MACHADO-JOSEPH DISEASE IS NOT AN ALLELE OF THE SPINOCEREBELLAR ATAXIA-2 LOCUS

Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost comple te penetrance. Clinically, it is difficult to distinguish it from othe r autosomal dominantly inherited ataxias, and it has been suggested th at MJD may be caused by an allelic variant of SCA. Exclusion of MJD fr om the SCA1 locus on chromosome 6p has previously been demonstrated. H owever, following the recent assignment of a second locus for spinocer ebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Sp anish origin, we have investigated linkage in MJD families using the t wo markers, D12S58 and PLA2, that flank this disease gene. The MJD loc us was definitively excluded from an interval spanning approximately 7 0 cM, which includes these loci. These studies demonstrate that MJD an d SCA2 are genetically distinct despite similarities in disease phenot ype and ancestral origins of the patients. Thus, the as yet unmapped M JD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.