Objective:

To investigated the existence of a female protective effect in ALS, meaning that females have an inherent biological advantage that raises their threshold for developing disease manifestations.

Background:

Male sex has long been considered a risk factor for ALS, with females showing a lower incidence and later onset compared to male patients. However, the underlying reasons for these differences are still not well understood. 

Design/Methods:

In this study, we analyzed a cohort of 2264 ALS patients and asymptomatic carriers of pathogenic mutations in ALS genes from the Piemonte and Sardinia regions of Italy. We first assessed the differences in the burden of rare ALS-related damaging variants between sexes. Subsequently, we calculated the ratio of females to males among all mutation carriers and the recurrence rate among relatives of ALS patients carrying a disease-related mutation. We performed a separate analysis for carriers of the TARDBP:A382T founder mutation, that is relatively common in Italy.

Results:

The analysis of our Italian cohort revealed a higher burden of rare damaging variants in female ALS cases compared to males (OR 1.51, 95%CI 1.13-2.01, P=0.0037). Among 93 TARDBP A382T mutation carriers identified in our Italian cohort, we observed a striking female:male ratio of 2:1. Moreover, affected mothers displayed a 10% higher recurrence rate of passing the mutation to their children compared to affected fathers (29% vs 19%). Similar results were seen in the separate group of 48 non-A382T TARDBP mutation carriers. In contrast, no imbalanced sex ratios or recurrence rate differences were detected among high penetrance SOD1 and C9orf72 mutation carriers.

Conclusions:

Our findings demonstrate an apparent female protective effect in ALS caused, suggesting that females require a higher burden of genetic and/or environmental risk factors before developing motor neuron disease. Whether this protective effect is gene-specific and its potential underlying biological should be further investigated.