Causes of Amyotrophic Lateral Sclerosis (ALS)
ALS is a multifactorial disease with approximately 10-20% of cases caused by known genetic mutations, while the remaining 80-90% of sporadic cases result from complex interactions between genetic susceptibility, environmental exposures, and aging-related factors. 1, 2, 3, 4
Genetic Causes
Familial ALS (10-15% of cases)
- Over 40 ALS-related genes have been identified since the discovery of SOD1 in 1993, with known genetic mutations accounting for approximately 70% of familial ALS cases 5, 4
- Recently discovered ALS genes include ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7 4
- Heritability estimates range from 8% to 61%, indicating substantial genetic contribution beyond identified mutations 5
Sporadic ALS (85-90% of cases)
- Known genetic mutations account for only 15% of sporadic cases, suggesting multigenetic contributions may account for another 20-80% 6, 4
- Annual incidence is 1-2 per 100,000 people 1, 3
Environmental Factors
The "ALS exposome" refers to the lifetime accumulation of environmental exposures that increase disease risk, though definitive causation remains difficult to establish. 5
Established Risk Factors
- Older age is the only firmly established demographic risk factor 7
- Male gender (males may be selectively exposed to different environmental influences or genetically predisposed to susceptibility) 6, 7
- Family history of ALS 7
Potential Environmental Contributors
- Smoking has been investigated as a potential risk factor 6
- Military service shows epidemiological associations 6
- Excessive physical exercise may contribute in susceptible individuals 6
- Electrical exposure has been studied but causation remains unproven 6
- Heavy metals exposure is a potential contributor 6
- Agricultural chemicals have been investigated in geographic clusters 6
Pathophysiological Mechanisms
The etiology involves multiple cellular and molecular pathways leading to progressive motor neuron degeneration. 1, 2
Core Pathogenic Mechanisms
- Increased oxidative stress contributes to neuronal damage 1, 2
- Glutamate excitotoxicity causes motor neuron death 1, 2
- Mitochondrial dysfunction impairs cellular energy metabolism 1, 2
- Chronic inflammation and microglial activation occur at sites of neurodegeneration 1, 7
- Apoptosis (programmed cell death) of motor neurons 1, 2
Competing Theories on Disease Initiation
- Dying-forward hypothesis: Motor neuron degeneration begins with hyperexcitable corticomotoneurons causing anterograde transsynaptic excitotoxic damage (supported by transcranial magnetic stimulation studies) 8
- Dying-back hypothesis: Disease begins peripherally with toxic factors retrogradely transported to the central nervous system 8
- Independent hypothesis: Upper and lower motor neurons degenerate independently 8
Integrated Causation Models
Gene-Time-Environment Hypothesis
- ALS onset occurs through interaction of genetic susceptibility with environmental exposures during the aging process 5
Multistep Model
- Several "hits" (at least some environmental) are required to trigger disease onset, even in presence of highly penetrant ALS-associated mutations 5
Clinical Implications
- No single cause explains all ALS cases; the disease represents a final common pathway of motor neuron degeneration from multiple etiologies 8, 7
- Autoimmune mechanisms may contribute to pathogenesis, with evidence of innate immune system involvement 7
- No naturally occurring animal models exist, and transgenic mouse models fail to faithfully reproduce human ALS 8
- Median time from symptom onset to diagnosis is 14 months, primarily due to the heterogeneous presentation and lack of definitive biomarkers 3, 7