not reduced but the quality of life can be significantly affected. Mean age when aid walking needed is about 53 years, and mean age when wheelchair needed is approximately 60 years.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


An autosomal dominant cerebellar ataxia type II that is characterized by progressive ataxia, motor system abnormalities, dysarthria, dysphagia and retinal degeneration leading to progressive blindness.

Summary:
Epidemiology
The worldwide prevalence of the disease is estimated to be less than 1/100,000 and it is thought to account for 2-4 % of all forms of spinocerebellar ataxia (up to 7 % in Asian populations). Higher prevalence is described in some populations such as in Scandinavia or South Africa.
Clinical description
Onset of Spinocerebellar ataxia type 7 (SCA7) is generally in the second to fourth decade but can range from infancy to the sixth decade of life. Manifestations that present in infancy and early childhood include muscle weakness, wasting, hypotonia, poor feeding, failure to thrive and loss of motor milestones. Changes in visual acuity and color vision (tritanopia) may be the earliest signs of the disease, especially in younger-onset patients. In those where initial symptoms occur before adolescence, the disease progresses much faster and blindness can occur within a few years. In those with adult-onset disease, manifestations include dysmetria, poor coordination and dysdiadokinesia with progression into severe dysarthria, dysphagia and loss of motor control. Visual symptoms (hemeralopia, photophobia, abnormalities in color vision and central visual acuity) may precede, accompany or follow cerebellar ataxia in those with adult-onset SCA7 but progression is slower, with blindness occurring 10 or more years after initial symptom onset. Psychosis and cognitive decline has also been reported in some cases. Patients eventually become bedridden.
Etiology
SCA7 is due to a CAG trinucleotide repeat in the ataxin 7 (ATXN7) gene (3p21.1-p12). This mutation leads to degeneration in the cells of the retina, cerebellum and brainstem. A larger CAG-repeat expansion is associated with an earlier onset and more severe disease course.
Diagnostic methods
Diagnosis is based on characteristic clinical findings (progressive incoordination and cone-rod retinal dystrophy) as well as molecular genetic testing. A CAG trinucleotide expansion (usually 36 or more CAG repeats) in the ATXN7 gene confirms diagnosis of SCA7. Magnetic resonance imaging usually shows severe atrophy of the cerebellum and the brainstem. Electroretinogram testing reveals rod and cone abnormalities and fundoscopic examination shows macular changes later in the disease course.
Differential diagnosis
Differential diagnoses include lipid storage diseases (such as neuronal ceroid lipofuscinosis) and Leber hereditary optic neuropathy. Other forms of ADCA should also be considered but can be excluded based on the absence of retinal degeneration, which is unique to SCA7.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known ATXN7 mutation.
Genetic counseling
The disorder is inherited autosomal dominantly and genetic anticipation is observed. Genetic counseling can inform parents with the disease of the 50% risk of passing it on to their children.
Management and treatment
There is no cure for SCA7 and treatment is supportive. Activity should be maintained as much as possible with the help of canes and walkers. Motorized chairs may eventually be necessary. Speech therapy and communication devices should be offered to those with dysarthria. UV exposure should be limited and sunglasses worn in order to limit damage to the retina. Low vision aids may also be beneficial. Ophthalmological follow-up is essential to monitor visual acuity. Dysphagia must also be monitored and a feeding tube may be required in those with advanced disease, in order to lower the risk of aspiration pneumonia (most common cause of death).
Prognosis
The prognosis depends on the age of symptom onset. An earlier onset is associated with a more severe and rapidly progressive disease. Mean age when aid walking needed is about 35 years, and mean age when wheelchair needed is approximately 37 years.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 8 (SCA8) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by cerebellar ataxia and cognitive dysfunction in almost three quarters of patients and pyramidal and sensory signs in approximately a third of patients.

Summary:
Epidemiology
Prevalence is unknown. However, SCA8 accounts for approximately 3% of ADCA cases.
Clinical description
Other features include dysexecutive disorders and commonly psychiatric disorders.
Etiology
SCA8 is caused by a trinucleotide repeat on 13q21 that produces a polyglutamine expansion in the ataxin 8 gene (ATXN8). SCA8 is thought to result from RNA-mediated neurotoxicity.
Prognosis
Prognosis is relatively good. Disease usually progresses slowly over decades. Life expectancy is not significantly reduced.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia with axonal neuropathy type 1 is a rare, genetic neurological disorder characterized by a late childhood onset of slowly progressive cerebellar ataxia. Initial manifestations include weakness and atrophy of distal limb muscles, areflexia and loss of pain, vibration and touch sensations in upper and lower extremities. Gaze nystagmus, cerebellar dysarthria, peripheral neuropathy, stepagge gait and pes cavus develop as disease progresses. Cerebellar atrophy (especially of the vermis) is present in all affected individuals. Additional reported manifestations include seizures, mild brain atrophy, mild hypercholesterolemia and borderline hypoalbuminemia.


Spinocerebellar ataxia with axonal neuropathy type 2

A rare autosomal recessive cerebellar ataxia (ARCA), characterized by progressive cerebellar ataxia associated with frequent oculomotor apraxia, severe neuropathy and an elevated serum alpha-fetoprotein (AFP) level.

Summary:
Epidemiology
The prevalence of spinocerebellar ataxia with axonal neuropathy type 2 (SCAN2) in France is estimated to be 1/900,000.
Clinical description
SCAN2 is mostly an adolescent onset disorder (age at onset ranges between 10 and 25 years), with a mean age of 14-15 years, that manifests as progressive cerebellar ataxia associated with peripheral neuropathy (98%), cerebellar atrophy (96%), occasional oculomotor apraxia (OMA; 51%; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes), pyramidal signs (21%), head tremor (14%), dystonia (14%), strabismus (12%), chorea (10%) and saccadic pursuit without OMA (4.5%).
Etiology
SCAN2 results from mutations in SETX gene (9q34), encoding senataxin protein, a DNA/RNA helicase localized in nucleus which is implicated in DNA break repair. Some correlations between genotype and phenotype have been established for example deletions and nonsense mutations are correlated to more severe phenotypes than missense mutations. Mutations in the gene PIK3R5 (17p13.1) have also been implicated in the pathogenesis of SCAN2. PIK3R5 encodes a regulatory subunit that interacts with class 1B phosphoinositide-3-kinase (key enzymes in various signal transduction pathways that regulate cell survival and growth, metabolism, immune, and cardiac functions).
Diagnostic methods
Diagnosis is based on clinical features, progressive evolution leading to important motor handicap, absence of extra-neurologic findings and family history. Laboratory findings show an elevated AFP serum level (above 7 µg/L). Electromyography findings reveal axonal sensory-motor neuropathy. Oculographic recordings can demonstrate OMA. Cerebral magnetic resonance imagery displays cerebellar atrophy. Diagnosis is confirmed by molecular analysis of the pathogenic gene.
Differential diagnosis
Differential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay.
Antenatal diagnosis
Carrier testing for at-risk family members and prenatal testing are possible if the disease-causing alleles in a family are known.
Genetic counseling
Transmission of SCAN2 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being neither affected nor a carrier.
Management and treatment
No specific treatment exists for SCAN2 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Routine follow-up with a neurologist or a neurogenetician is recommended.
Prognosis
SCAN2 is a progressive neurodegenerative disorder and most patients will become wheelchair bound at a mean age of 29.9 years ± 3.84 after a mean disease duration of 15.3 years ± 3.52.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Dr Perrine CHARLES


