Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia.

OBJECTIVE: To characterize a distinct form of spinocerebellar ataxia (SCA) clinically and genetically.

BACKGROUND: The SCAs are a genetically heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. The mutations for SCA1, 2, 3, 6, and 7 have been identified and shown to be due to expansion of a CAG repeat in the coding region of these genes. Two additional SCA loci on chromosomes 16 and 11 have been designated SCA4 and SCA5. However, up to 20% of individuals with autosomal dominant forms of ataxias cannot be assigned any of these genotypes, implying the presence of other unidentified genes that may be involved in the development of ataxia.

METHODS: We ascertained and clinically characterized a six-generation pedigree segregating an autosomal dominant trait for SCA. We performed direct mutation analysis and linkage analysis for all known SCA loci.

RESULTS: The mutation analysis excludes SCA1, 2, 3, 6, and 7, and genetic linkage analysis excludes SCA4 and SCA5 (multipoint location scores < -2 across the candidate region). Clinical analysis of individuals in this family shows that all affected members have dysarthria, gait and limb ataxia, and nystagmus. No individuals have major brainstem or long-tract findings. Analysis of age at disease onset through multiple generations suggests anticipation.

CONCLUSION: This pedigree represents a genetically distinct form of SCA with a phenotype characterized by predominantly cerebellar symptoms and signs.