Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

Francesca Trojsi,Gioacchino Tedeschi,Giulia D’Alvano,Simona Bonavita

doi:10.3390/ijms21103647

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure
In the light of the current need to reclassify Amyotrophic Lateral Sclerosis (ALS) patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex, as both independent and synergic factors, on the pathophysiology, clinical presentation, and prognosis of ALS
ALS is a complex disease, and this complexity is mostly due to the heterogeneity of its phenotype, influenced by genetics through oligogenic mechanisms, that is, through gene–gene interactions [12,19] and by demographic factors, including age and sex, and by environment, which have longstanding negative effects, probably interacting with genetics through epigenetic mechanisms [38,47,110]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Defects in some of these pathways may represent a secondary phenomenon, and taking into account that 5–15% of ALS patients have a familial disease (FALS) and that multiple genetic risk factors have been recently revealed for sporadic ALS (SALS) [3], genetics has provided relevant insights regarding pathophysiology underlying ALS It is considered a multifactorial disease, influenced by genetic and environmental factors. Data from ALS population registers in Italy and the Republic of Ireland confirmed that deficits in multiple pathways, reflecting a “multistep” model of disease consistent with a six-step process, are required to develop ALS, they revealed that a reduced number of steps are detected in patients with ALS with genetic mutations compared to those without mutations [7] These findings from the interrogation of population-based registers further emphasize the need to study the interaction between genetic, demographic, environmental, and lifestyle risk factors. The role of sex in clinical presentation and prognosis of ALS patients carrying superoxide dismutase-1 (SOD1) mutations and chromosome 9 open reading frame 72 (C9orf72) repeat expansion has been explored [6,7,8,9,10]

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