A rare, mitochondrial DNA maintenance syndrome characterized by cerebellar ataxia, sensory peripheral neuropathy, myoclonus, epilepsy, progressive cognitive impairment, late-onset ptosis and external ophthalmoplegia. Liver failure may also occur, most often in association with the use of antiepileptic drug sodium valproate.


A rare hereditary ataxia characterized by unusual facies (i. e. gross, rough and abundant hair, mild palpebral ptosis, thick lips, and down-curved corners of the mouth), dysarthria, delayed psychomotor development, scoliosis, foot deformities, and ataxia. There have been no further descriptions in the literature since 1985.


Spinocerebellar degeneration-corneal dystrophy syndrome

A rare, genetic, neurological disorder characterized by the association of slowly progressive spinocerebellar degeneration and corneal dystrophy, manifesting with bilateral corneal opacities (which lead to severe visual impairment), mild intellectual disability, ataxia, gait disturbances, and tremor. Additional manifestations include facial dysmorphism (i.e. triangular face, ptosis, low-set, posteriorly angulated ears, and micrognathia), as well as mild upper motor neuron involvement with hypertonia, lower limb hyperreflexia and extensor plantar responses. There have been no further descriptions in the literature since 1985.


Spirillary rat-bite fever (RBF), also known as Sodoku (Japanese for so: rat and doku: poison), is caused by the Gram-negative bacillus Spirillum minus and is transmitted to humans through the bites and scratches of rats. The disease is mostly present in Asia.

Summary:
Epidemiology
The exact incidence is unknown.
Clinical description
The bite is often small and heals quickly. However, after an incubation period of around 14 to 18 days, an inflammation appears at the site of the bite that becomes painful, indurated, edematous and may ulcerate. The inflammation is followed by fever, vomiting and chills and is associated with local lymphadenopathy. In 50% of the cases, a macular rash develops and in rare cases, swollen, red, and painful joints can appear. Occasionally, diarrhea, vomiting, neuralgias and complications, such as endo- and myocarditis, hepatitis and meningitis, can occur.
Etiology
Spirillum minus is present in the saliva of rats and is only transmitted through bites and scratches. A few cases of transmission by other animals (monkeys, mice) have been reported.
Diagnostic methods
Without a noticeable bite, diagnosis is based solely on detection of the germ. However, this is difficult due to its poor growth on culture media.
Differential diagnosis
The differential diagnosis includes streptobacillary RBF and Haverhill fever (see these terms) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever, malaria, typhoid fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthems, secondary syphilis, Epstein-Barr virus, and coxsackieviruses).
Management and treatment
Management requires a prophylactic (avoiding direct or indirect contact with host-animals) and therapeutic approach (local treatment and antimicrobial therapy). Treatment of this form of rat-bite fever is primarily based on penicillin G administration as little is known about the susceptibility of this germ to other antibiotics.
Prognosis
Without treatment, symptoms disappear within 3-4 days but regular relapses can occur 3-10 days later. The initial lesion can become necrotic and can desquamate. The relapses can go on for a year but normally the symptoms disappear within two months. If left untreated, RBF carries a mortality rate of 6.5% due to complications.

                            Last update:
                            August 2009

                            - Expert reviewer(s):
                            Dr François TREMOLIERES


Splenic diffuse red pulp small B-cell lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal proliferation of small, monomorphous, basophilic B-lymphocytes, with villous cytoplasm, in the splenic red pulp, bone marrow and peripheral blood. It typically presents in the late clinical stages with splenomegaly and moderate lymphocytosis. Cytopenias are rare and likely associated with hypersplenism.


Splenic marginal zone lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal clonal proliferation of mature B-lymphocytes with involvement in the spleen, bone marrow and, frequently, the blood. It usually presents with splenomegaly, lymphocytosis, anemia and/or thrombocytopenia. Hepatitis C virus and autoimmune manifestations, such as autoimmune hemolytic anemia and autoimmune thrombocytopenia, could be associated.


Splenogonadal fusion-limb defects-micrognathia syndrome

A rare dysostosis syndrome characterized by abnormal fusion of the spleen with the gonad (or more rarely with remnants of the mesonephros), limb abnormalities (consisting of amelia or severe reduction defects leading to upper and/or lower rudimentary limbs) and orofacial abnormalities such as cleft palate, bifid uvula, microglossia and mandibular hypoplasia. It could also be associated with other malformations such as cryptorchidism, anal stenosis/atresia, hypoplastic lungs and cardiac malformations.


A rare subtype of split cord malformation characterized by each hemicord contained in its own dural sac, typically with a intervening bony septum.


A rare subtype of split cord malformation characterized by both hemicords included in the same single dural sac. An intradural intervening mesenchymal septum may be present.


A rare malformation characterized by localized longitudinal division of the spinal cord into two "hemicords". Vertebro-costal anomalies are commonly associated. Classic overlying skin stigmata is a focal hypertrichosis/hairy patch. Split cord malformations may be associated with other dysraphic anomalies (eg: filum lipoma).


Split hand - split foot - deafness is an extremely rare genetic syndrome reported in a few families to date and characterized clinically by split hand/split foot malformation (SHFM; see this term) and mild to moderate sensorineural hearing loss, sometimes associated with cleft palate and intellectual deficit.


Split-foot malformation-mesoaxial polydactyly syndrome

A rare genetic syndrome with limb malformations as a major feature characterized by unilateral or bilateral split-foot malformation, nail abnormalities of the hand, and bilateral sensorineural hearing impairment. Mesoaxial polydactyly of the foot has also been described.


A rare, genetic, spondyloepimetaphyseal dysplasia disease characterized by short-limbed short stature (more pronounced in lower limbs) associated with characterisitic facial dysmorphism (i.e. relative macrocephaly, frontal bossing, midface hypoplasia, depressed nasal root, small upturned nose, prognathism) and abnormal radiological findings, which include abnormal vertebral bodies (particularly in the lumbar region), striated metaphyses, generalized mild osteoporosis, and delayed ossification of the carpal bones. Progressive coxa vara, short dental roots, hypogammaglobulinemia and cataracts may be occasionally associated.


