Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis

Conforti, Francesca Luisa; Spataro, Rossella; Sproviero, William; Mazzei, R.; Cavalcanti, Francesca; Condino, Francesca; Simone, I. L.; Logroscino, Giancarlo; Patitucci, A; Magariello, A.; Muglia, M.; Rodolico, Carmelo; Valentino, Paola; Bono, Francesco; Colletti, Tiziana; Monsurrò, Maria Rosaria; Gambardella, Antonio; Bella, Vincenzo La

doi:10.1212/wnl.0b013e318278b618

Cited by 77 publications

(55 citation statements)

References 27 publications

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“…Several of the aforementioned studies highlighted that ATXN2 repeat length did not appear to influence clinical characteristics, including age at onset and survival after onset (Chen et al, 2011; Conforti et al, 2012; Corrado et al, 2011; Daoud et al, 2011; Gispert et al, 2012; Lee et al, 2011; Liu et al, 2013; Soraru et al, 2011; Van Damme et al, 2011), which is well in line with our present findings. Furthermore, our results are consistent with reports that did not find associations between ATXN2 repeat lengths and FTD (Ross et al, 2011; Van Langenhove et al, 2012).…”

Section: Discussionsupporting

confidence: 92%

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

Blitterswijk

Mullen

Heckman

et al. 2014

Neurobiology of Aging

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Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated four genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1) and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 controls, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1 or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% versus 0% in controls, P=0.013), whereas the frequency in probands with FTD was identical to controls. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.

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Section: Discussionsupporting

confidence: 92%

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

Blitterswijk

Mullen

Heckman

et al. 2014

Neurobiology of Aging

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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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“…The authors went on to describe that the degree of ATXN2 polyglutamine expansion was correlated with the extent of TDP-43 toxicity in both Drosophila and yeast models. Furthermore, ATXN2 intermediate repeat expansion was confirmed as a risk factor in ALS patients [20,106,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159], and more recently as a possible modifier of C9orf72 repeat expansion toxicity in ALS/FTD [107,108].…”

Section: Reviewmentioning

confidence: 91%