Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease

The autosomal dominant spinocerebellar ataxias are clinically and genetically a heterogeneous group of neurodegenerative disorders. Genetic studies have classified some of these disorders based on the mapping of their respective genes. The gene for Machado-Joseph disease, one type of spinocerebellar ataxia, has been mapped to the long arm of chromosome 14q24.3-ter. The gene for another spinocerebellar ataxia, which is clinically distinct from Machado-Joseph disease, has been also localized to the same region on 14q and has been named type 3 spinocerebellar ataxia. Recently, expansions of a CAG trinucleotide repeat in a novel gene on chromosome 14q32.1 were shown in 11 patients affected with Machado-Joseph disease. In this study, we analyzed the DNA samples from 103 individuals representing 42 independent families with dominantly inherited ataxia to determine whether any had the Machado-Joseph disease mutation. The Machado-Joseph disease CAG expansion was detected in 5 of these 42 families. Sixteen affected individuals displayed a normal allele containing 14 to 31 CAG repeats and an expanded allele ranging between 66 and 79 CAG repeats. Seven asymptomatic individuals showed an allele ranging between 67 and 80 CAG repeats. Two of these families had a phenotype consistent with Machado-Joseph disease while the other 3 had clinical features of type 3 spinocerebellar ataxia. These data suggest that a single locus at 14q32.1 is responsible for two forms of spinocerebellar ataxia, spinocerebellar ataxia type 3 and Machado-Joseph disease, and that this locus may account for approximately 11% of this group of dominantly inherited ataxias.