A rare, genetic primary bone displasia characterized by disproportionate short stature with short, stiff neck and trunk and relatively long limbs, fingers and toes (which may present flexion contractures), severe vertebral body ossification delay (with frequent pycnodysostosis), markedly enlarged round epiphyses of the long bones, absent ossification of pubic bones and multiple pseudoepiphyses of the short tubular bones in hands and feet. Neurological manifestations resulting from cervical spine instability may be observed.


Spondylo-ocular syndrome is a very rare association of spinal and ocular manifestations that is characterized by dense cataracts, and retinal detachment along with generalized osteoporosis and platyspondyly. Mild craniofacial dysphormism has been reported including short neck, large head and prominent eyebrows.


A rare spondylodysplastic syndrome characterized by camptodactyly, cervical platyspondyly, and variable degrees of thoracic scoliosis. There have been no further descriptions in the literature since 1995.


A spondylodysplasic dysplasia clinically characterized by postnatal progressive vertebral fusions frequently manifesting as block vertebrae, contributing to an shortened trunk and hence disproportionate short stature, scoliosis, lordosis, carpal and tarsal synostosis and infrequently, club feet.

Summary:
Epidemiology
Spondylocarpotarsal synostosis (SCT) is very rare. To date, less than 40 cases have been reported in the medical literature.
Clinical description
While the clinical onset is postnatal, the diagnosis becomes clinically evident in early in childhood. Primary clinical characteristics of SCT syndrome include progressive vertebral fusions manifesting as block vertebrae leading to a shortened trunk resulting in disproportionate short stature that becomes apparent with physical growth. Scoliosis, lordosis, carpal and tarsal synostosis are frequent with club feet being observed in a minority of cases. A mild facial dysmorphism with a round face with frontal bossing and anteverted nostrils can be evident. Midline cleft palate, conductive hearing loss, joint laxity and dental enamel hypoplasia are uncommonly reported.
Etiology
SCT syndrome is due to biallelic mutations in FLNB (localized to 3p14.3) that encodes cytoskeletal protein filamin B. A very similar condition is caused by either monoallelic or biallelic mutations in MYH3.
Diagnostic methods
Diagnosis is confirmed by skeletal x-rays and genetic testing. Radiographs demonstrate progressive vertebral fusions and lumbar spine, carpal and tarsal synostosis without rib anomalies. Occasionally, delayed ossification of epiphyses and bilateral epiphyseal femur dysplasia are reported.
Differential diagnosis
Differential diagnosis may include isolated Klippel-Feil syndrome and other vertebral dysplasias, such as autosomal dominant spondylocostal dysplasia and multiple synostoses syndrome.
Genetic counseling
SCT syndrome follows an autosomal recessive inheritance (FLNB, MYH3) or occasionally autosomal dominant inheritance (MYH3). Genetic counseling should be proposed to at risk couples informing them that there is 25% (autosomal recessive) or 50% (autosomal dominant) risk of tranmitting the disease to offspring.
Management and treatment
Management involves ophthalmologic, audiologic and spine assessments. Scoliosis is treated medically; no effective surgical intervention has been described. The cervical spine should be evaluated for features of instability prior to general anesthesia. Pain management is indispensable as patients suffer from much continuing physical pain due to the spinal deformities and fused block vertebrae.
Prognosis
It has not been formally evaluated if SCT syndrome affects life expectancy.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON  - Dr Emma WADE


A rare connective tissue disorder for which three subtypes exist, either related to the gene B4GALT7, B3GALT6 or SLC39A13, and for which the clinically overlapping characteristics include short stature (progressive in childhood), small joint hypermobility, skin hyperextensibility with soft, doughy skin especially on the hands and feet muscular hypotonia (ranging from congenitally severe to mild with later_onset), skeletal anomalies and, more variably, osteopenia, delayed motor development and bowing of the limbs. Gene-specific features, with variable presentation, are additionally observed in each subtype.


Spondyloenchondrodysplasia (SPENCD) is a very rare genetic skeletal dysplasia characterized clinically by skeletal anomalies (short stature, platyspondyly, short broad ilia) and enchondromas in the long bones or pelvis. SPENCD may have a heterogeneous clinical spectrum with neurological involvement (spasticity, mental retardation and cerebral calcifications) or autoimmune manifestations, such as immune thrombocytopenic purpura, systemic lupus erythematosus (see these terms) hemolytic anemia and thyroiditis.


Spondyloepimetaphyseal dysplasia congenita, Strudwick type is characterized by disproportionate short stature from birth (with a very short trunk and shortened limbs) and skeletal abnormalities (lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses).

Summary:
Epidemiology
The syndrome has been described in less than 30 patients so far.
Clinical description
Cleft palate and eye abnormalities (severe myopia and retinal detachment) are frequently associated. Arthritis may develop early in life.
Etiology
This condition is caused by mutations in the COL2A1 gene (12q13.11-q13.2).
Genetic counseling
It is inherited in an autosomal dominant manner.

                            Last update:
                            September 2009


Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type

Spondyloepimetaphyseal dysplasia with multiple dislocations is a rare genetic primary bone dysplasia disorder characterized by midface hypoplasia, short stature, generalized joint laxity, multiple joint dislocations (most frequently of knees and hips), limb malalignment (genu valgum/varum) and progressive spinal deformity (e.g. kyphosis/scoliosis). Radiography reveals distinctive slender metacarpals and metatarsals, as well as small, irregular epiphyses, metaphyseal irregularities with vertical striations, constricted femoral necks and mild platyspondyly, among others.


Spondyloepimetaphyseal dysplasia, aggrecan type is a new form of skeletal dysplasia characterized by severe short stature, facial dysmorphism and characteristic radiographic findings.

Summary:
Epidemiology
To date, three cases have been described, all originating from the same family.
Clinical description
Facial features include midface hypoplasia with almost absent nasal cartilage, and relative prognathism and macrocephaly. Radiographic findings include irregular epiphyses of long bones with widened metaphyses, platyspondyly, multiple cervical-vertebral clefts and brachydactyly.
Etiology
The disease results from a missense mutation affecting the C-type lectin domain of aggrecan (AGC1 gene; chromosome 15) which regulates endochondral ossification. Transmission is autosomal-recessive.

                            Last update:
                            October 2009


Spondyloepimetaphyseal dysplasia, Geneviève type is a rare primary bone dysplasia characterized by severe developmental delay and skeletal dysplasia (including short stature, premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses), as well as moderate to severe intellectual disability and facial dysmorphism, including prominent forehead, mild synophrys, depressed nasal bridge, prominent bulbous nasal tip and full lips.


