Clinical and molecular correlations in spinocerebellar ataxia type 6 - A study of 24 Dutch families

Background: Autosomal dominant cerebellar ataxias (ADCAs), or spinocerebell ar ataxias (SCAs), are a heterogeneous group of neurodegenerative disorders . Mild CAG repeat expansions in the a, voltage-dependent calcium channel ge ne are associated with SCA type 6 (SCA6). Objective: To obtain further insight into the contribution of SCA6 mutation s to the phenotypic variability in Dutch patients with ataxia. Design: Survey and case series. Setting: Hospitalized care, referral center. Patients and Methods: The SCA6 locus was analyzed for CAG repeat expansions in a referred sample of 220 Dutch families with progressive cerebellar ata xia. Clinical characteristics of patients with SCA6 were investigated and c orrelated with molecular findings. Results: The diagnosis SCA6 was confirmed in 24 families comprising 30 fami lial and 4 sporadic cases. Mean +/- SD age at onset was 50.1 +/- 11.1 years . Expanded CAG repeats with sizes 22, 23, and 25 were found. These sizes co rrelated inversely with age at onset. No intergenerational changes in CAG r epeat size were detected. Despite this, 2 families showed clinical anticipa tion. Conclusions: This study provides the first detailed description of Dutch pa tients with SCA6. Clinical analysis identifies SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early mani festations. No single clinical sign can be considered specific for SCA6. So me patients have ataxia combined with episodic headaches or nausea, suggest ing an overlap among SCA6, eposidic ataxia type 2, and familial hemiplegic migraine. Spinocerebellar ataxia type 6 accounts for approximately 11% of a ll Dutch families with ADCA. Analysis of SCA6 contributes further to the ge netic classification of patients with ADCA. including patients without a cl ear family history of the disease.