What are the genetics components of Amyotrophic Lateral Sclerosis (ALS)?

Genetic Components of Amyotrophic Lateral Sclerosis (ALS)

Approximately 10% of ALS cases have identifiable genetic mutations, while 90% are sporadic without known genetic causes, though genetic susceptibility factors contribute to an overall heritability of 40-60% for ALS. 1, 2

Key Genetic Factors in ALS

Familial ALS (FALS)

• Represents 5-10% of all ALS cases with family history of ALS or related conditions like frontotemporal dementia 2
• Approximately 80% of familial cases can have an identifiable pathogenic gene variant 2
• Inheritance patterns include:
  • Autosomal dominant (most common)
  • Autosomal recessive
  • X-linked 3
• Families with low disease penetrance are frequently observed, which may lead to misclassification as sporadic ALS 3

Most Common ALS-Associated Genes

1. C9orf72 - Hexanucleotide repeat expansion

   • Most common genetic cause (30-50% of familial ALS and 7% of sporadic ALS)
   • Also a frequent cause of frontotemporal dementia, highlighting molecular overlap between ALS and FTD 4

2. SOD1 (Superoxide dismutase 1)

3. TARDBP (TAR DNA-binding protein 43)

4. FUS (Fused in sarcoma) 5

Genetic Architecture

• More than 40 genes have been identified as contributing to ALS susceptibility 5
• Genetic variants include:
  • Single base changes
  • Repeat expansions (like in C9orf72)
  • Copy number variants
  • Other structural variations 2

Sporadic ALS and Genetic Factors

• Represents approximately 90% of ALS cases 4
• Despite no family history, genetic factors still play a role:
  • Some carry the same mutations as familial cases but with reduced penetrance
  • Age-dependent expression of genetic variants
  • Complex interplay between multiple genetic and environmental factors 1, 6
• The genetic architecture includes both rare variants with variable effect size and more common variants with small effect size 5

Clinical Implications of Genetics in ALS

Phenotypic Variability

• Considerable variation in disease presentation and progression
• Survival typically ranges from 2-5 years from onset
• Variable expression includes presence/absence of cognitive impairment 1
• No clear clinical features distinguish hereditary from sporadic ALS except lower mean age of onset in hereditary cases 3

Genetic Testing Considerations

• No consensus on which genes to test for, despite emerging gene-targeted therapies 5
• The National Academies of Sciences, Engineering, and Medicine recommends:
  • Development of specific research programs for individuals at risk for ALS
  • Insurance coverage of genetic testing and counseling services for all living with ALS and their families 7

Future Directions

• Large-scale natural history studies of at-risk genetic carriers are needed 7
• International collaborative genetic epidemiological studies are essential to better understand the complex interplay between genetic and environmental factors 1
• Emerging gene silencing therapies for specific genetic subtypes highlight the need for improved access to genetic testing 5

The genetic landscape of ALS continues to evolve with ongoing research, emphasizing the need for comprehensive genetic studies to improve understanding, diagnosis, and development of targeted therapies for this devastating disease.