Amyotrophic lateral sclerosis

It is a degenerative disease that mainly affects the neurons that control voluntary muscle movement. It rapidly leads to a limiting state caused by weakness of the muscles needed to move, speak, eat or breathe. It is a rare disorder with an overall incidence of 0.6 to 3.8 cases per 100,000 population per year.

The cause of ALS is not known, however, scientific evidence suggests that both genetics and environment play a role in the degeneration of motor neurons and the development of ALS. In addition to the hereditary factor that accounts for 5-10% of cases, some of the established risk factors for ALS include the following:

  • Age: The risk of ALS increases with age, and is most common between the ages of 40 and mid-60s.
  • Gender: Before age 65, ALS is slightly more common in men than in women. This gender difference disappears after age 70.
  • Smoking. Smoking is the only likely environmental risk factor for ALS. The risk appears to be higher for women, particularly after menopause.
  • Exposure to environmental toxins. Some evidence suggests that exposure to lead or other substances may be related to amyotrophic lateral sclerosis, although currently no agent or chemical has been consistently associated.
  • Exposure to infectious agents or viruses, physical trauma, diet, strenuous physical activity, and behavioral and occupational factors may have an impact on the development of this disease.

Ten percent of ALS cases have a family history, whereas apparently sporadic ALS is considered a complex trait whose heritability is estimated at 40-50%. There is no accepted definition of familial or sporadic ALS, they probably represent extremes of a spectrum with overlapping genetic architectures in which the same genes are implicated. In this context, the largest trans-ethnic GWAS study to date consisting of 27000 cases and nearly 140000 controls has shown 9 significant loci that would contribute to ALS risk, and has suggested a causal role for cholesterol, which may be linked to ALS susceptibility.


Symptoms of amyotrophic lateral sclerosis vary greatly from person to person. The onset usually begins with muscle weakness that may be so subtle that the symptoms go unnoticed. Over time it worsens and symptoms become more obvious weakness or atrophy that makes it impossible to perform routine activities. The most common symptoms include:

  • Muscle spasms and cramps especially in hands and feet.
  • Loss of motor control in the hands and arms, muscle stiffness (spasticity) and impaired use of arms and legs.
  • Weakness and fatigue.
  • Stumbling and falling.
  • Uncontrollable periods of laughing or crying.
  • Difficulty speaking or projecting the voice.

As the disease progresses, symptoms may include shortness of breath, difficulty breathing and swallowing, and paralysis. ALS sufferers eventually lose the ability to breathe on their own and must rely on a ventilator. Affected individuals also face an increased risk of pneumonia during the later stages of the disease. Fifty percent of affected patients live at least three or more years after diagnosis; 20% live five years or more; and up to 10% will survive more than ten years. The outcome is usually fatal, and results from respiratory failure and respiratory insufficiency.


Except for hereditary cases, which account for a minority of ALS cases, the cause is unknown, so there is no method of prevention.

Number of observed variants

13.5 million variants

Number of risk loci analyzed in the study

9 loci


Longinetti E et al. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019;32(5):771-776.

National Institute of Neurological Disorders and Stroke [March 2022]

Johns Hoskins Medicine Institute [March 2022]

Van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nature Genetics. 2021 Dec;53(12):1636-1648.

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