Spinocerebellar ataxia (repeat expansion analysis)

The spinocerebellar ataxias tested here present with progressive cerebellar ataxia, dysarthria and oculomotor abnormalities, with extracerebellar features that differ by type. SCA1 shows progressive cerebellar ataxia, dysarthria and later bulbar dysfunction. SCA2 is marked by nystagmus and slow saccadic eye movements. SCA3 adds pyramidal signs, a dystonic-rigid extrapyramidal syndrome, peripheral amyotrophy, generalised areflexia and progressive external ophthalmoplegia. SCA6 is an adult-onset, slowly progressive and relatively pure cerebellar ataxia with dysarthria and nystagmus. SCA7 is distinguished by accompanying cone-rod retinal dystrophy with progressive visual loss. SCA17 is characterised by ataxia, dementia and involuntary movements including chorea and dystonia.

Reliable type-specific population prevalence figures for the spinocerebellar ataxias tested here are not well established and vary considerably between populations and ancestries.

Each tested type results from an expanded repeat in a distinct gene: SCA1 (ATXN1), SCA2 (ATXN2), SCA3 (ATXN3), SCA6 (CACNA1A), SCA7 (ATXN7) and SCA17 (TBP). In SCA1, SCA2, SCA3, SCA6 and SCA7 the expansion is a translated CAG (polyglutamine) repeat; SCA17 results from an expanded CAG/CAA repeat in TBP. Anticipation due to repeat instability is a well-recognized feature of SCA1, SCA2, SCA3 and SCA7, is generally not observed in SCA6, and has been reported less consistently in SCA17.

All six spinocerebellar ataxia types tested by this panel are inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the expanded allele. Anticipation, with earlier onset and greater severity in successive generations, is seen in some types, as mentioned above. Reduced-penetrance alleles are a recognized feature of SCA17 (TBP). Borderline or intermediate repeat sizes have also been described for several other repeat-expansion SCAs.

Where an autosomal dominant cerebellar ataxia is suspected, this panel sizes the disease-associated repeat in the genes underlying SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. A pathogenic expansion confirms the specific type, while a normal result does not exclude ataxias caused by other genes or mechanisms.

Main differential diagnoses include:

• : early-onset recessive ataxia from an FXN repeat expansion; tested under a separate analysis.
• Fragile X-associated tremor/ataxia syndrome (FXTAS): late-onset ataxia and tremor in FMR1 premutation carriers; tested under a separate analysis.
• RFC1 spectrum disorder (CANVAS): recessive late-onset ataxia with neuropathy and vestibular involvement; RFC1.
• Dentatorubral-pallidoluysian atrophy and further repeat-expansion SCAs not on this panel; ATN1 and others.
• Acquired and non-repeat genetic ataxias: gene varies.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic repeat expansion, clarifying which spinocerebellar ataxia type is present and providing a basis for genetic counselling.
• A confirmed molecular diagnosis may inform management, surveillance and genetic counselling.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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