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

Abstract

ObjectivesTo 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).MethodsTwo 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).ResultsEleven 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.ConclusionsCurrent 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.

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

“…No gender difference was observed (data not shown). The length of the expanded CAG repeat explained 49.39% of the AO variation in this cohort (Fig 1), which is slightly lower than the percentage reported in a recent meta‐analysis, 26 but consistent with another report on Dutch patients with SCA3/MJD 3 . The database with all variables under study is available in the Supplementary Material SS3.…”

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

“…As with other diseases caused by repeat expansions, such as Huntington's disease (HD) and other spinocerebellar ataxias, there is an inverse correlation between expanded repeat size and the age at which pathogenesis leads to disease onset [3]. Depending on the cohort structure, the size of the repeat expansion explains 55 to 70% of the age at onset (AO) variability in MJD, suggesting the existence of additional modifying factors [3,4]. Although several genetic factors have been proposed as modifiers, such as CAG repeat size of normal ATXN3 (SCA3), HTT (HD), ATXN2 (SCA2) and ATN1 (DRPLA) alleles, APOE status, and expression level of HSP40 [4][5][6], these were not replicated by subsequent studies [7,8].…”

“…Depending on the cohort structure, the size of the repeat expansion explains 55 to 70% of the age at onset (AO) variability in MJD, suggesting the existence of additional modifying factors [3,4]. Although several genetic factors have been proposed as modifiers, such as CAG repeat size of normal ATXN3 (SCA3), HTT (HD), ATXN2 (SCA2) and ATN1 (DRPLA) alleles, APOE status, and expression level of HSP40 [4][5][6], these were not replicated by subsequent studies [7,8]. Since CAG tract profile and allelic frequencies of the potential modifier loci can have unique characteristics in different populations, large collaborative studies are required to identify genetic modifiers in MJD, as well as replicate the findings of such studies [8].…”

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

“…As with other diseases caused by repeat expansions, such as Huntington’s disease (HD) and other spinocerebellar ataxias, there is an inverse correlation between expanded repeat size and the age at which pathogenesis leads to disease onset [3]. Depending on the cohort structure, the size of the repeat expansion explains 55 to 70% of the age at onset (AO) variability in MJD, suggesting the existence of additional modifying factors [3,4]. Although several genetic factors have been proposed as modifiers, such as CAG repeat size of normal ATXN3 (SCA3), HTT (HD), ATXN2 (SCA2) and ATN1 (DRPLA) alleles, APOE status, and expression level of HSP40 [4,5,6], these were not replicated by subsequent studies [7, 8].…”

“…Depending on the cohort structure, the size of the repeat expansion explains 55 to 70% of the age at onset (AO) variability in MJD, suggesting the existence of additional modifying factors [3,4]. Although several genetic factors have been proposed as modifiers, such as CAG repeat size of normal ATXN3 (SCA3), HTT (HD), ATXN2 (SCA2) and ATN1 (DRPLA) alleles, APOE status, and expression level of HSP40 [4,5,6], these were not replicated by subsequent studies [7, 8]. Since CAG tract profile and allelic frequencies of the potential modifier loci can have unique characteristics in different populations, large collaborative studies are required to identify genetic modifiers in MJD, as well as replicate the findings of such studies [8].…”