MOLECULAR-FEATURES OF THE CAG REPEATS AND CLINICAL MANIFESTATION OF MACHADO-JOSEPH DISEASE

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the M JD1 gene was identified as the cause of the disease, We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas nor mal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association wi th the clinical anticipation of the disease, a parent-child analysis s howed the unidirectional expansion of CAG repeats and no case of dimin ution in the affected family, The differences in CAG repeat length bet ween parent and child and between siblings are greater in paternal tra nsmission than in maternal transmission. Detailed analysis revealed th at a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission, On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission, Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the ge ne and younger ages of onset than the other types.