Spondyloepimetaphyseal dysplasia, Handigodu type is a rare, genetic, primary bone dysplasia disorder characterized by three distinct phenotypes, namely: 1) patients of average height with painful, osteoarthritic changes of the hip joints and no spinal abnormalities, 2) short-statured patients with predominantly truncal shortening, arm span exceeding height, dysplastic changes of hips and varying degrees of platyspondyly, and 3) patients with dwarfism, various associated skeletal abnormalities (particularly of the knees and hands) and severe epiphyseal dysplasia (of hips, knees, hands, wrists) associated with significant platyspondyly. Most patients cannot walk long distances, and many have decreased joint spaces, as well as sclerotic and cystic changes on imaging.


Spondyloepimetaphyseal dysplasia, Irapa type is characterized by disproportionate short-trunked short stature, pectus carinatum, short arms, short and broad hands, short metatarsals, flat and broad feet, coxa vara, genu valgum, osteoarthritis, arthrosis and moderate-to-serious gait impairment.

Summary:
Epidemiology
The syndrome has been described among Venezuelan Indians of the Yukpa (Irapa) tribe and three sibs from a Mexican mestizo family.
Etiology
Autosomal recessive inheritance has been suggested, but the causative gene has not yet been identified.

                            Last update:
                            November 2009


Spondyloepimetaphyseal dysplasia, Isidor-Toutain type

A rare primary bone dysplasia disorder characterized by normal birth length with early postnatal growth deficiency resulting in severe disproportionate short stature (with short trunk and limbs), severe genu varum, flexion contractures in the hips and lumbar hyperlordosis. Radiological findings reveal platyspondyly with central indentation of vertebral endplates, progressive and severe epimetaphyseal abnormalities that primarily affect the lower limbs and include very small, irregular proximal femoral and knee epiphyses, severe coxa vara, delayed ossification of proximal femoral epiphyses, and irregular distal femoral and proximal tibial metaphyses.


Spondyloepimetaphyseal dysplasia, Maroteaux type

Spondyloepiphyseal dysplasia, Maroteaux type is a very rare type of spondyloepiphyseal dysplasia (see this term) described in fewer than 10 patients to date and characterized clinically by dysplastic epiphyses, short stature appearing in infancy, short neck, short and stubby hands and feet, scoliosis, genu valgum, abnormal pelvis, osteoporosis and osteoarthritis.


Spondyloepimetaphyseal dysplasia, matrilin-3 type

A rare primary bone dysplasia due to matrilin-3 varaints and characterized by disproportionate early-onset dwarfism, bowing of the lower limbs, short, wide and stocky long bones with severe epiphyseal and metaphyseal changes, lumbar lordosis, hypoplastic iliac bones, flat ovoid vertebral bodies and normal hands.


Spondyloepimetaphyseal dysplasia, Missouri type is characterized by moderate-to-severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood.

Summary:
Epidemiology
The syndrome has been described in a large Missouri (US) kindred with 14 affected members in 4 generations.
Clinical description
Though some spontaneous improvement of the skeletal defects may occur in adolescence, the affected individuals remained shorter than their age-matched unaffected sibs. Predisposition deformities to osteoarthritis (especially of the knees) have been noted.
Etiology
This condition is caused by mutation in the MMP13 gene (locus 11q22.3) and transmitted in an autosomal dominant manner.

                            Last update:
                            November 2009


Spondyloepimetaphyseal dysplasia, PAPSS2 type

Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type is characterized by short stature, short and bowed lower limbs, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence.

Summary:
Epidemiology
The syndrome has been described a large eight-generation consanguineous Pakistani family.
Clinical description
Radiographic features include delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse early osteoarthritic changes (in the spine and hands), mild brachydactyly, and mild metaphyseal abnormalities (predominantly involving the hips and knees).
Etiology
SEMD, Pakistani type is caused by mutations in the PAPSS2 gene (10q22-q24). Mutations in the same gene have been identified in a 14.5-year-old Turkish girl with premature pubarche, hyperandrogenic anovulation, short stature and skeletal dysplasia.
Genetic counseling
SEMD, Pakistani type is inherited in an autosomal recessive manner.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondyloepimetaphyseal dysplasia, Shohat type

Spondyloepimetaphyseal dysplasia congenita, Shohat type is characterized by severely disproportionate short stature, short limbs, small chest, short neck, thin lips, severe lumbar lordosis, marked genu varum, joint laxity, distended abdomen, mild hepatomegaly and splenomegaly.

Summary:
Epidemiology
The syndrome has been described in three members of a Jewish family of Iraqi origin and one Mexican boy.
Clinical description
The long bone changes in adolescence show general metaphyseal irregularities and significant epiphyseal ossification delay.
Etiology
Autosomal recessive inheritance has been suggested, but the causative gene has not yet been identified.

                            Last update:
                            November 2009


Spondyloepimetaphyseal dysplasia-abnormal dentition syndrome is a rare primary bone dysplasia disorder characterized by the association of dental anomalies (oligodontia with pointed incisors) and generalized platyspondyly with epiphyseal and metaphyseal involvement. Thin tapering fingers and accentuated palmar creases are additional features.


Spondyloepimetaphyseal dysplasia-hypotrichosis syndrome is a rare primary bone dysplasia disorder characterized by congenital hypotrichosis associated with rhizomelic short stature (more pronounced in upper limbs than lower limbs), limited hip abduction and mild genu varum. Flared and irregular metaphyses, delayed and irregular epiphiseal ossification and pear-shaped vertebral bodies are characteristic radiologic findings.


Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome is a rare, genetic primary bone dysplasia disorder characterized by disproportionate short stature with shortening of upper and lower limbs, short and broad fingers with short hands, narrowed chest with rib abnormalities and pectus excavatum, abnormal chondral calcifications (incl. larynx, trachea and costal cartilages) and facial dysmorphism (frontal bossing, hypertelorism, prominent eyes, short flat nose, wide nostrils, high-arched palate, long philtrum). Platyspondyly (esp. of cervical spine) and abnormal epiphyses and metaphyses are observed on radiography. Atlantoaxial instability causing spinal compression and recurrent respiratory disease are potential complications that may result lethal.


Spondyloepiphyseal dysplasia congenita (SEDC) is a chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses and flattened vertebral bodies.

Summary:
Epidemiology
The prevalence is approximately 1 per 100,000 live births. Males and females are equally affected.
Clinical description
Clinical manifestations may include short stature with a very short trunk and neck and shortened limbs, clubfoot, coxa vara, cleft palate, flat facial features, hypertelorism, eye abnormalities (nystagmus, congenital cataracts, glaucoma, retinal detachment), decreased hearing, and characteristic radiologic findings (flattened vertebral bodies, flat acetabular roof, delayed ossification of the femoral heads with degenerative changes). Decreased joint mobility and arthritis often develop early in life. Intelligence is usually unaffected.
Etiology
SEDC is caused by mutation in the COL2A1 gene (locus 12q13.11-q13.2).
Genetic counseling
The inheritance is autosomal dominant.

