Brain Primer

Amyotrophic Lateral Sclerosis

  • Published17 Apr 2023
  • Author Clinton Parks
  • Source BrainFacts/SfN
Amyotrophic Lateral Sclerosis
iStock.com via Sinhyu

Amyotrophic Lateral Sclerosis (ALS) isn’t one thing, it’s a group of progressive, ultimately fatal motor neuron diseases. ALS is also called Lou Gehrig’s disease after the renowned New York Yankee first baseman, who was one of the most famous patients with the disease. ALS forced Gehrig to retire at age 36; he died two years later. ALS affects as many as 15,000 Americans, most are between the ages of 50 and 70.

Men are slightly more likely than women to develop the disorder; however, the gap decreases with age. For unknown reasons, non-Hispanic whites are more likely than other ethnicities to develop ALS. Military veterans’ likelihood of developing the disease is as much as 1.5 to 2 times higher than the rate in the general population — possibly due to exposure to environmental toxins like lead and pesticides.

Symptoms

Unlike other neurodegenerative disorders, generally neither cognition nor personality is affected in individuals with ALS. Early ALS symptoms include muscle weakness, twitching, and eventual paralysis in the hands and feet. These symptoms gradually spread as patients lose strength and the ability to move, speak, and eat. Most ALS patients die within three to five years after symptoms appear due to nerve damage affecting the respiratory muscles. However, 10% of ALS patients — like the physicist Stephen Hawking — survive 10 years or more.

Pathology and Causes

Motor neurons connect the brain to the spinal cord and to the voluntary muscles throughout the body. In ALS, the motor neurons degenerate and then die. Without this neural communication, a person’s voluntary muscles weaken, start to twitch, and finally atrophy.

Only 5% to 10% of ALS cases are solely due to genetic factors — a condition called “familial ALS;” the non-familial disease is called “sporadic ALS.” While several genes have been identified that increase susceptibility to ALS, there is no clear pattern of inheritance. Among cases with a genetic component, about 25% to 40% are caused by a harmful mutation in the C9ORF72 gene. Some individuals with this mutation show symptoms of both motor neuron and dementia disorders, a condition known as ALS-FTD (ALS-frontotemporal dementia). Another 12% to 20% of hereditary cases result from mutations that prevent the SOD1 gene from coding for superoxide dismutase — an enzyme that catalyzes the breakdown of cell-damaging superoxide radicals into more benign molecular oxygen or hydrogen peroxide. These and other hereditary forms of ALS, such as those involving UBQLN2 and VEGF genes, provide valuable insights into the mechanisms of the disease.

Research and Treatments

There is no cure for ALS, nor has any medication been found that can stop or reverse its progression. But the U.S. FDA has approved edaravone, riluzole, and sodium phenylbutyrate/taurursodiol for treating ALS. Edaravone, an antioxidant that inhibits the production of cell-damaging free radicals, can ameliorate disease symptoms. Riluzole decreases glutamate levels and has been shown clinically to extend the life of ALS patients by a few months. Sodium phenylbutyrate/taurursodiol is a combination medication aimed at reducing cell death pathways in neurons’ mitochondria and endoplasmic reticulum.

For those with the SOD1 mutation, there is also hope for a gene silencing technique using an artificial RNA snippet. Lab tests in mouse models have preserved muscle strength and motor and respiratory functions, and delayed disease onset and death. This treatment has also safely silenced SOD1 in the lower motor neurons of nonhuman primate models. One drug, tofersen, has demonstrated its potential to slow the progression of SOD1 ALS and has been granted priority review by the FDA.

Participation in a multidisciplinary ALS clinic, an ALS Association Certified Treatment Center of Excellence, or a Recognized Treatment Center can also improve ALS patients’ quality of life. 


Adapted from the 8th edition of Brain Facts by Clinton Parks.

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