Erfan Bashar
Back to ALS and Motor Neuron Disease

ALS — Pathophysiology

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

ALS destroys upper motor neurons (UMN) in the motor cortex and lower motor neurons (LMN) in the brainstem and spinal cord. Sensory, autonomic, and most cognitive systems stay largely intact. Why the motor system fails first remains incompletely understood.

Why motor neurons are vulnerable

Three hypotheses try to explain the selective damage. None is proven, and they likely combine.

  1. Axonal length. Motor neurons are among the largest cells in the body. Axons supplying leg muscles can exceed a metre. That length imposes transport and energy demands that may leave the cell with little reserve.
  2. Cortical origin (“dying forward”). Some evidence places the start in the motor cortex, with disease spreading anterogradely to spinal motor neurons. This model remains debated.
  3. Combined risk. Genes, metabolism, and environmental exposures appear to interact in susceptible cells. No single factor explains sporadic disease.

Glutamate and oxidative injury

Excess synaptic glutamate overstimulates motor neurons. The resulting calcium entry kills the cell. This sequence is called excitotoxicity. Riluzole is believed to reduce this damage by decreasing glutamate release, though its exact action remains uncertain.

Motor neurons also face oxidative stress from free radicals. Edaravone is thought to neutralise these radicals. Its clinical benefit is small and limited to selected patients.

In 2006, TDP-43 was identified as the deposited protein in most ALS and in the common behavioural forms of frontotemporal dementia (FTD). The two diseases are now seen as different expressions of one TDP-43 proteinopathy. About 97% of motor neuron disease shows this molecular pathology.

In cohorts, roughly half of ALS patients develop cognitive or behavioural change. About 10% develop full FTD. A comparable share of FTD patients develops motor signs over time. The C9orf72 repeat expansion is the most common genetic cause of both.

Genes: C9orf72 and SOD1

C9orf72 hexanucleotide expansions cause about 25–40% of familial ALS. SOD1 mutations cause another 12–20% of familial cases, roughly 2% of all ALS.

Genetic testing is offered when family history, young onset, or FTD features suggest inherited disease. A confirmed SOD1 mutation is required before tofersen treatment. Prevention trials in carriers without symptoms, such as the ATLAS study, are ongoing and not established care.

Evidence anchors

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