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The size of the CAG tract only partially explains age at onset (AO), highlighting the existence of disease modifiers. Mitochondrial DNA (mtDNA) haplogroups have been associated with clinical presentation in other polyglutamine disorders, constituting potential modifiers of MJD phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cross\u2010sectional study, using 235 unrelated patients from Portugal, Brazil, India and Japan, was performed to investigate if mtDNA haplogroups contribute to AO of MJD. mtDNA haplogroups were obtained after sequencing the mtDNA hypervariable region I. Patients were classified in 15 phylogenetically related haplogroup clusters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The AO was significantly different among populations, implying the existence of other non\u2010CAG factors, which seem to be population specific. In the Portuguese population, patients classified as belonging to haplogroup JT presented the earliest onset (estimated onset 34.6\u00a0years of age). Haplogroups W and X seem to have a protective effect, causing a delay in onset (estimated onset 47\u00a0years of age). No significant association between haplogroup clusters and AO was detected in the other populations or when all patients were pooled. Although haplogroup JT has already been implicated in other neurodegenerative disorders, no previous reports of an association between haplogroups W and X and disease were found.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggest that haplogroups JT, W and X modify AO in MJD. Replication studies should be performed in European populations, where the frequency of the candidate modifiers is similar.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.13860","type":"journal-article","created":{"date-parts":[[2018,11,10]],"date-time":"2018-11-10T11:02:22Z","timestamp":1541847742000},"page":"506-512","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mitochondrial<scp>DNA<\/scp>haplogroups and age at onset of Machado\u2013Joseph disease\/spinocerebellar ataxia type 3: a study in patients from multiple populations"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-6651","authenticated-orcid":false,"given":"A.","family":"Ramos","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias e Tecnologia Universidade dos A\u00e7ores Ponta Delgada Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto Porto Portugal"},{"name":"IBMC \u2013 Instituto de Biologia Molecular e Celular Universidade do Porto Porto Portugal"},{"name":"Departamento Biologia Animal Biologia Vegetal i Ecologia Unitat d'Antropologia Biol\u00f2gica Universitat Aut\u00f2noma de Barcelona Cerdanyola del Valles Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Planchat","sequence":"additional","affiliation":[{"name":"Departamento Biologia Animal Biologia Vegetal i Ecologia Unitat d'Antropologia Biol\u00f2gica Universitat Aut\u00f2noma de Barcelona Cerdanyola del Valles Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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