SCA6 is caused by moderate CAG expansion in the alpha1A-voltage- dependent calcium channel gene

Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage-dependent calcium channel gene (CACNL1A4) have been identified in apreviously unmapped type of SCA which has been named SCA6. We investigatedthe (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadicataxia and in 46 German families with dominantly inherited SCA which do notharbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)nexpansion was identified in 32 patients most frequently with latemanifestation of the disease. The (CAG)n stretch of the affected allelevaried between 22 and 28 trinucleotide units and is therefore the shortesttrinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)nrepeat length is inversely correlated with the age at onset. In 11 parentaltransmissions of the expanded allele no repeat instability has beenobserved. Repeat instability was also not found for the normal alleleinvestigating 431 meioses in the CEPH families. Analyzing 248 apparentlyhealthy octogenerians revealed one allele of 18 repeats which is thelongest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutationcauses the disease in approximately 10% of autosomal dominant SCA inGermany. Most importantly, the trinucleotide expansion was observed in fourataxia patients without obvious family history of the disease whichnecessitates a search for the SCA6 (CAG)n expansion even in sporadicpatients.