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 geneticall y heterogeneous group of neurodegenerative disorders affecting the cer ebellum and its connections. The mutations for SCAI, 2, 3, 6, and 7 ha ve 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 chromoso mes 16 and 11 have been designated SCA4 and SCA5. However, up to 20% o f individuals with autosomal dominant forms of ataxias cannot be assig ned any of these genotypes, implying the presence of other unidentifie d genes that may be involved in the development of ataxia. Methods: We ascertained and clinically characterized a six-generation pedigree se gregating an autosomal dominant trait for SCA. We performed direct mut ation analysis and linkage analysis for all known SCA loci. Results: T he mutation analysis excludes SCA1, 2, 3, 6, and 7, and genetic linkag e analysis excludes SCA4 and SCA5 (multipoint location scores <-2 acro ss the candidate region). Clinical analysis of individuals in this fam ily shows that all affected members have dysarthria, gait and limb ata xia, and nystagmus. No individuals have major brainstem or long-tract findings. Analysis of age at disease onset through multiple generation s suggests anticipation.; Conclusion: This pedigree represents a genet ically distinct form of SCA with a phenotype characterized by predomin antly cerebellar symptoms and signs.