Chiò, Adriano; Mazzini, Letizia; D'Alfonso, Sandra; Corrado, Lucia; Canosa, Antonio; Moglia, Cristina; Manera, Umberto; Bersano, Enrica; Brunetti, Maura; Barberis, Marco; +11 more... Veldink, Jan H; van den Berg, Leonard H; Pearce, Neil; Sproviero, William; McLaughlin, Russell; Vajda, Alice; Hardiman, Orla; Rooney, James; Mora, Gabriele; Calvo, Andrea; Al-Chalabi, Ammar; (2018) The multistep hypothesis of ALS revisited: The role of genetic mutations. Neurology, 91 (7). e635-e642. ISSN 0028-3878 DOI: https://doi.org/10.1212/WNL.0000000000005996
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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.
Item Type | Article |
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Faculty and Department | Faculty of Epidemiology and Population Health > Dept of Medical Statistics |
PubMed ID | 30045958 |
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Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 3.0
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