The multistep hypothesis of ALS revisited: The role of genetic mutations

Neurology. 2018 Aug 14;91(7):e635-e642. doi: 10.1212/WNL.0000000000005996. Epub 2018 Jul 25.

Abstract

Objective: Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins.

Methods: We generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene.

Results: Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r2 = 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r2 = 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP.

Conclusion: The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / epidemiology*
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein / genetics
  • DNA-Binding Proteins
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation / genetics*
  • RNA-Binding Protein FUS / genetics
  • Retrospective Studies
  • Superoxide Dismutase-1 / genetics

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • FUS protein, human
  • RNA-Binding Protein FUS
  • SOD1 protein, human
  • TARDBP protein, human
  • Superoxide Dismutase-1