                            Last update:
                            September 2009


Spondyloepiphyseal dysplasia tarda, Kohn type is characterized by short trunk dwarfism, progressive involvement of the spine and epiphyses and mild-to-moderate intellectual deficit.

Summary:
Epidemiology
The syndrome has been described in three daughters born to healthy consanguineous parents.
Clinical description
The skeletal disorder usually manifests in late childhood. Typical radiographical features include platyspondyly, abnormal lumbar vertebrae and degenerative large joint changes.
Genetic counseling
Autosomal recessive transmission has been suggested.

                            Last update:
                            September 2009


Spondyloepiphyseal dysplasia tarda (SEDT) is characterized by disproportionate short stature in adolescence or adulthood, associated with a short trunk and arms and barrel-shaped chest.

Summary:
Epidemiology
The X-linked variant of the disease is most common, with an estimated prevalence of 1 in 150,000-200,000.
Clinical description
Patients may have normal body proportions at birth. The condition typically manifests around puberty with a short neck, scoliosis or thoracic kyphosis, lumbar hyperlordosis, and early-onset progressive osteoarthritis of the hips and knees. Many patients achieve an adult height of more than 153 cm and true dwarfism may not be present. Radiographic findings appear prior to puberty and may include multiple epiphyseal abnormalities, flattened vertebral bodies, narrow disc spaces, hypoplastic odontoid process, short femoral neck, and coxa vara.
Etiology
The X-linked recessive type is caused by mutations in the TRAPPC2 gene (locus Xp22.2-p22.1).
Genetic counseling
SEDT may be transmitted as an X-linked recessive, autosomal recessive or autosomal dominant trait.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondyloepiphyseal dysplasia with metatarsal shortening

A rare, genetic, primary bone dysplasia disorder characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and hypoplasia/dysplasia of the third and fourth metatarsals, in the absence of ophthalmologic, cleft palate, and height anomalies.

Summary:
Epidemiology
To date, fewer than 15 families have been reported worldwide.
Clinical description
The first clinical signs appearing in childhood are broad knees and flat nasal bridge, followed in late childhood and adolescence by short 3rd and 4th metatarsals (not always present), joint pain in knees and hips and later osteoarthritis of the spine, shoulder, hips, and knees. Shortening of the metacarpals may also be present. Vertebral abnormalities include mild platyspondyly, irregular end plates, and reduced intervertebral distances. Stature is within average range. Brachydactyly is restricted to metatarsals III, IV and, more variably, V. Progressive hearing loss may be associated and typically starts in early adulthood, although subclinical hearing impairment for high frequencies may be detected in children.
Etiology
The disorder is due to the R275C mutation in the geneCOL2A1 (12q13.11).
Diagnostic methods
Disorder is suspected based on family history and clinical presentation, but this may be difficult to detect in early childhood. Skeletal radiographs showing platyspondyly and shortened metatarsals and metacarpals may be helpful in the diagnosis work up. Diagnosis is confirmed by genetic testing for the R275C mutation in COL2A1.
Differential diagnosis
Disorders with early-onset osteoarthritis and polyarticular arthritis form the main differential diagnoses and include juvenile idiopathic osteoarthritis and mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis. Whilst COL2A1 mutations are involved in a spectrum of skeletal dysplasias, this specific disorder is typically distinguished by the absence of cleft palate, ophthalmologic pathology and short stature.
Antenatal diagnosis
Genetic prenatal diagnosis is possible when the mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk of transmission to offspring is 50% and there is full disease penetrance.
Management and treatment
Treatment is symptomatic and frequently includes hip replacement (often by the age of 40), hearing aids for hearing loss, and anti-rheumatic medication for osteoarthritis. Appropriate surveillance of hearing loss and progression of osteoarthritis is required.
Prognosis
The disorder is associated with early-onset, progressive arthritis that is typically associated with significant joint pain and restricted mobility that can adversely impact quality of life. Early joint replacements are often recommended. Longevity does not appear to be different to that of the general population.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Lindsay BURRAGE


Spondyloepiphyseal dysplasia, Kimberley type (SEDK) is characterized by short stature and premature degenerative arthropathy.

Summary:
Epidemiology
It has been described in one multigenerational South African family of English white descent.
Clinical description
The main clinical features may include proportionate short stature (<5th percentile for age), stocky habitus and early-onset progressive osteoarthropathy of the weight-bearing joints. Radiographical features are flattened vertebral bodies with sclerosis and prominent endplate irregularity and flattened femoral epiphyses.
Etiology
SEDK is caused by mutation in the aggrecan gene (AGC1, locus 15q26.1).
Genetic counseling
SEDK is transmitted as an autosomal dominant trait.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondyloepiphyseal dysplasia, MacDermot type

Spondyloepiphyseal dysplasia (SED), MacDermot type is characterized by short stature, femoral epiphyseal dysplasia, mild vertebral changes and sensorineural deafness.

Summary:
Epidemiology
The syndrome has been described in a family in which females in four successive generations were affected.
Clinical description
Myopia and retinal detachment were present in adult life.
Genetic counseling
Autosomal dominant transmission has been suggested.

                            Last update:
                            September 2009


Spondyloepiphyseal dysplasia, Reardon type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in several members of a single family to date and characterized by short stature, vertebral and femoral abnormalities, cervical instability and neurologic manifestations secondary to anomalies of the odontoid process.


Spondyloepiphyseal dysplasia, Stanescu type

A rare spondyloepiphyseal dysplasia characterized by progressive joint contractures with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Patients are of normal height and present with gait problems, joint pain, and enlarged joints with joint restriction and contractures. Radiological features include generalized platyspondyly, hypoplastic ilia, epiphyseal flattening with metaphyseal splaying of the tubular bones, and broad, elongated femoral necks with marked coxa valga. Histopathologic examination of cartilage shows PAS-positive cytoplasmic inclusion bodies in chondrocytes.


Spondyloepiphyseal dysplasia-brachydactyly-speech disorder syndrome

Spondyloepiphyseal dysplasia, Cantu type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in about 5 patients to date and characterized by clinical signs including short stature, peculiar facies with blepharophimosis, upward slanted eyes, abundant eyebrows and eyelashes, coarse voice, and short hands and feet (brachymetacarpalia, brachymetatarsalia and brachyphalangia).


Spondyloepiphyseal dysplasia-craniosynostosis-cleft palate-cataracts-intellectual disability syndrome

Spondyloepiphyseal dysplasia Nishimura type is characterized by spondyloepiphyseal dysplasia, craniosynostosis, cataracts, cleft palate and intellectual deficit.

