SPINOCEREBELLAR ATAXIA TYPE-6 - GENOTYPE AND PHENOTYPE IN GERMAN KINDREDS

Objective-Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominan t cerebellar ataxia (ADCA) of which the mutation causing the disease h as recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the alpha(1A)-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenoty pe Methods-The SCA6 mutation was investigated in 69 German families wi th ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. Results-Expanded alleles were found in nine of 69 f amilies as well as in four patients with sporadic disease. Disease ons et ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar s ystems were only mildly affected with external ophthalmoplegia, spasti city, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. Conclusi ons-This study provides the first detailed characterisation of the SCA 6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SC A3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical inve stigations. In Germany, SCA6 accounts for about 13% of families with A DCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinicall y as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutatio n also in patients with putative sporadic ataxia.