Machado-Joseph disease in Brazil and other South American countries: A systematic Review and Meta-analysis of Prevalence, CAG Repeat Lengths, Age At Onset, and Ancestry.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a CAG expansion (CAGexp) disease whose genetic characteristics in South America (SA) are not well known. Our aim was to perform a systematic review and meta-analysis on the subject. Number of SA cases, ages at onset (AO), normal CAG repeats (CAGnormal) and CAGexp, and haplotypes, were searched in Pubmed, Embase, Lilacs, SciELO, ProQuest™ Dissertations & Theses Citation Index, BDTD and La Referencia by a PROSPERO registered protocol. Quantitative data were meta analysed. 26 non-replicated papers and dissertations out of 713 publications were included. 2,111 SCA3/MJD patients were reported, 16 living in Argentina, 10 in Chile, 41 in Venezuela, 18 in Peru, and 2,026 in Brazil between 2011 and 2024. Four individual-participant data (IPD) were obtained. The mean (95% CI; sample size) of CAGnormal, CAGexp and AO were 21.90 (21.53-22.27; 802) and 74.65 (74.43-74.87; 1,100) repeats, and 34.90 (34.25-35.31; 1,102) years. CAGexp explained 62% of the AO variability in IPD (789). The CAGexp effects over AO varied according to geographical origin, impacting in the models to predict AO. It was similar in three Brazilian cohorts, while among Peruvians the AO seemed to be earlier than expected by their CAGexp legths. Three studies found the rs1048755-rs12895357-rs7158733 haplotypes ACA, CCG and AGA in Brazilian patients. In conclusion, current evidence supports the relationship between SCA3/MJD and Portuguese-Azoreans, while the different CAGexp effects on AO across SA populations need to be studied to determine the underlying modifying factors.