Summary:
Epidemiology
The syndrome has been described in four Japanese sibs (three brothers and one sister born to nonconsanguineous parents).
Clinical description
Most clinical manifestations are evident at birth, but skeletal changes and cataracts may become evident during early childhood.
Genetic counseling
Autosomal recessive inheritance has been suggested.

                            Last update:
                            September 2009


Spondylometaphyseal dysplasia, 'corner fracture' type is a skeletal dysplasia associated with short stature, developmental coxa vara, progressive hip deformity, simulated 'corner fractures' of long tubular bones and vertebral body abnormalities (mostly oval vertebral bodies).

Summary:
Epidemiology
Less than 30 patients have been reported in the literature.
Clinical description
Tetralogy of Fallot and odontoid hypoplasia have been reported in single patients with this syndrome.
Etiology
Currently, there are no human genes associated with the disease.
Genetic counseling
Autosomal dominant inheritance has been suggested.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondylometaphyseal dysplasia, A4 type is a rare primary bone dysplasia disorder characterized by disproportionate short stature, severe femoral neck deformity, marked metaphyseal abnormalities and platyspondyly consisting of ovoid vertebral bodies that have an anterior tongue-like deformity.


Spondylometaphyseal dysplasia, Golden type is a rare primary bone dysplasia disorder characterized by severe short stature, coarse facies, thoracolumbar kyphoscoliosis and enlarged joints with contractures. Psychomotor delay and intellectual disability may also be associated. Radiographic features include flat vertebral bodies, lacy ossification of the metaphyses of long bones and iliac crests, and marked sclerosis of the skull base.


Spondylometaphyseal dysplasia, Kozlowski type is characterized by short stature (short-trunk dwarfism), scoliosis, metaphyseal abnormalities in the femur (prominent in the femoral neck and trochanteric area), coxa vara and generalized platyspondyly.

Summary:
Epidemiology
Prevalence is estimated at less than one in one million people.
Clinical description
Intelligence is usually normal.
Etiology
The syndrome is caused by a mutation in the TRPV4 gene (12q24.1) and is transmitted in an autosomal dominant manner.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondylometaphyseal dysplasia, Schmidt type is characterized by short stature, myopia, ,small pelvis, progressive kypho-scoliosis, wrist deformity, severe genu valgum, short long bones, and severe metaphyseal dysplasia with moderate spinal changes and minimal changes in the hands and feet.

Summary:
Epidemiology
This condition has been reported in five members of an Algerian family and one Polish boy; the patient reported by Schmidt et al. possibly had this disorder.
Etiology
Autosomal dominant inheritance has been suggested, but the causative gene has not yet been identified.

                            Last update:
                            November 2009


Spondylometaphyseal dysplasia, Sedaghatian type

A rare neonatal lethal form of spondylometaphyseal dysplasia characterized by severe metaphyseal chondrodysplasia, mild rhizomelic shortness of the upper limbs, and mild platyspondyly.

Summary:
Epidemiology
Nine cases have been reported so far in patients of Iranian, Yemeni and Caucasian origin.
Clinical description
A lacy appearance of the iliac crests, long fibulae, abnormal tarsal bones, cardiac arrhythmia, and intracranial anomalies have been described. Intrauterine growth is normal. The majority of patients die in the first days of life with symptoms of cardiorespiratory insufficiency. Subacute myocarditis, cortical necrosis of kidneys, adrenal and pulmonary hemorrhage, absence of the corpus callosum and marked frontotemporal pachygyria have been found at autopsy.
Etiology
Etiology remains unknown.
Genetic counseling
Autosomal recessive inheritance has been suggested.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome

A rare, genetic, primary bone dysplasia disorder characterized by short stature, hyperlordosis, protuberant abdomen, mild bilateral genu varum, bowed and shortened forearms with limited elbow extension, and discrete facial dysmorphism (prominent forehead, hypertelorism, flat nasal bridge). Radiographically, moderate platyspondyly, including posterior wedging with anterior bullet-shaped vertebral bodies, with minimal metaphyseal abnormalities are observed.


Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome is characterised by the association of spondylometaphyseal dysplasia (marked by platyspondyly, shortening of the tubular bones and progressive metaphyseal irregularity and cupping), with postnatal growth retardation and progressive visual impairment due to cone-rod dystrophy. So far, it has been described in eight individuals. Transmission appears to be autosomal recessive.


Spondylometaphyseal dysplasia-corneal dystrophy syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay with intellectual disability, postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, abnormalities of the spine, pelvis, and metaphyses, corneal clouding, and patent ductus arteriosus. Dysmorphic facial features include hypertelorism, prominent eyes, depressed nasal bridge, and short upturned nose.


Spondylometaphyseal dysplasias are a heterogeneous group of disorders associated with walking and growth disturbances that become evident during the second year of life.

Summary:
Epidemiology
Prevalence is estimated at around 1/100,000.
Clinical description
The disorders are characterized by platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localization and severity of involvement of the affected metaphyses. The most common form is the Kozlowski type of spondylometaphyseal dysplasia (see this term). The form of spondylometaphyseal dysplasia referred to as the 'corner fracture' or Sutcliffe type (see this term) results in very severe coxa vara. A rarer form (Algerian or Schmidt type; see this term) appears to have more predominant knee involvement. Lastly, some moderate forms are at present not well classified and other forms have also been identified, including type A4, and an axial type associated with retinitis pigmentosa and optic atrophy (see these terms). Spondylometaphyseal dysplasia may also occur in association with other clinical manifestations such as facial dysmorphism and dentinogenesis imperfecta (see this term).
Etiology
Kozlowski type of spondylometaphyseal dysplasia results in severe kyphoscoliosis and is caused by mutations in the TRPV4 gene (locus 12q24.1).
Genetic counseling
Kozlowski type of spondylometaphyseal dysplasia is transmitted in an autosomal dominant manner, as well as the form of spondylometaphyseal dysplasia referred to as the 'corner fracture' or Sutcliffe type and the Algerian (or Schmidt) type. Some moderate forms also generally appear to be transmitted as autosomal dominant traits. Several autosomal recessive forms have also been identified, including type A4 and an axial type associated with retinitis pigmentosa and optic atrophy. A form of spondylometaphyseal dysplasia with X-linked transmission has also been reported (see this term).

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Spondyloperipheral dysplasia-short ulna syndrome is a rare, genetic, primary bone dysplasia, with highly variable phenotype, typically characterized by platyspondyly, brachydactyly type E changes (short metacarpals and metatarsals, short distal phalanges in hands and feet), bilateral short ulnae and mild short stature. Other reported features include additional skeletal findings (e.g. midface hypoplasia, degenerative changes in proximal femora, limited elbow extension, bilateral sacralization of L5, clubfeet), as well as myopia, hearing loss, and intellectual disability.


