What are the causes of Amyotrophic Lateral Sclerosis (ALS), including environmental and genetic factors?

Causes of Amyotrophic Lateral Sclerosis (ALS): Environmental and Genetic Factors

ALS is caused by a complex interplay of genetic and environmental factors, with approximately 90% of cases being sporadic without a known genetic mutation, requiring more research to define the underlying mechanisms including environmental risk factors and gene-environment interactions. 1

Genetic Factors

Familial ALS (10% of Cases)

• Approximately 10% of ALS cases show autosomal dominant inheritance pattern 2
• More than 20 genes have been associated with ALS development 2
• Key genetic mutations include:
  • C9orf72 gene hexanucleotide repeat expansion (most common genetic cause)
    • Responsible for 30-50% of familial ALS
    • Accounts for 7% of sporadic ALS cases 2
  • SOD1 gene mutations
  • TDP-43 gene mutations
  • TBK1 gene mutations 3

Sporadic ALS (90% of Cases)

• Most cases have no known genetic mutation 1
• May involve genetic predisposition that interacts with environmental factors
• Genetic variants affecting elimination of toxic chemicals from the body may increase susceptibility to environmental exposures 1

Environmental Risk Factors

Environmental factors that have been implicated in ALS development include:

• Occupational exposures:

  • Heavy metals
  • Pesticides
  • Industrial chemicals 4

• Lifestyle factors:

  • Tobacco use
  • Athletic activity/excessive physical exertion 5

• Other potential factors:

  • Exposure to toxins
  • Viral infections
  • Head trauma
  • Military service 6

Gene-Environment Interactions

The current understanding suggests that ALS likely develops through:

• Environmental risks acting on pre-existing genetic susceptibility 6
• Time as a critical factor (age-related degeneration) 5
• Environmental factors that may appear to have small individual effects but could be magnified in genetically susceptible individuals 4

Climate Considerations

Climate may influence various environmental exposures implicated in ALS development:

• Global temperature increases could potentially affect gene-environment interactions 4
• Climate-related changes in exposure to environmental toxins may influence disease risk

Pathophysiological Mechanisms

Multiple pathophysiological processes contribute to motor neuron degeneration:

• Mitochondrial dysfunction
• Aggregation of misfolded proteins
• Oxidative stress
• Excitotoxicity
• Neuroinflammation
• Apoptosis 5

Challenges in Understanding ALS Etiology

• Heterogeneous disease with multiple potential causes
• Difficulty in establishing definitive environmental risk factors
• Limited large cohorts with detailed genetic and environmental information 4
• Complex spread of pathology throughout the central nervous system once initiated 7

Future Directions

• Machine learning approaches may help identify gene-environment interactions 4
• Better understanding of disease mechanisms may lead to more effective treatments
• Research into environmental risk factors and gene-environment interactions is needed to support earlier diagnosis, therapeutic development, and prevention efforts 1

The complexity of ALS etiology highlights the need for comprehensive research approaches that consider both genetic and environmental factors, as well as their interactions, to develop effective prevention strategies and treatments for this devastating disease.