Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease

Lattante, Serena; Conte, Amelia; Zollino, Marcella; Luigetti, Marco; Grande, Alessandra Del; Marangi, Giuseppe; Romano, Ângela; Marcaccio, Alessandro; Meleo, Emiliana; Bisogni, Giulia; Rossini, Paolo Maria; Sabatelli, Mario

doi:10.1212/wnl.0b013e31825dceca

Cited by 104 publications

(72 citation statements)

References 39 publications

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“…The occurrence of mutations in more than one gene supports the idea that ALS could be considered an oligogenic disease, 30,35 with some of these genes displaying mendelian inheritance and a number of other genes acting as disease modifiers by influencing penetrance and pleiotropy. Indeed, in support of this view, C9orf72 repeat expansions have also been found to occur in Table 3 ATXN2 intermediary polyglutamine repeats co-occur with C9orf72 hexanucleotide repeat expansions patients carrying variants in a major ALS-or FTDcausing gene, such as TARDBP, SOD1, FUS, GRN, UBQLN2, OPTN, VAPB, and ANG.…”

Section: Figurementioning

confidence: 69%

“…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%

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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: 69%

Section: Figurementioning

confidence: 70%

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

et al. 2014

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“…Since the first clinical study initiated in Ireland by Greenway et al [2], several SNPs encoding missense mutations in the coding region of ANG have been identified in ALS patients of Irish and Scottish background. Later studies confirmed the association of ANG mutations with ALS across diverse ethnic groups [3][4][5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 86%

Fast prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

et al. 2013

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a b s t r a c tCertain single nucleotide polymorphisms causing missense mutations in angiogenin result in its loss-of-function and onset of amyotrophic lateral sclerosis (ALS). Although several such associations are reported across diverse ethnic groups, no method is available for predicting if a new mutation is deleterious. We present here a fast molecular dynamics based method for determining the mechanisms of functional loss caused by mutations, and attributes to ascertain whether a mutation causes ALS.

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“…In all patients, ALS is thought to arise from a combination of genetic susceptibility (Renton, Chio et al 2014, Marangi and Traynor 25 Alruwaili thesis 2016 2015), and environmental exposure (Fang, Kamel et al 2009), and may be due to a multi-stage process (Al-Chalabi, Calvo et al 2014). Causative genes have been identified in fALS, with some of these genetic mutations also found in patients with sporadic ALS (sALS) (Lattante, Conte et al 2012). It has been estimated that 61% of the variance in risk of developing sALS is due to genetic factors (Al-Chalabi, Fang et al 2010).…”

Section: List Of Supplementary Tablesmentioning

confidence: 99%

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

Alruwaili¹

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Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease

Cited by 104 publications

References 39 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

Fast prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

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