ORIGINS OF A MUTATION - POPULATION-GENETICS OF MACHADO-JOSEPH-DISEASEIN THE AZORES (PORTUGAL)

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerativ e disorder of adult onset. In the islands of the Azores (Portugal), MJ D reaches the highest prevalence reported worldwide. It has been postu lated that it is highly represented in the Azorean population as a res ult of a founder effect. To test this hypothesis, we reconstructed the ascending genealogies of the 32 Azorean families presently identified as harboring the disease (103 patients), using parish records as the main source of data. These patients were originally from the islands o f Sao Miguel, Terceira, Graciosa, and Flores. The genealogies of the t wo main Azorean American families (Machado and Joseph) were also recon structed. To identify the links between the MJD families, we calculate d the kinship coefficient between the proponents of these genealogies. The family from Terceira was linked to three different MJD families f rom Flores through common ancestors. No kinship was observed between t he MJD families from Sao Miguel and families from any other island. Li nks between the two Azorean American families and Azorean MJD families were found. The founders present in more than one ascendance were ide ntified. Their chronological and geographic distribution indicates tha t more than one MJD mutation was introduced in the Azores, probably by settlers coming from the Portuguese mainland. The molecular evidence to date corroborates these results, because two distinct haplotypes ha ve been established, one on the island of Sao Miguel and the other on Flores. Therefore molecular biology studies confirm the accuracy of th e conclusions drawn from the genealogical evidence supporting the abse nce of a founder effect for MJD in the Azorean population.