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

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.

Figure 1. Slope estimation for all patients with ALS

(A) Log incidence vs log age for all patients with incident amyotrophic lateral sclerosis (ALS) who have been genetically tested (n = 1,077) (y = 4.65x − 7.60, r² = 0.98). (B) Log incidence vs log age for all patients with incident ALS in the register (n = 1,309) (y = 4.83x − 7.85, r² = 0.99).

Figure 2. Slope estimation for all those with familial ALS

Log incidence vs log age for all patients with incident familial amyotrophic lateral sclerosis (ALS) (n = 111) (y = 2.95x − 5.45, r² = 0.92).

Figure 3. Slope estimation for all patients with ALS carrying a mutation in 1 of 4 tested genes

Log incidence vs log age for C9orf72 amyotrophic lateral sclerosis (ALS) (74 cases) (y = 2.22x − 4.33, r² = 0.94) (red line), for SOD1 ALS (20 cases) (y = 0.758x − 2.43, r² = 0.53) (green line), and for TARDBP ALS (15 cases) (y = 3.24x − 6.76, r² = 0.93) (blue line). The fit to a straight line is good, consistent with a multistep model.

Figure 4. Slope estimation for patients with type 1 and 2 diabetes mellitus

Data from Piemonte diabetes register. Log incidence vs log age for type 1 diabetes mellitus (y = 0.96x − 0.66, r² = 0.98) (red line) and type 2 diabetes mellitus (y = 5.28x − 6.78, r² = 1.0) (blue line).