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Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis
  1. Eduardo Preusser de Mattos1,2,3,
  2. Maiara Kolbe Musskopf2,
  3. Vanessa Bielefeldt Leotti4,5,
  4. Maria Luiza Saraiva-Pereira1,2,6,7,
  5. Laura Bannach Jardim1,2,7,8
  1. 1 Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  2. 2 Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
  3. 3 Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen/Groningen University, Groningen, The Netherlands
  4. 4 Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  5. 5 Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  6. 6 Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  7. 7 Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
  8. 8 Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  1. Correspondence to Dr Laura Bannach Jardim, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rua Ramiro Barcelos 2350, Brazil; ljardim{at}


Objectives To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).

Methods Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071).

Results Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27–33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance.

Conclusions Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.

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  • Correction notice Since this paper was first published online, the author name Vanessa Leotti Torman has been updated to Vanessa Bielefeldt Leotti.

  • Contributors EPDM, MLS-P and LBJ designed the study. EPDM, MKM and LBJ performed the systematic review. EPDM and VBL performed the statistical analysis. EPDM, MKM, VBL, MLS-P and LBJ wrote the manuscript.

  • Funding This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant no. 402968/2012-3), Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (grant no. GPPG HCPA 13-0303GPPG HCPA 14-0204) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (grant no. 99999.01528/2015-2017).

  • Disclaimer Funding organisations had no role in study design; collection, analysis and interpretation of data; writing of the report; or decision to submit the article for publication.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.