Association of Long ATXN2 CAG Repeat Sizes With Increased Risk of Amyotrophic Lateral Sclerosis

Daoud, Hussein; Belzil, Véronique V.; Martins, Sandra; Sabbagh, Mike; Provencher, Pierre; Lacomblez, Lucette; Meininger, Vincent; Camu, William; Dupré, Nicolas; Dion, Patrick A.; Rouleau, Guy A.

doi:10.1001/archneurol.2011.111

Cited by 82 publications

(55 citation statements)

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“…20 Because of the presence of TDP-43 inclusions in many neurodegenerative diseases and the heterogeneity of their clinical presentation, a number of studies have evaluated ATXN2 repeat sizes in patients with neurodegenerative diseases. 17,[21][22][23][24][25][26][27][28][29][30][31][32][33] All the studies confirmed a significant association between intermediary repeat lengths and ALS, which is even stronger when familial cases are considered separately from sporadic cases. An association has also been found with PSP.…”

Section: Figurementioning

confidence: 70%

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

et al. 2014

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Objective: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.Methods: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS).Results: We found a significant association with intermediate repeat size ($29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls.Conclusions: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS.Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered part of a spectrum of neurologic diseases because they share pathologic hallmarks, consisting of TAR DNA-binding protein 43 (TDP-43) pathology, and a similar genetic background, including C9orf72 expansion. On the other hand, FTD shares a prominent frontal cognitive syndrome and parkinsonism signs with progressive supranuclear palsy (PSP). Spinocerebellar ataxia type 2 (SCA2), characterized by cerebellar ataxia, parkinsonism, and mild dementia, is caused by an expanded CAG trinucleotide repeat encoding for a polyglutamine (polyQ) tract in ataxin-2 protein (ATXN2; OMIM: *601517). A link between SCA2 and ALS was established in 2010, when ATXN2 intermediate-length expansions were found to be significantly associated with ALS and it was shown that ATXN2 protein modifies TDP-43 toxicity.1 In this study, we analyzed the size of ATXN2 repeats in a large French cohort of 1,624 patients with ALS, FTD, FTD-ALS, and PSP to evaluate the exact contribution of the ATXN2 repeat size to

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Section: Figurementioning

confidence: 70%

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

et al. 2014

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“…In all cases, this resembles hereditary spastic paraparesis or primary lateral sclerosis [30,34,67] [33]. This association has been independently replicated in several studies and raises the possibility that ALS and ataxia may also form a spectrum of disease in the same way as ALS and FTD [18,25,39,97,113,119,132].…”

Section: Als2mentioning

confidence: 72%

The genetics and neuropathology of amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.

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“…The identification of SCA2 LNAs as a risk factor for amyotrophic lateral sclerosis (ALS) and the possible genetic link between ALS and SCA2 (Elden et al 2010;Daoud et al 2011;Laffita-Mesa et al 2013) pose a new challenge for this program. Even among those families where some members carrying SCA2 LNAs have been affected with ASL, the accurate prediction of the phenotype for other LNAs carriers is not possible at present.…”

Section: Expanding the Risk Boundaries In Sca2 Prenatal Diagnosismentioning

confidence: 99%

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution

Mariño¹,

Vázquez‐Mojena

Velázquez‐Pérez

et al. 2015

J Community Genet

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Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/10 5 inhabitants) of SCA2 in the world. The existence of 753 affected individuals and 7173 relatives at risk prompted the development in 2001 of the first predictive testing program in the country. The medical records of over 1193 individuals, who requested the test within a 13-year period, were analyzed retrospectively. The presymptomatic and the prenatal tests had uptake rates of 43.4 and 23.9 %, respectively. Several ethical challenges resulted from this program. These include the following: (1) withdrawal due to the initial protocol's length; (2) the request to participate by 16 at-risk adolescents; (3) the decision made by ten out of 33 couples with a test-positive fetus to carry the pregnancy to term, leading to de facto predictive testing of minors; (4) the elevated frequency of the ATXN2 gene large normal alleles (≥23 to 31 repeats) in the reference population. These issues have led to major changes in the guidelines of the predictive testing protocol: (1) the protocol length was shortened; (2) the inclusion criteria were expanded to reach at-risk adolescents with an interest in prenatal diagnosis; (3) interdisciplinary follow-up was offered to families in which test-positive fetuses were not aborted; (4) prenatal testing was made available to carriers of large normal alleles with ≥27 CAG repeats. The profiles of the participants were similar to those reported for other predictive testing programs for conditions like Huntington disease and familial adenomatous polyposis. The genetic counseling practices at the community level, the ample health education provided to the at-risk population, together with multidisciplinary and specialized attention to the affected families, are lessons from the Cuban experience that can be relevant for other international teams conducting predictive testing for other late-onset neurodegenerative disorders.

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Association of Long ATXN2 CAG Repeat Sizes With Increased Risk of Amyotrophic Lateral Sclerosis

Abstract: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG) n alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS.

Cited by 82 publications

References 20 publications

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

The genetics and neuropathology of amyotrophic lateral sclerosis

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution

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