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Classification of Ataxias (Cerebellar and Spinocerebellar Degenerations)
05 November 2004
Primary Inherited Autosomal recessive Autosomal dominant Sex linked Sporadic Multisystem atrophy Idiopathic cerebellar degeneration
Secondary Metabolic disorders Mitochondrial disease Toxic disorders Vascular disease Infective disorders Prion disease Paraneoplastic cerebellar degeneration
Classification of inherited ataxias Autosomal recessive Friedreich’s ataxia Spinocerebellar ataxia with retained tendon reflexes Spinocerebellar ataxia with isolated Vitamin E deficiency Ataxia telengiectasia Other rare recessive ataxias Hypogonadotrophic hypogonadism (Matthews – Rundle syn) Learning disability, optic atrophy, spasticity (Behr’s syn) Learning disability, cataracts, short stature, myopathy (Marinesco Sjogren syn) Deafness Deafness with neuropathy
Autosomal Dominant Cerebellar ataxia (ADCA / Harding’s Classification)
Harding A.E. Classification of the hereditary ataxias and paraplegias. Lancet1983: 1151-55. Harding A.E The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of “the Drew family of Walworth”. Brain 1982; 105: 1-28.
ADCA I Pure cerebellar syndrome plus cognitive impairment, slow saccades, ophthalmoplegia, optic atrophy, facial fasciculation, bulbar weakness, chorea, dystonia, Parkinsonism, pyramidal signs, peripheral neuropathy, amyotrophy. SCA 1: normal 19-36 CAG on Chr 6p, abnormal 42-81 (ataxin ) SCA2: CAG expansion on Chr 12q SCA3 (Machado – Joseph, Groote Eylandt Disease): CAG rpt on Chr 14q; commonest spinocerebellar ataxia SCA4: Chr 16q SCA5: Chr 11centromere SCA6: CAG expansion on Chr 19p with close relationship to familial hemiplegic migraine, episodic ataxia type 2, responsive to acetazolamide.
ADCA II / SCA7 Ataxia with retinal degeneration Chr 3p
ADCA III Pure cerebellar syndrome after age 50.
ADCA IV Probable mitochondrial encephalopathy (ataxia, myoclonus, deafness, dementia, optic atrophy, myopathy, neuropathy) DRPLA (Dentatorubropallidoluysian atrophy) CAG expansion on Chr 12p Mostly Japanese population Ddx is Huntington’s Ataxia, chorea, myoclonic epilepsy, dementia.
Episodic Ataxia (EA) EA 1: ataxia for seconds or minutes Provoked by startle or exercise Persistent myokymia in hand and face Missense point mutation for K channel on Chr 12p Acetazolamide responsive EA 2: ataxia for hours or days Progressive cerebellar syn Familial hemiplegic migraine, CADASIL as possible allelic variants Acetazolamide responsive
Differentiation of SCA 1, 2, 3. Pyramidal tract signs, pale discs, dysphagia: SCA 1> SCA2,3 VEP, MEP: SCA 1> SCA2,3 SSEP: abnormal in SCA 1,2, 3 Abnormal NCS: abnormal in SCA 1,2, 3 56% SCA1,2 reduced saccade velocity cf SCA3 MRI in SCA2:
severe OPCA
Mendelian autosomal dominant pattern Trinucleotide sequence repeats Anticipation: increase triplet expansion size with each successive generation Increase triplet expansion size results in earlier clinical manifestation and worse prognosis. Poorer outcome if inherited from father Within ADCA I much clinical, pathological heterogeneity; marked intrafamilial variability. Genetic diagnosis is important for : Formal diagnosis Prognosis Genetic counselling.
Diseases with Trinucleotide Sequence Repeats Friedreich’s ataxia (AR) Fragile X syndrome Myotonia dystrophica ADCA Kennedy’s syndrome Huntington’s disease / Westphal variant
Clinical features that can indicate specific spinocerebellar ataxia (SCA) genotypes
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