Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia reported worldwide, but it shows marked geographic differences in prevalence. The study of ancestral origins and spreading routes of MJD mutational events has contributed to explain such differences. During human evolution, at least two independent de novo MJD expansions occurred in distinct haplotype backgrounds: TTACAC and GTGGCA (named Joseph and Machado lineages). The most ancient Joseph lineage, probably of Asian origin, has been introduced recently in Europe, where founder effects are responsible for the high MJD prevalence, as occurs in the Portuguese/Azorean island of Flores and Northeastern mainland. The Machado lineage is geographically more restricted, with most known families in Portugal (island of São Miguel and along the Tagus valley). The hypothesis of other mutational origins has been raised, namely to explain the disease among Australian aborigines; however, a comprehensive haplotype study suggested the introduction of the Joseph lineage in that community via Asia. Also, additional SNP-based haplotypes (TTAGAC, TTGGAC and GTGCCA) were observed in other MJD families, but phylogenetic analysis with more polymorphic flanking markers did not point to independent mutational events, reinforcing the hypothesis of a very low mutation rate underlying this repeat expansion locus.
Keywords: Geographic clusters; Haplotype; MJD; Mutational origins; Prevalence; SCA3.