A rare headache resulting from a cerebrospinal fluid (CSF) leak with subsequent lowered CSF pressure, characterized clinically by severe headaches which typically worsen upon standing up and get better when lying down. Additional features may include neck stiffness, nausea, vomiting, vertigo, tinnitus, visual disturbances, and cognitive abnormalities, among others, as sagging and displacement of the brain can lead to a variety of lesions and symptoms.


A rare neurologic disorder characterized by spontaneous periodic hypothermia and hyperhidrosis in the absence of hypothalamic lesions.

Summary:
Epidemiology
Spontaneous periodic hypothermia (SPH) prevalence is unknown but to date more than 50 cases of spontaneous periodic hypothermia have been described in the world literature.
Clinical description
SPH can occur at any age (ranging from 6 months to 62 years). The clinical manifestations of the disease comprise recurrent episodes of hypothermia (core temperature <35°C) with profuse sweating, nausea and vomiting, that occur in the absence of any detectable infectious or endocrine cause. Periodicity of hypothermic episodes may range from hours to years and the episodes themselves may last from hours to weeks. The sensation is usually experienced as a ''funny feeling'' in the head and is described as powerful, consuming and combined with a sense of weakness, incoordination and gait unsteadiness. Additional features include drowsiness, deep sleep, hypothermic syncope, mild bradycardia, and pale and cool skin. There are usually no associated complaints of diarrhea, confusion, wheezing, rash, seizure activity, shivering or shakiness. Polyuria and polydipsia during the attacks have been described in only one case. Recurrent hypothermia attacks were reported in two siblings.
Etiology
The exact pathophysiological mechanism for this syndrome is still not understood. Postulated mechanisms include hypothalamic dysfunction, neurochemical abnormalities, inflammatory processes, and epileptic activity.
Diagnostic methods
Diagnosis includes physical and systemic examinations which show a pale, cold skin and normal blood count and electrolyte levels. Imaging studies may in some cases reveal confluent lesions in the corpus callosum and a circumscribed lesion in the right posterior thalamus. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels in cerebrospinal fluid may be below the normal ranges.
Differential diagnosis
Differential diagnosis of SPH severe hypothyroidism, hypoglycemia or attacks of diabetic ketoacidosis.
Management and treatment
There is no cure for SPH. Management is mainly supportive and includes re-warming with a warm blanket. Carbamazepine, clonidine, cyproheptadine, glycopyrrolate, bromocriptine, chlorpromazine, beta1 blockers or sympathectomy are used with varying responses.
Prognosis
SPH is a benign disease and may cease spontaneously. Some patients have been reported to have hyperthermia attacks during the course of the disease.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Ozgur DUMAN


Sporadic adult-onset ataxia of unknown etiology

A rare non-hereditary degenerative ataxia disease characterized by a slowly progressive cerebellar syndrome (with ataxia of stance and gait, upper limb dysmetria and intention tremor, ataxic speech, and oculomotor abnormalities), presenting in adulthood (at around 50 years of age), that is not due to a known cause. Extracerebellar symptoms (e.g., decreased vibration sense and absent or decreased ankle reflexes), polyneuropathy and mild autonomic dysfunction may also be present. Mild cognitive impairment has also rarely been reported.


A rare sporadic human prion disease characterized by rapidly progressive cognitive impairment in combination with variable neurologic signs and symptoms including myoclonus, visual or cerebellar problems, pyramidal or extrapyramidal features, or akinetic mutism. Brain imaging may show high signal intensity in caudate, putamen, and/or cortical regions, and a typical EEG pattern consisting of generalized periodic sharp wave complexes is observed in many cases. The disease is invariably fatal within less than two years. Neuropathologic examination reveals deposition of abnormal prion protein in brain tissue, as well as spongiform change and massive neuronal loss and gliosis.


A rare sporadic human prion disease characterized by adult onset of progredient neurodegeneration presenting as a combination of psychiatric, sleep, and oculomotor disturbances, with development of progressive cognitive impairment (the predominantly affected cognitive domains being memory, temporal and/or spatial orientation, language, executive functions, and attention), postural instability, and sometimes additional motor abnormalities and autonomic hyperactivity, in the course of the disease. Bilateral thalamic hypometabolism on FDG-PET imaging and positive prion seeding activity in the cerebrospinal fluid are present in many cases. The disease is fatal within typically two to three years.


Sporadic fetal brain disruption sequence is a rare, non-syndromic, central nervous system malformation disorder characterized by severe microcephaly (average occipitofrontal circumference -5.8 SD), overlapping sutures, keel-like occipital bone prominence, scalp rugae with normal hair pattern and signs of neurological impairment. Brain imaging may show ventriculomegaly, cortical tissue deficit, and hydranencephaly.


A rare neurologic disease characterized by excessive startle response to unexpected auditory, tactile or visual stimuli, associated with hyperreflexia.


Sporadic infantile bilateral striatal necrosis

Sporadic infantile bilateral necrosis is the sporadic form of infantile bilateral striatal necrosis (IBSN; see this term), a syndrome of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis.

Summary:
Epidemiology
Prevalence has been estimated at 1-9/1,000,000.
Clinical description
Sporadic IBSN can occur any time from the neonatal period through childhood and even in adolescence. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus.
Etiology
The disease is associated with abrupt neurologic dysfunction following an acute systemic febrile illness such as a mycoplasma, measles or streptococcus infection.
Diagnostic methods
Diagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.
Differential diagnosis
Differential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.
Management and treatment
Treatment is based on treatment of the causal infection.
Prognosis
Prognosis is variable, with either gradual improvement in symptoms and complete recovery, observed after recovery from the infection, or severe neurological sequelae.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Rachel STRAUSSBERG


A rare, isolated, non-familial pheochromocytoma/paraganglioma tumor arising from neuroendocrine chromaffin cells of the adrenal medulla (pheochromocytoma) or from extra-adrenal chromaffin tissue (paraganglioma). The majority of these tumors are benign and the presenting symptoms are typically caused by the increased catecholamine production of the tumor, including hypertension (often paroxysmal), tachycardia, anxiety and/or excessive sweating.


A rare thoracic malformation characterized by an underdeveloped and abnormally high scapula due to its failure to descend to the regular position during embryonic development. The defect is in most cases unilateral and may be associated with other abnormalities, such as deformities of vertebral bodies, fused or absent ribs, or genitourinary anomalies, among others.


Squamous cell carcinoma of gallbladder and extrahepatic biliary tract

A rare hepatic and biliary tract tumor, arising either in the gallbladder itself or in the epithelium lining the extrahepatic biliary tree, the cystic duct and peribiliary glands. It is characterized by a substantial keratinization with abundant keratohyalin pearls and central deposition of dense keratin material within infiltrative nests and locally aggressive nature. In the early stages of the disease symptoms are vague and nonspecific (abdominal pain, jaundice and vomiting). In the advanced stages it may present with a bulky tumor and symptoms of adjacent organ involvement.


