Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Eduardo Preusser de Mattos, Maiara Kolbe Musskopf, Vanessa Bielefeldt Leotti, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim*

*Corresponding author for this work

    Research output: Contribution to journalReview articleAcademicpeer-review

    16 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)203-210
    Number of pages8
    JournalJournal of Neurology, Neurosurgery, and Psychiatry
    Issue number2
    Early online date18-Oct-2018
    Publication statusPublished - Feb-2019



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