Causes of Amyotrophic Lateral Sclerosis (ALS)
The causes of ALS remain largely unknown, with approximately 90% of cases being sporadic without an identified genetic mutation, while the remaining 10% are familial cases linked to specific genetic defects. 1
Genetic Causes
Familial ALS accounts for approximately 10% of all cases and is associated with mutations in over 40 identified genes. 1, 2, 3 The four principal genes definitively linked to ALS pathogenesis include:
- SOD1 gene - the first familial ALS pathogenic gene discovered in 1993 2, 3
- C9orf72 - a major genetic contributor to both familial and sporadic ALS 2
- TDP-43 - involved in RNA processing and protein aggregation 2
- TBK1 - a more recently identified causative gene 2
Additional genes recently discovered include ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. 3 Monogenetic determinants are involved in roughly 20% of all ALS cases when including both familial and some sporadic cases. 4
Sporadic ALS and Unknown Etiology
Approximately 85-90% of ALS cases are sporadic with no known genetic mutation, representing the vast majority of disease burden. 1, 5 The National Academies of Science, Engineering, and Medicine emphasizes that more research is urgently needed to define the mechanisms underlying sporadic ALS. 1
Environmental Risk Factors
Environmental factors likely play a role in disease development in susceptible individuals, though proved causation remains elusive. 4 The complex role of environmental risk factors and gene-environment interactions requires further investigation to support earlier diagnosis and prevention efforts. 1
Potential environmental contributors include:
- Male gender - males may be selectively exposed to different influences or genetically predisposed to susceptibility 4
- Smoking - investigated as a potential risk factor 4
- Military service - associated with increased ALS risk 4
- Exercise - paradoxically may contribute in certain contexts 4
- Electrical exposure - studied as a potential environmental trigger 4
- Heavy metals - implicated in some epidemiological studies 4
- Agricultural chemicals - potential neurotoxic exposures 4
- Geographic clusters - suggesting localized environmental factors 4
Pathophysiological Mechanisms
The etiology is multifactorial, involving multiple interconnected pathways. 5 Key mechanisms include:
- Increased oxidative stress - contributing to neuronal damage 5
- Glutamate toxicity - excitotoxic injury to motor neurons 5
- Mitochondrial dysfunction - impaired cellular energy metabolism 5
- Inflammation - neuroinflammatory processes 5
- Apoptosis - programmed cell death of motor neurons 5
Gene-Environment Interactions
A critical concept is that gene-environment interactions likely account for a substantial portion of the unknown etiology in ALS. 6 While the risk exerted by many environmental factors may appear small individually, their effect could be magnified by the presence of genetic predisposition. 6 Climate underlies multiple environmental factors that have been implicated in ALS etiology, and the impact of global temperature increase on gene-environment interactions should be carefully monitored. 6
Disease Model
ALS should be considered the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline. 7 This model explains why ALS typically manifests in mid-to-late life despite genetic predispositions being present from birth. 7
Clinical Implications
The heterogeneity of ALS causes necessitates understanding this complexity to find effective treatments. 2 Less well understood multigenetic causes may contribute to another 20-80% of cases beyond the clearly monogenetic forms. 4 The lack of large cohorts with detailed genetic and environmental information currently hampers the search for gene-environment interactions, though newer algorithms and machine learning approaches offer opportunities to advance this understanding. 6