What is the cause of amyotrophic lateral sclerosis (ALS)?

What Causes ALS?

ALS is caused by progressive degeneration and death of motor neurons in the brain and spinal cord, with approximately 90% of cases being sporadic (occurring without known genetic mutation) and 10% being familial (inherited genetic mutations). 1, 2

Etiologic Classification

Sporadic ALS (90% of cases)

• Sporadic ALS represents 85-90% of all cases and occurs without a known genetic mutation or family history. 2, 3, 4
• The etiology is multifactorial, involving several interconnected pathological mechanisms: 2, 4
  • Increased oxidative stress
  • Glutamate excitotoxicity
  • Mitochondrial dysfunction
  • Chronic inflammation
  • Apoptotic cell death pathways
• The annual incidence is 1-2 per 100,000 people. 2
• More research is needed to define the mechanisms underlying sporadic ALS, including the complex role of environmental risk factors and gene-environment interactions. 1

Familial ALS (10% of cases)

• Familial ALS accounts for 10-20% of cases and is caused by inherited genetic mutations. 5
• More than 20 genes have been identified as causative for familial ALS, with four major genes explaining >50% of familial cases: 5
  • SOD1 (superoxide dismutase 1) - the most common cause of familial ALS 6, 5
  • C9orf72 - the most common genetic cause of FTD and ALS 1
  • TARDBP (TDP-43) 7
  • FUS (fused in sarcoma) 7
• Other rare genetic causes include mutations in CHMP2B, VCP, TBK1, TIA1, OPTN, CCNF, and CHCHD10. 1
• Genetic causes are found in 1-10% of apparent sporadic disease cases, meaning some patients without family history still carry pathogenic mutations. 1

Fundamental Pathophysiology

• ALS is fundamentally a disease of axonal degeneration affecting motor neurons, NOT a primary demyelinating disease. 4
• The primary pathological process is progressive degeneration and death of both upper motor neurons (in the brain/corticospinal tracts) and lower motor neurons (in the spinal cord anterior horns). 4
• Any demyelination observed on imaging is secondary to the primary axonal degeneration, not the initial insult. 4

Important Clinical Considerations

• The exact pathogenic mechanisms remain incompletely understood despite decades of research. 1, 6
• There is no definitive biomarker or test for ALS, complicating early diagnosis. 1
• Gene-environment interactions likely contribute to disease development in both sporadic and familial cases, though specific environmental risk factors remain poorly defined. 1, 8
• ALS is considered a paradigm for multifactorial diseases, where most cases result from interactions between multiple genes and environmental factors. 8
• Understanding the genetic basis of familial ALS has provided essential insights into the pathogenesis of sporadic ALS as well. 7