The influence of genetic mutations on the multistep process in ALS

Objective: To test the hypothesis that carrying a large effect mutation might account for one or more of the molecular steps through the effect of the mutation, and thus leave fewer remaining steps before ALS begins. Background: In a previous study (Al-Chalabi et al, Lancet Neurology 2014), we assessed whether ALS incidence is consistent with the causal disease mechanism being a multistep process. We found evidence that process leading to ALS needs on average six molecular steps. Design/Methods: We used the incidence and genetic data of an ALS population register in Italy (2007–2015) and, as confirmation, the data from ALS cases diagnosed in the Republic of Ireland (2006–2014). 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 was regressed, using the regression coefficient and slope parameters to assess the evidence for a multistep model. Results: We identified 1077 cases of ALS with genetic test data (82.2% of all incident patients). C9orf72 mutations were detected in 74 cases (6.9%), SOD1 in 20 (1.9%), TARDBP in 15 (1.4%) and FUS in 3 (0.3%). In these patients, there was a linear relationship between log(incidence) and log(age) (r 2 =0.98) with a slope estimate of 4.99, consistent with a 6-step process. The analysis for C9orf72 mutated patients confirmed a linear relationship (r 2 =0.94) with a slope estimate of 2.22 suggesting a 3-step process. This estimate was confirmed by the data of the Irish ALS register. A linear relationship was also found for SOD1 mutated patients (r 2 =0.53; slope=0.76; 2-step process), and for TARDBP (r 2 =0.94; slope=3.24; 4-step process). Conclusions: The identification of a reduced number of steps in ALS patients with genetic mutations compared to those without mutations supports the concept of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS. Study Supported by: This is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND: UK, Medical Research Council and Economic and Social Research Council; Ireland, Health Research Board; Netherlands, ZonMw; Italy, Ministry of Health and Ministry of Education, University and Research. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867). OH and JR are funded by grants from the Irish Health Research Board, and by the charity Research Motor Neurone. Disclosure: Dr. Chio has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Mazzini has nothing to disclose. Dr. D9Alfonso has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Barberis has nothing to disclose. Dr. Hardiman has nothing to disclose. Dr. Rooney has nothing to disclose. Dr. Veldink has nothing to disclose. Dr. Pearce has nothing to disclose. Dr. Sproviero has nothing to disclose. Dr. Van den Berg has nothing to disclose. Dr. Al-Chalabi has nothing to disclose.