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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.
de Mattos, Eduardo Preusser; Kolbe Musskopf, Maiara; Bielefeldt Leotti, Vanessa; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach.
Afiliação
  • de Mattos EP; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  • Kolbe Musskopf M; Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Bielefeldt Leotti V; Department of Biomedical Sciences of Cells & Systems, Section of Molecular Cell Biology, University Medical Center Groningen/Groningen University, Groningen, The Netherlands.
  • Saraiva-Pereira ML; Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Jardim LB; Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
J Neurol Neurosurg Psychiatry ; 90(2): 203-210, 2019 02.
Article em En | MEDLINE | ID: mdl-30337442
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Machado-Joseph / Predisposição Genética para Doença Tipo de estudo: Diagnostic_studies / Etiology_studies / Guideline / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: J Neurol Neurosurg Psychiatry Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Machado-Joseph / Predisposição Genética para Doença Tipo de estudo: Diagnostic_studies / Etiology_studies / Guideline / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: J Neurol Neurosurg Psychiatry Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido