Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis
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PROVIDER: S-EPMC10998343 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis.
| S-EPMC9890463 | biostudies-literature
Project description:Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
| S-EPMC7425293 | biostudies-literature
Project description: Not available
| S-EPMC9626461 | biostudies-literature
Project description:ImportanceA family with coexistence of spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis (ALS) is described.ObservationsIntermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of spinocerebellar ataxia type 2 and ALS in a family has been reported in the literature.We describe a 47-year-old woman with an 11-year history of ataxia and her paternal uncle with ALS who were evaluated at Columbia University Medical Center since July 2006. Both our patient with ataxia and her uncle with ALS have full pathological CAG repeat expansions of ATXN2.Conclusions and relevanceThe diverse clinical phenotypes of ATXN2 CAG expansions and their coexistence in a single family are highlighted. A clinician should consider the diagnosis of spinocerebellar ataxia type 2 when encountering a patient with ataxia and a family history of ALS.
| S-EPMC4039635 | biostudies-literature
Project description:The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic variant found in individuals with sporadic amyotrophic lateral sclerosis (ALS), occurring at a frequency of between 7 and 11% in cohorts of European ancestry. While limited data suggest that C9-expansions (>30 repeats) are less frequent in African-Americans with ALS, there is no data on the frequency of C9-expansions among ALS subjects residing in Africa. We therefore investigated the frequency of this expansion mutation (using repeat-primed PCR) in a cohort of 143 South Africans (SA) with ALS. The cohort included different genetic ancestry subgroups who self-identified as black African (n = 24), Cape mixed-African (M/A) (n = 65), white European ancestry (n = 51), and Indian ancestry (n = 3). Three M/A individuals had a family history of ALS (2%) and all had normal C9orf72 alleles. Of the 140 individuals with sporadic ALS who were successfully genotyped, 10 (7%) carried pathogenic C9-expansions; four white and six M/A ancestry individuals, respectively. Our results highlight the importance of including Africans in genetic studies aimed at unravelling the genomic architecture in ALS and suggest pathogenetic mechanisms other than the C9orf72 expansion in black Africans with ALS.
| S-EPMC6556408 | biostudies-literature
Project description:ObjectiveGiven the recent finding of an association between intermediate-length polyglutamine (polyQ) expansions in ataxin 2 and amyotrophic lateral sclerosis (ALS), we sought to determine whether expansions in other polyQ disease genes were associated with ALS.MethodsWe assessed the polyQ lengths of ataxin 1, ataxin 3, ataxin 6, ataxin 7, TBP, atrophin 1, and huntingtin in several hundred patients with sporadic ALS and healthy controls.ResultsOther than ataxin 2, we did not identify a significant association with the other polyQ genes and ALS.ConclusionsThese data indicate that the effects of ataxin 2 polyQ expansions on ALS risk are likely to be rooted in the biology of ataxin 2 or ataxin 2-specific interactions, rather than the presence of an expanded polyQ repeat per se. These findings have important consequences for understanding the role of ataxin 2 in ALS pathogenesis and provide a framework for future mechanistic studies.
| S-EPMC3111240 | biostudies-literature
Project description:HTT full-penetrance pathogenic repeat expansions, the genetic cause of Huntington's disease (HD), have been recently reported in a minority of frontotemporal dementia/amyotrophic lateral sclerosis (ALS) patients (0.13%). We analyzed HTT CAG repeats in an Italian cohort of ALS patients (n = 467) by repeat-primed polymerase chain reaction. One patient harbored two expanded alleles in the HTT gene (42 and 37 CAG repeats). The absence of HD typical symptoms and the clinical picture consistent with ALS, corroborated by the diagnostic assessment, apparently excluded a misdiagnosis of HD.
| S-EPMC9639631 | biostudies-literature
Project description:Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.
| S-EPMC10162670 | biostudies-literature
Project description:Parkinson's disease genetic embraces genetic and non-genetic factors. It has been suggested a link between CAG repeat number in the HTT, ATXN1 and ATXN2 genes and different neurodegenerative diseases. Several genetic factors involved in Parkinson's disease development are indeed associated with cancer pathways. Moreover, several studies found a low prevalence of cancer in neurodegenerative diseases that can be associated with a low CAG repeat size in several genes. This study aimed to investigate the influence of CAG repeat sizes in ATXN1, ATXN2 and HTT genes on the risk for developing cancer and Parkinson's disease in a large cohort of patients with idiopathic Parkinson's disease and healthy controls. The work included 1052 patients with idiopathic Parkinson's disease and 1070 controls of European ancestry. CAG repeat sizes in HTT, ATXN1 and ATXN2 genes were analysed. Dunn's multiple comparison test for quantitative variables and logistic and linear regression were used. The long ATXN1 and HTT alleles and CAG size and both the ATXN2 short and long alleles were predictors for the Parkinson's disease risk. The long CAG ATXN1 allele gene was associated with the risk of cancer. No association was observed between CAG size in the HTT and ATXN2 genes and risk of cancer in patients with Parkinson's disease. We described an association of HTT, ATXN1 and ATXN2 with the risk of Parkinson's disease, which reinforce the hypothesis of the common pathway of neurodegeneration. Besides, ATXN1 could be a predictor of cancer risk among patients with Parkinson's disease, and these results suggest that cancer and neurodegeneration processes can share common pathways.
| S-EPMC11837329 | biostudies-literature
Project description:ImportanceRepeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometimes referred to as intermediate) have been identified as modifiers of amyotrophic lateral sclerosis (ALS) risk. Prior studies have used thresholding considering various cutoffs for ATXN2 repeat length.ObjectiveTo calculate association between ATXN2 CAG repeat alleles and increased risk of ALS across multiple ethnic groups.Data sourcesThe MEDLINE database was searched for studies published by December 29, 2013, reporting ATXN2 CAG repeat length in patients with ALS and controls.Study selectionStudies were included if they reported original data on relative risks or odds ratios (ORs) from ALS and control populations for individual ATXN2 alleles. Review articles that reported no new data were not included in the analysis.Data extraction and synthesisAnalysis of allele distribution was performed to ensure that all studies followed identical allele sizing. The ORs, 95% confidence intervals, and population attributable risk percentages were calculated according to standard procedures.Main outcomes and measuresOccurrence of ALS associated with ATXN2 repeat alleles, expressed as ORs.ResultsNine studies were analyzed, including 7505 controls and 6151 sporadic ALS cases. The ALS and control cohorts were recruited from different geographical and ethnic regions including the United States, French Canada/Canada, Belgium and the Netherlands, Germany, Italy, mainland China, Turkey, and Flanders-Belgium. The ATXN2 CAG repeat lengths ranged from 13 to 39 in patients with ALS and from 13 to 34 in controls. The ORs were less than 1.00 for alleles with 25 to 28 repeats. The OR was 1.55 for 30 repeats, but this elevation was not statistically significant (95% CI, 0.88-2.73). The ORs were 2.70 (95% CI, 1.47-4.93) for 31 CAG repeats, 11.09 (95% CI, 4.16-29.57) for 32 repeats, and 5.76 (95% CI, 1.79-18.57) for 33 repeats.Conclusions and relevanceIn contrast to prior studies with smaller numbers, risk for ALS associated with long-normal alleles is complex. Alleles with 27 and 28 repeats lower ALS risk slightly. The risk for ALS increases beginning with 29 repeats and reaches a maximum at 32 and 33 repeats. Of note, alleles with repeats of these lengths are known to be predisposed to meiotic expansion to full-penetrance mutant alleles. In patients with ALS, alleles with 31 to 33 repeats may have undergone preferential expansion in motor neurons during mitosis or DNA repair. Our meta-analysis provides a framework for counseling individuals with long-normal ATXN2 repeats.
| S-EPMC4939089 | biostudies-literature