Overview

• Prevalence: 5/100,000 population in the US [1]

• Incidence: 2–3 cases/100,000 population per year worldwide [2]

• Sex: ♂ > ♀

• Mean age of onset is 65 years.

• Familial history of ALS in 5–10% of cases ; 90–95% are sporadic

Mutations of the following genes have been found in approx. 70% of familial clusters and some sporadic cases. [4]

• SOD1 [5]

  • Codes for superoxide dismutase

  • Mutations are associated with either a very aggressive or very slow disease progression

  • Account for 15–20% of familial ALS cases

• TARDBP

  • Сodes for the TDP-43 protein involved in DNA repair

  • In ALS, abnormally ubiquitylated TDP-43 forms inclusions within motor neurons.

  • Accounts for ∼ 5% of familial ALS cases

• C9orf72

  • Most common mutated gene in familial ALS (account for 30–40% of familial ALS cases)

  • Associated with a combination of ALS and frontotemporal dementia

• FUS

  • Mutations are associated with a young-onset rapidly-progressing ALS. [1]

  • Accounts for ∼ 5% of familial ALS cases

• Exposure to the following substances:

  • β-N-methylamino-L-alanine [7]

  • Pesticides (e.g., cis-chlordane, pentachlorobenzene) [8]

  • Lead

• Head trauma

• Individuals serving in US military [6][9]

• Smoking

• Classically affects the entire motor neuron system at two or more levels (both upper and lower motor neuron degeneration).

  • Upper motor neurons in the precentral gyrus and, frequently, prefrontal cortex

  • Lower motor neurons in the anterior horn of the spinal cord and brainstem

• Potential underlying mechanisms include abnormal RNA processing and protein aggregation, excitotoxicity, mitochondrial dysfunction, and defective neurofilaments.