Sunday, February 14, 2010

Autosomal dominant ataxias with known causation

Most common types are SCA I,II, III, VI which comprise > 50 % cases in USA.  * indicates caused by polyglutamine CAG repeat expansion

SCA I--*-- begins as gait disorder, progresses to four extremity ataxia with dysarthria leaving patient wheelchair bound within 15-20 years.There is phenotypic variability and anticipation (genetically).  Clinically there is involvement of cerebellum with neuronal dropout of Purkinje cell layer and clinical involvement of the brainstem.  No supratentotial involvement.  Not as common as type II but well worked out molecularly,

SCA II--*--characterized by ataxia, dysarthria, slow saccades and neuropathy.  Originally Cuban description.  Very common worldwide, especially in India.  Slow saccades are not pathognomonic, they also are seen in SCA I and III.   Dementia, areflexia, myokymia also are seen. Gene expansion includes cytoplasmic protein ataxin, function of which is unknown.  Anticipation is marked, and disease may present in one generation in old age, in the next much earlier.  Number of repeats are 35-77 , with 32-34 "zone of reduced penetrance."

SCA III--*--Very common, is aka Machado-Joseph disease.  Presents with ataxia, eye movement abnormalities (bulging eyes, opthalmoparesis, staring eyes), speech and swallowing abnormalities.  Pathologic abnormalities include cerebellar afferent and efferents, pontine and dentate nuclei, substantia nigra, subthalamic, GP, cranial motor nuclei and anterior horn cells.  Ataxin 3 gene is at fault.  Repeats: normal 12-42, high is 52-84.  Early onset rigidity and dystonia (largest expansions), middle onset adult ataxia, late onset neuropathy (smallest expansions).  A few patients have Parkinson's that is dopamine responsive and even fewer have RLS.  Peripheral involvement is especially variable.  MRI shows range from fourth ventricle enlargement to severe olive sparing spino pontine cerebellar atrophy.

SCA-- V-- "Lincoln family ataxia"--slowly progressive dominant ataxia found in grandparents of Lincoln.  SPTBN2 gene ecoding B III spectrin is at fault. 

SCA VI  --*--  milder disease, pure cerebellar associated with normal lifespan.  Presentation is gaze evoked nystagmus, dysarthria, onset at age 50 or so, impaired vibratory and position sense.Its fairly common in Japan and in Germany.  Caused by expansion/repeat in voltage dependent calcium channel,same gene  that causes episodic ataxia type 2 and familial hemiplegic migraine.  However, mutations in these conditions in the same gene are different mutations.

SCA 7--*-- cerebellar brainstem disease associated with retinal degeneration and blindness.  It has striking instability of transmission especially with paternal transmission, with cases in utero and in childhood.

SCA 8--*-- classical presentation of disease with gait and limb ataxia, swallowing speech and eye movement abnormalities.  Most have progressive ataxia.

SCA 10 --*-- Mexicans with cerebellar symptoms and seizures.  Extremely large expansion is found in SCA 10 gene. Ashizawa.

SCA 11--*--  2 British families reported with benign gait and limb ataxia.  TTBK2 gene.

SCA 12 --*--PP2R2 gene with dominant ataxia presenting with upper extremity tremor, progressing to head tremor, bradykinesia, abnormal eye movements.  Onset 8-55 years.

SCA 13 --*-- dominant ataxia, may present in childhood with MR, dysarthria, nystagmus, +/- hyperreflexia.  Due to KCNC3 gene mutation in voltage gated K channel subunit.

SCA 14 --not repeat--slowly progressive ataxia with dysarthria in early adulthood.  May be pure cerebellar or accompanied by myokymia, hyperreflexia, axial myoclonus, dystonia and vibratory sense loss. 

SCA 15-16-- allelic (ie same allele) disorder occurring in Austrailian and Japanese families, slowly progressive pure cerebellar disorder.  Dysarthria, horizontal gaze evoked nystagmus, sometimes head tremor.  Disease is due to deletions in IPTR gene

SCA 17 --*--Widespread cerebral/cerebellar dysfunction, rare in US, more common in Japan.  Presents with gait and limb ataxia, psychiatric dysfunction, EPS, seizures, may resemble Huntington;s disease.  MRI shows widespread cerebral and cerebellar dysfunction.  Onset in mid to young adulthood.

SCA 26 -- Norwegian pure cerebellar ataxia that maps closely to gene affecting Cayman ataxia and SCA 6 with Purkinje cell degeneration. 

SCA 27-- Dutch disease manifests with hand tremor in childhood.

DRPLA-- *--  progressive ataxia, choreoathetosis, dementia, seizures, myoclonus, and dystonia. Before age 20 there are almost always seizures and a progressive myoclonic seizure like presentation.  Older patients get ataxia with choreoathetosis and dementia.  More common in Japan, but Haw River phenotype is an African American family in the Carolinas with seizures and cerebral calcifications.

episodic ataxias--EA1 and EA2 are due to mutations in K and Ca channel genes.  EA1-- patients ahve minutes of ataxia due to stress, exercise or change in posture. Patients also may have myokymia.   KCNA1 gene. EA2 has ataxia that lasts days , precipitated by stress, exercise or fatigue and is due to mutation of same gene as SCA 6 (CACNA1A4 gene). Acetozolamide may help.  Other EA's with prominent vertigo also are described.

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