Clinical and molecular correlations in spinocerebellar ataxia type 6:a study of 24 Dutch families

BACKGROUND: Autosomal dominant cerebellar ataxias (ADCAs), or spinocerebellar ataxias (SCAs), are a heterogeneous group of neurodegenerative disorders. Mild CAG repeat expansions in the alpha(1A) voltage-dependent calcium channel gene are associated with SCA type 6 (SCA6).OBJECTIVE: To obtain further insight into the contribution of SCA6 mutations 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 ataxia. Clinical characteristics of patients with SCA6 were investigated and correlated with molecular findings.RESULTS: The diagnosis SCA6 was confirmed in 24 families comprising 30 familial 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 correlated inversely with age at onset. No intergenerational changes in CAG repeat size were detected. Despite this, 2 families showed clinical anticipation.CONCLUSIONS: This study provides the first detailed description of Dutch patients with SCA6. Clinical analysis identifies SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early manifestations. No single clinical sign can be considered specific for SCA6. Some patients have ataxia combined with episodic headaches or nausea, suggesting an overlap among SCA6, eposidic ataxia type 2, and familial hemiplegic migraine. Spinocerebellar ataxia type 6 accounts for approximately 11% of all Dutch families with ADCA. Analysis of SCA6 contributes further to the genetic classification of patients with ADCA, including patients without a clear family history of the disease.