CACNA1A – Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6; [MONDO:0008457]) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansions in the CACNA1A gene ([HGNC:1388]). Affected individuals present with adult‐onset progressive cerebellar ataxia (mean onset 45–55 y), dysarthria, nystagmus, external ophthalmoplegia, and occasionally parkinsonism. Brain MRI consistently shows isolated cerebellar atrophy without multisystem involvement. Clinical severity and age at onset inversely correlate with repeat length, supporting a toxic gain‐of‐function mechanism of expanded polyglutamine tracts (r = −0.87)(PMID:9371901).

Genetic evidence spans multiple independent cohorts: a Spanish pedigree with 13 affected and stable transmission over 29 meioses(PMID:10051016); nine German kindreds and four sporadic cases with expanded alleles (22–28 repeats)(PMID:9436730); seven Japanese families with 22–25 repeats exhibiting pure cerebellar phenotypes(PMID:9600677); and 12 French patients in 91 families confirming SCA6 as a minor locus but with strong genotype–phenotype correlation(PMID:9371901).

Inheritance is autosomal dominant with high intergenerational stability of expanded repeats. Segregation is demonstrated in large families with complete cosegregation of the expanded allele and phenotype over 29 informative meioses(PMID:10051016). Homozygous individuals (25/25 repeats) exhibit earlier onset (27 y) than heterozygotes (44 y) but retain intra‐family phenotypic variability, highlighting additional genetic modifiers(PMID:10945665).

The variant spectrum comprises small CAG expansions ranging from 21 to 30 repeats in exon 47 of CACNA1A, with repeat size inversely correlating with age at onset. Meiotic stability is high, though rare maternal instability and anticipation have been reported (22→23 repeats)(PMID:16310805). No recurrent point mutations are associated with SCA6.

Functional studies provide concordant experimental evidence: positron emission tomography with ¹¹C‐flumazenil and ¹⁸F‐FDG demonstrates cerebellar glucose hypometabolism and decreased GABA-A receptor binding in SCA6 patients, mirroring mouse models of CACNA1A dysfunction(PMID:26675662). These findings support a toxic gain‐of‐function mechanism leading to Purkinje cell dysfunction.

A conflicting case of a homozygous patient with retinitis pigmentosa and ataxia suggests that retinal degeneration may be secondary to another recessive trait rather than SCA6 itself, underscoring careful phenotypic interpretation(PMID:12081723).

Overall, the association between CACNA1A CAG repeat expansions and SCA6 is supported by robust genetic and experimental data across diverse populations. Molecular testing for CAG repeat length in CACNA1A is a reliable diagnostic tool, enables predictive testing, and informs family counseling. Key take-home: Direct PCR‐based analysis of CACNA1A CAG expansions is clinically useful for confirming SCA6 and guiding genetic counseling.

References

• Neurology • 1997 • Clinical and molecular features of spinocerebellar ataxia type 6. PMID:9371901
• Journal of medical genetics • 1999 • Genetics of the SCA6 gene in a large family segregating an autosomal dominant "pure" cerebellar ataxia. PMID:10051016
• Journal of neurology, neurosurgery, and psychiatry • 1998 • Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. PMID:9436730
• Journal of the neurological sciences • 1998 • Clinical and molecular genetic study in seven Japanese families with spinocerebellar ataxia type 6. PMID:9600677
• Clinical genetics • 2000 • Sisters homozygous for the spinocerebellar ataxia type 6 (SCA6)/CACNA1A gene associated with different clinical phenotypes. PMID:10945665
• Journal of the neurological sciences • 2006 • Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case. PMID:16310805
• BBA clinical • 2014 • An altered GABA-A receptor function in spinocerebellar ataxia type 6 and familial hemiplegic migraine type 1 associated with the CACNA1A gene mutation. PMID:26675662
• Clinical genetics • 2002 • A patient homozygous for the SCA6 gene with retinitis pigmentosa. PMID:12081723

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