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

Adriano Chiò, Letizia Mazzini, Sandra D'Alfonso, Lucia Corrado, Antonio Canosa, Cristina Moglia, Umberto Manera, Enrica Bersano, Maura Brunetti, Marco Barberis, Jan H Veldink, Leonard H van den Berg, Neil Pearce, William Sproviero, Russell McLaughlin, Alice Vajda, Orla Hardiman, James Rooney, Gabriele Mora, Andrea CalvoAmmar Al-Chalabi

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)e635-e642
Issue number7
Publication statusPublished - Aug 14 2018

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    Chiò, A., Mazzini, L., D'Alfonso, S., Corrado, L., Canosa, A., Moglia, C., Manera, U., Bersano, E., Brunetti, M., Barberis, M., Veldink, J. H., van den Berg, L. H., Pearce, N., Sproviero, W., McLaughlin, R., Vajda, A., Hardiman, O., Rooney, J., Mora, G., ... Al-Chalabi, A. (2018). The multistep hypothesis of ALS revisited: The role of genetic mutations. Neurology, 91(7), e635-e642.