Ethnic differences in the expression of neurodegenerative disease: Machado‐Joseph disease in Africans and Caucasians

Abstract

We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.

Psychiatric Disorder Criteria and their Application to Research in Different Racial Groups

“…In the limited number of times this biological validation has been compared retrospectively against the clinical (and pathologic) characterization of neurological disease, it has become clear that the clinical characterization holds up poorly in different racial groups. For example, the phenotypes of both Spinocerebellar Ataxia types 2 and 3 (SCA2 and SCA3) are different in Eastern Asians and Sub-Saharan-Africans respectively from their phenotypes in Caucasians [10-13]. Dentatorubral-Pallidoluysian Atrophy in the Japanese is different from Haw River syndrome in African-Americans despite being caused by the same polyglutamine expansion [14,15].…”

Machado–Joseph disease in a Nigerian family: mutational origin and review of the literature

“…This clinical presentation, although common among patients of African extraction, is rare in families of European extraction. 10 The hypothesis of cis effects responsible for this variation has, however, been weakened by the absence of a haplotype shared by all families with type 4 MJD; instead, trans-acting genetic factors could explain this rare presentation in a restricted ethnic background. 10 The proband from a Nigerian family had, however, type 2 MJD with no Parkinsonian features.…”

“…10 The hypothesis of cis effects responsible for this variation has, however, been weakened by the absence of a haplotype shared by all families with type 4 MJD; instead, trans-acting genetic factors could explain this rare presentation in a restricted ethnic background. 10 The proband from a Nigerian family had, however, type 2 MJD with no Parkinsonian features. In general, heterogeneity of neurologic findings in MJD seems to be partly explained by duration of the disease, clinical type and CAG repeat length.…”

“…4,5,7 Previous haplotype studies have shown different genetic backgrounds associated with expanded alleles in patients of African origin: AGA, ACA and GCC (rs1048755-rs12895357-rs7158733). 5,7,10 These suggested that (1) the disease heterogeneity (namely, type 4 MJD) cannot be explained exclusively by the haplotype background and (2) more than one mutational origin has been introduced in Africa. These studies included the genotyping of a few SNPs that, when analyzed together with other markers, proved to be very informative for clarifying the mutational origin in populations with a large number of families.…”

“…4 MJD has been found in a few African families, including those from Morocco, Algeria, Ghana, Ivory Coast, Mali, Somalia and families of African descent in the USA. [5][6][7][8][9][10] Whether independent mutational origin(s) underlie all these families remains unclear as haplotype studies are scarce. The presence of MJD worldwide is mainly explained by two ancestral lineages: the first seems to have occurred about 7000 years ago, in Asia (TTACAC, or the Joseph lineage, seen in the vast majority of non-Portuguese families, in the five continents), and another, more recent, which occurred less than 2000 years ago, responsible for MJD in some regions of Portugal (as the island of São Miguel, in the Azores and the Tagus valley) and in a few other families of proven or suspected Portuguese ancestry (GTGGCA, or the Machado lineage).…”