Squamous cell carcinoma of liver and intrahepatic biliary tract is an extremely rare, primary, malignant liver and biliray tract epithelial tumor originating in the intrahepatic bile duct epithelium histologically characterized by the presence of keratinization and/or intracellular bridges. Patients typically present abdominal pain in the right upper quadrant, jaundice, nausea, vomiting, anorexia, weight loss, fever and/or dyspepsia.


A rare epithelial tumor of the exocrine pancreas, histologically characterized by presence of keratinization and/or intracellular bridges and lymphovascular and perineural invasion, as well as high metastatic potential. Patients present with upper abdominal and back pain, anorexia, weight loss, nausea, vomiting and jaundice.


Squamous cell carcinoma of the anal canal is a rare epithelial intestinal neoplasm, arising from squamous epithelial cells in the anal canal, with variable macroscopic appearance, ranging from small, benign lesions (that mimick fissures, hemorrhoids or anorectal fistulae) to a large, exophytic or ulcerating tumor localized within the anal canal. Patients may be asymptomatic or present difficulty to defecate, anal bleeding, pain and/or discharge, and often have a history of chronic anal fistulae and abscesses, Crohn's disease, hemorrhoids, or, especially in younger patients, immunosuppression (such as HIV infection). Association with HPV infection is commonly reported.


A rare epithelial tumour of the colon arising from squamous cells of the colorectal epithelium without the presence of squamous-lined fistulous tracts or a proximal extension of an anal squamous cell carcinoma. It usually presents with nonspecific symptoms, such as anorexia, weight loss, abdominal pain, changes of bowel habits, hematochesia or melena. Cases of severe, symptomatic hypercalcemia have been reported.


Squamous cell carcinoma of the corpus uteri is a rare cancer of corpus uteri composed of squamous cells of varying degree of differentiation that usually affects postmenopausal women and presents with abnormal vaginal discharge, dysfunctional bleeding, abdominal pain and distension. It is often associated with cervical stenosis and pyometra.


Squamous cell carcinoma of the esophagus

Esophageal squamous cell carcinoma (ESCC) is a type of esophageal carcinoma (EC; see this term) that can affect any part of the esophagus, but is usually located in the upper or middle third.

Summary:
Epidemiology
ESCC has an estimated annual incidence of 1/29,400.
Clinical description
The average age of onset of ESCC is between the ages of 60 to 70 years and it is more frequently seen in males. It is usually asymptomatic until an advanced disease stage with common presenting symptoms being dysphagia (at first with solids then progressing to fluids) and weight loss. Less commonly odynophagia, hoarseness of voice, coughing, or chest pain can be presenting features. Tumors are typically found in the middle and the upper third of the esophagus.
Etiology
The exact etiology is unknown. Cigarette smoking and alcohol abuse are the principal risk factors. There is also an association with idiopathic achalasia (see this term), a motility disorder of the esophagus.
Diagnostic methods
Endoscopy and a biopsy will establish the diagnosis. For staging, a computed tomography (CT) scan of the neck, chest and abdomen, or CT combined with a positron emission tomography (CT-PET) scan will identify the primary tumor in most cases as well as any spread to the lymph nodes and organs such as the liver, lungs and bone. Endoscopic ultrasound (EUS), the combination of an ultrasound probe on an endoscope, is also increasingly used for staging, and is of particular value for early cancers. In upper or mid-esophageal tumors where there is a possibility of invasion of the airway (trachea or bronchi) a bronchoscopy may also be required.
Differential diagnosis
Differential diagnoses include idiopathic achalasia (see this term), benign esophageal stricture, an esophageal web, and occasionally lung cancer.
Management and treatment
Treatment may be with curative intent when the disease is confined to the esophagus and even when local nodes of the primary tumor are involved, and when the patient is fit enough for treatment. Treatment with palliative intent, targeted on symptom control and quality of life, but not cure, is the mainstay of treatment when the disease is advanced or incurable, or the patient is unfit for therapy due to significant co-morbidities. The traditional treatment of ESCC is surgical resection; this is usually via a transthoracic resection, and occasionally by a neck incision. In some cases a transhiatal esophagectomy is performed. The use of minimally invasive approaches to perform these operations is increasing in use. There is also an increasing use of chemotherapy or of the combination of chemotherapy and radiotherapy before and after surgery. A number of clinical trials support this practice, particularly where the tumor is locally advanced, and this is increasingly the standard of care in Europe and North America. The chemotherapeutic drugs most often used in combination are epirubicin, cisplatin and 5-fluorouracil (known as ECF). Capecitabine and oxaliplatin are less toxic agents that can be used in those with cardiac and renal problems. There is also an increasing use of radical, high-dose radiotherapy and chemotherapy for ESCC which avoids a surgery, and the outcomes are equivalent to surgical or multimodality approaches. For palliative approaches, self-expanding metal stents (SEMS) can relieve dysphagia, and chemotherapy, radiation therapy and laser-based approaches are also considered. Palliation may also involve nutritional support via feeding devices such as percutaneous endoscopic gastrostomy (PEG) tubes.
Prognosis
As ESCC is usually diagnosed at an advanced disease stage, the overall prognosis is poor, with an overall 5-year survival of between 10-20%. In patients treated with curative intent the cure rate currently approaches 40%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Claire DONOHOE  - Dr John REYNOLDS


Squamous cell carcinoma of the hypopharynx

A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, most commonly located in the piriform sinus, less frequently the posterior pharyngeal wall or the postcricoid area. The tumor can spread directly to adjacent structures or metastasize via lymphatic and blood vessels to regional lymph nodes, or lung, liver, and bones, respectively. Primary risk factors are tobacco smoking and (to a lesser extent) alcohol consumption. Patients may present with odynophagia, dysphagia, signs and symptoms related to a neck mass, voice changes, otalgia, and constitutional symptoms.


A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, most commonly located in the supraglottis or glottis. The tumor can spread directly to adjacent structures or metastasize via lymphatic and blood vessels to regional lymph nodes, or lung, liver, and bones, respectively. Primary risk factors are tobacco smoking and (to a lesser extent) alcohol consumption. Patients may present with hoarseness, dyspnea, stridor, dysphagia, hemoptysis, or odynophagia.


A rare head and neck tumor characterized by a firm infiltrative neoplasm with squamous differentiation, most commonly arising at the vermilion border of the lower lip. Patients present with a usually asymptomatic lesion of variable appearance, such as ulceration, a focus of whitish thickening, a dry atrophic area, or an area of persistent chapping and localized flaking and crusting. Carcinomas of the lower lip tend to progress slowly (as opposed to those of the upper lip). Invasion of adjacent structures, including perineural spread, is typical, with a variable rate of metastasis, depending on the location.