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

Abstract

Machado-Joseph disease (MJD) has been described in Africans, but no cases have been reported from Nigeria. Current MJD global distribution results from both the ancestral populations-of-origin and the founder effects of mutations, some as a consequence of the Portuguese sea travels in the 15th to 16th century. Two main ancestral haplotypes have been identified: the Machado lineage, which is more recent, predominant in families of Portuguese extraction, and the Joseph lineage, which is much older and worldwide spread, postulated to have an Asian origin. We report a Nigerian family with MJD from Calabar, once settled by Portuguese slave traders, and assessed its mutational origin. The proband was a 33-year-old man with progressive unsteady gait, weakness of all limbs, dysphagia, dysarthria, urinary frequency and diaphoresis. He had end-of-gaze nystagmus, spastic quadriparesis and atrophic small muscles of the hand. He showed fibrillation potentials on EMG, and nerve conduction studies suggested a central axonopathy without demyelination. This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around 7000 years.

Spinocerebellar ataxia type-7: Report of a family in Northwest Nigeria

“…[ 2 ] The only autosomal dominant SCA described in Nigeria was SCA3, also known as Machado–Joseph disease, which was detected in a family in Calabar, Cross River State. [ 3 ] We herein describe nine members of a family in Northwest Nigeria affected by SCA7, which was confirmed in three individuals through DNA analysis. We then review relevant literature on the subject.…”

Selective forces acting on spinocerebellar ataxia type 3/Machado–Joseph disease recurrency: A systematic review and meta‐analysis

“…The haplotypes described here covered at least the classical three SNPs, as proposed by the first paper that described SCA3/MJD ancestral haplotypes: A 669 TG/G 669 TG (rs1048755), C 987 GG/G 987 GG (rs12895357), and TAA 1118 /TAC 1118 (rs7158733) 37 . From these 13 publications, five included both SCA3/MJD index cases as well as controls, 11,37‐40 six included SCA3/MJD subjects only, 41‐46 and two studied the general population only 47,48 . Besides those three classical SNPs (rs1048755, rs12895357, and rs7158733), these studies included different combinations of 31 additional intragenic markers (other SNPs and the CAG repeat tract) and/or four short tandem repeats (STRs) close to ATXN3 .…”

A Pipeline to Assess Disease-Associated Haplotypes in Repeat Expansion Disorders: The Example of MJD/SCA3 Locus

“…We selected a set of 26 SNPs within a region of 4 kb encompassing the (CAG) n , based on (1) minor allele frequencies (MAF > 5%; Ensembl 1 ); (2) recombination hotspots (within the same haplotype block; The International Genome Sample Resource and The 1000 Genomes Project); and (3) sequence alignments of previously analyzed patients (to include SNPs that discriminate MJD lineages (Martins et al, 2012; Ogun et al, 2015); Supplementary Table S1).…”

“…Geographical differences in disease prevalence may be explained by haplotype studies, as shown for Huntington disease (HD), with the highest risk HD haplogroups being found in Europe, while absent in East Asia (Warby et al, 2011). In MJD two de novo expansions seem to have occurred, and, so far, its presence in remote and ethnically diverse populations has been explained by genetic drift and founder effects (Gaspar et al, 2001; Martins et al, 2007, 2012; Ogun et al, 2015); This optimized protocol could clarify remaining questions about the origins and history of MJD mutations. By following the same pipeline to study other expanding loci , one could understand better disease prevalence and provide a clearer scenario about the occurrence of de novo expansions (Venkatesh et al, 2018).…”