Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

Abstract

Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)_n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago.

Fig. 1

Pedigree of a Sudanese family affected with Machado-Joseph disease, showing the haplotypes of 30 SNPs and 7 STRs segregating with ATXN3_(CAG)_n alleles in 3 siblings and their unaffected father. The proband is marked with an arrow. Individual F49-397 had several inconsistencies in his paternal haplotype (not shown), which were not possible to clarify further. Ages of onset (o.) and death (d.) are described next to the symbol of the respective patient. Individuals sampled for haplotype analysis are marked with a dash above the symbol; in case a neurological exam was performed, an X sign was added. Patients affected by history have hatched symbols

Fig. 2

Phylogenetic network showing the most parsimonious relationships among haplotypes of 7 STRs in 82 MJD families of the Machado lineage. Circle size is proportional to number of families. The length of lines reflect the number of stepwise mutations. Dashed diamonds indicate recombination. Non-Portuguese families are represented in black: 2 from the USA (H3 and H7), 2 Spanish (H12); and 1 Sudanese (H11)