What causes amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)?

Updated: Apr 28, 2014
  • Author: Hidehiro Takei, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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The etiology of sporadic amyotrophic lateral sclerosis (ALS) remains uncertain, however, ALS is considered to be a multifactorial disease that is triggered by a complex interaction of internal factors (eg, genetic susceptibility to different neuronal insults and immunologic alterations) and external factors (eg, environmental variables).

The key theories proposed to date for the pathogenesis of ALS include glutamate-induced excitotoxicity, oxidative injury, altered mitochondrial function, cytoskeleton alterations, axonal transport dysregulation, neuroinflammation, immunomodulation, and autoimmunity. [18]

Of these, the leading theory is excitotoxicity induced by glutamate, the major excitatory neurotransmitter, which may disrupt intracellular calcium homeostasis, resulting in motor neuron death. Riluzole, a glutamate-release inhibitor, is licensed for the slowing of ALS progression, and randomized controlled trials have demonstrated a relatively mild effect, with a small positive effect on bulbar and limb function but not on muscle strength. [19]

An alternative hypothesis for which there are some current supporting data suggests that mitochondrial dysfunction acts with oxidative stress to cause abnormal neurodegeneration via calcium-mediated motor neuron injury. [20] As external or environmental factors, neurotoxicants such as various metals, chemicals, and foods have been proposed.

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