Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 64; no. 1; pp. 67 - 73
• Main Authors: Schöls, Ludger, Krüger, Rejko, Amoiridis, Georgios, Przuntek, Horst, Epplen, Jörg T, Riess, Olaf
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.1998; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Age; Aged; Ataxia; Atrophy; Biological and medical sciences; Calcium Channels - genetics; Case-Control Studies; Chromosomes; Chromosomes, Human, Pair 19 - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; DNA - genetics; Dysarthria; Dysphagia; electrophysiology; Families & family life; Female; Gait; Gene Frequency; Genes, Dominant - genetics; Genetic testing; genetics; Genotype; Genotype & phenotype; Germany; Humans; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Mutation; Mutation - genetics; Neurology; Patients; Pedigree; Peripheral neuropathy; Phenotype; Spasticity; spinocerebellar ataxia; Spinocerebellar Degenerations - classification; Spinocerebellar Degenerations - genetics; Spinocerebellar Degenerations - pathology; Spinocerebellar Degenerations - physiopathology; Trinucleotide Repeats - genetics; Germany; Denmark; Calcium; Sporadic; Trinucleotide; German; Ionic channel; Genetic determinism; Gene; Spinocerebellar ataxia; Degenerative disease; Dominant character; Diagnosis; Public health; Human; Nervous system diseases; Family study; Idiopathic; Genotype; Cerebral disorder; Genetic disease; Phenotype; Type; Autosomal character; Central nervous system disease; Mutation; Spinal cord disease; Comparative study
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.64.1.67

OBJECTIVE Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the α1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype METHODS The SCA6 mutation was investigated in 69 German families with 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 families as well as in four patients with sporadic disease. Disease onset 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 systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. CONCLUSIONS This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.