Amyotrophic lateral sclerosis – etiology, pathogenesis, and clinical
manifestations.
ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to combined signs of both types of motor neuron dysfunction.
- Also called Lou Gehrig’s disease.
Etiology (Causes)
- 1 Sporadic (most common)
- Accounts for ~90–95% of cases.
- Exact cause unknown.
- Environmental factors implicated (e.g., toxins, oxidative stress).
- 2 Familial (5–10% of cases)
- Autosomal dominant inheritance most common.
- Mutations in:
- SOD1 gene (superoxide dismutase 1) — most studied; leads to toxic gain of function.
- C9orf72 gene (hexanucleotide repeat expansion).
- TARDBP (TDP-43 protein), FUS genes.
Pathogenesis
- 1 Motor neuron degeneration
- Loss of upper motor neurons (UMNs) in motor cortex.
- Loss of lower motor neurons (LMNs) in brainstem (especially hypoglossal nucleus) and anterior horns of spinal cord.
- 2 Mechanisms of neuronal death
- Excitotoxicity: excessive glutamate activity → intracellular calcium overload → neuron injury.
- Oxidative stress: SOD1 mutations → accumulation of reactive oxygen species.
- Abnormal protein aggregation: TDP-43 and other misfolded proteins accumulate in motor neurons.
- 3 Muscle denervation
- Progressive loss of LMNs → denervation atrophy (muscle wasting).
- UMN loss → impaired cortical control of movement.