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Most SOD1 mutations are pathogenic, and their identification can lead to early access to treatment
  1. Elisa De La Cruz1,2,
  2. Florence Esselin1,2,
  3. Anne Polge3,
  4. Kévin Mouzat2,3,
  5. Claire Guissart3
  1. 1University Hospital Centre of Montpellier, Montpellier, France
  2. 2Institute for Neurosciences of Montpellier, Montpellier, France
  3. 3Laboratoire de Biochimie et Biologie Moléculaire, CHU Nimes, Nimes, France
  1. Correspondence to Dr Elisa De La Cruz, Institute for Neurosciences of Montpellier, Montpellier, France; e-delacruz{at}chu-montpellier.fr

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Introduction

ALS is a neurodegenerative disease affecting motor neurons, leading to progressive loss of bulbar and limb motor function, respiratory insufficiency and death in a median of 3 years.1

About 10% to 20% of ALS are familial (fALS), meaning that at least one other member of the family is affected by the disease. In these families, a genetic cause is identified in 48% of cases within populations of European origin.2 However, sporadic forms of ALS are also found to be undermined by genetic mutations, the most frequent being the C9ORF72 GGGGCC-repeat expansion in intron 1A, followed by mutations in superoxide dismutase type 1 (SOD1) in Caucasian populations.

Coding mutations in the gene encoding SOD1 were found to co-segregate with disease in fALS cases in 1993, and since then, over 230 mutations in SOD1 have been reported in ALS showing heterogeneity in disease penetrance and phenotype. The suspected mechanism by which the SOD1 mutated protein causes ALS is by gain of a novel toxic function which includes the generation of prion-like SOD1 species.

Establishing whether all SOD1 mutations are pathogenic for ALS and disease risk for carriers of pathogenic variants are of crucial importance for genetic counselling, as well as access to innovative and promising precision medicines aiming at reducing the expression of SOD1.3 In 2011, Felbecker et al4 reported four ALS pedigrees (from Finland, France, Germany, Sweden) that carried SOD1 mutations, discordant for symptomatic status, with an asymptomatic carrier of a E101K mutation (formerly designated as E100K). More than 10 years later, we report that this asymptomatic individual finally developed symptoms …

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  • Contributors ED: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; guarantor. FE: drafting the work or revising it critically for important intellectual content; final approval of the version to be published. AP: drafting the work or revising it critically for important intellectual content; final approval of the version to be published. KM: drafting the work or revising it critically for important intellectual content; final approval of the version to be published. CG: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests ED has received support for attending meetings and/or travel from BIOGEN.

  • Provenance and peer review Not commissioned; externally peer reviewed.