IllnessSpinocerebellar ataxia, autosomal dominant; differential diagnosis

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[NGS + after analyses of most frequent repeat expansions]

Autosomal-dominantly inherited cerebellar ataxias (ADCAs) or spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders characterized by dysfunction of the cerebellum and brainstem aas well as associated tracts and connections. All patients with SCAs present with cerebellar ataxia. Other symptoms are variable and sometimes disease-specific, including extrapyramidal features, long pathway symptoms, peripheral neuropathy, cognitive decline and seizures. The so-called polyglutamine ataxias (intragenically triggered by prolonged CAG repeats), including the comparatively very common SCA1, SCA2, and SCA3, are progressive disorders and result in shortened life expectancy. Several other autosomal dominant ataxias cause significant morbidity but are not associated with earlier death. SCA6 is the most common form resulting in virtually isolated cerebellar ataxia. In SCA7, the ataxia is associated with pigmentary retinopathy. The next most common forms involve SCA17 and SCA12. All of the above SCA forms are caused by expanded CAG repeat blocks, with virtually every SCA entity having its own boundaries between physiological polymorphism and pathogenic expansion. Additional and rarer SCA forms are triggered either by expansion of other simple repetitive elements or by point mutations in the various SCA genes. In total, more than 40 dominantly inherited SCAs are currently defined by molecular genetics, and the diagnostic yield amounts up to 60%. Nevertheless, a negative DNA result does not constitute exclusion of the clinical diagnosis.

References: https://www.ncbs.nlm.nih.gov/books/NBK1138/

• Alias: Ataxia with cerebellar anomalies
• Alias: Cerebellar ataxia, AD
• Alias: SCA, AD
• Allelic: Alternating hemiplegia of childhood 2 (ATP1A3)
• Allelic: Brugada syndrome 9 (KCND3)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2T (MME)
• Allelic: Combined oxidative phosphorylation deficiency 13 (PNPT1)
• Allelic: Congenital hypotonia, epilepsy, developmental delay + digital anomalies (ATN1
• Allelic: Deafness, AR 70, with/-out adult-onset neurodegeneration (PNPT1)
• Allelic: Dystonia-12 (ATP1A3)
• Allelic: Epileptic encephalopathy, early infantile, 42 (CACNA1A)
• Allelic: Episodic ataxia, type 2 (CACNA1A)
• Allelic: Gillespie syndrome (ITPR1)
• Allelic: Hydrocephalus, congenital, 1 (CCDC88C)
• Allelic: Ichthyosis, spastic quadriplegia + mental retardation (ELOVL4)
• Allelic: Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Allelic: Migraine, familial hemiplegic, 1 (CACNA1A)
• Allelic: Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia (CACNA1A)
• Allelic: Neuropathy, hereditary sensory, type IE (DNMT1)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Spastic ataxia 5, AR (AFG3L2)
• Allelic: Spinocerebellar ataxia, AR 13 (GRM1)
• Allelic: Spinocerebellar ataxia, AR 14 (SPTBN2)
• Allelic: Spinocerebellar ataxia, AR 16 (STUB1)
• Allelic: Stargardt disease 3 (ELOVL4)
• CAPOS syndrome (ATP1A3)
• Cerebellar ataxia, deafness + narcolepsy, AD (DNMT1)
• Dentatorubral-pallidoluysian atrophy (ATN1^_CAG)
• Developmental + epileptic encephalopathy 47 (FGF12)
• Dystonia 4, torsion, AD (TUBB4A)
• Machado-Joseph disease (ATXN3_CAG)
• Spinocerebellar ataxia 1 (ATXN1_CAG)
• Spinocerebellar ataxia 10 (ATXN10_ATTCT)
• Spinocerebellar ataxia 11 (TTBK2)
• Spinocerebellar ataxia 12 (PPP2R2B)
• Spinocerebellar ataxia 13 (KCNC3)
• Spinocerebellar ataxia 14 (PRKCG)
• Spinocerebellar ataxia 15 (ITPR1)
• Spinocerebellar ataxia 17 (TBP_CAG)
• Spinocerebellar ataxia 19 (KCND3)
• Spinocerebellar ataxia 2 (ATXN2_CAG)
• Spinocerebellar ataxia 21 (TMEM240)
• Spinocerebellar ataxia 23 (PDYN)
• Spinocerebellar ataxia 25 (PNPT1)
• Spinocerebellar ataxia 26 (EEF2)
• Spinocerebellar ataxia 27A (FGF14)
• Spinocerebellar ataxia 27B, late-onset (FGF14)
• Spinocerebellar ataxia 28 (AFG3L2)
• Spinocerebellar ataxia 29, congenital nonprogressive (ITPR1)
• Spinocerebellar ataxia 31 (BEAN1)
• Spinocerebellar ataxia 34 (ELOVL4)
• Spinocerebellar ataxia 35 (TGM6)
• Spinocerebellar ataxia 36 (NOP56_GGCCTG)
• Spinocerebellar ataxia 37 (DAB1_ATTTC)
• Spinocerebellar ataxia 38 (ELOVL5)
• Spinocerebellar ataxia 40 (CCDC88C)
• Spinocerebellar ataxia 41 (TRPC3)
• Spinocerebellar ataxia 42 (CACNA1G)
• Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (CACNA1G)
• Spinocerebellar ataxia 43 (MME)
• Spinocerebellar ataxia 44 (GRM1)
• Spinocerebellar ataxia 45 (FAT2)
• Spinocerebellar ataxia 46 (PLD3)
• Spinocerebellar ataxia 47 (PUM1)
• Spinocerebellar ataxia 48 (STUB1)
• Spinocerebellar ataxia 5 (SPTBN2)
• Spinocerebellar ataxia 50 (NPTX1)
• Spinocerebellar ataxia 6 (CACNA1A)
• Spinocerebellar ataxia 7 (ATXN7_CAG)
• Spinocerebellar ataxia 8 (ATXN8OS_CTG)
• Spinocerebellar ataxia 8 (ATXN8_CAG)
• Spinocerebellar ataxia, AR 20 [both, AD + AR; biallelic more severe disease; panelapp] 20 (SNX14)