SOMATIC MOSAICISM IN THE CENTRAL-NERVOUS-SYSTEM IN SPINOCEREBELLAR ATAXIA TYPE-1 AND MACHADO-JOSEPH DISEASE

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autos omal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity o f cell death and the resulting characteristic neuropathological featur es in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and sever ity of these diseases, somatic mosaicism, the result of mitotic instab ility of the CAG repeat, could be the basis for specificity of neurode generation; brain structures with larger expanded repeats would be mor e severely affected. To study the association between neuropathologica l changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the s ize of the (CAG)n expansion in 20 different regions of the brain, brai nstem, cerebellum, and spinal cord from 3 patients with spinocerebella r ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the t wo disorders. We observed a considerable homogeneity of repeat size ra nges in all but 1 of the 20 regions examined: The cerebellar cortex sh owed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosai cism, similar in spinocerebellar ataxia type 1 and Machado-Joseph dise ase, reflects the developmental pathways and cell composition of diffe rent central nervous system regions and is not the cause of selective cell death in these disorders.