Familial amyotrophic lateral sclerosis (ALS) is an uncommon form of ALS that occurs due to an inherited gene. The disease causes motor neurons to die, which can lead to progressive muscle weakness.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a type of motor neuron disease. In some cases, ALS occurs due to an inherited gene. Experts usually refer to inherited ALS as familial ALS.

Familial ALS causes motor neurons to die. As motor neurons control movement, the death of these cells leads to muscle twitching and progressive muscle weakness. Currently, there is no effective treatment for familial ALS.

This article discusses the role of genetic factors in ALS, testing for familial ALS, and nongenetic causes of the disease.

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In some cases, genetics may play a role in the development of ALS. However, most cases of ALS occur without a known genetic connection. This means ALS occurs randomly without a family history of the condition and no known risk factors. But doctors classify about 10% of cases as familial ALS. In familial ALS, one or more blood relatives have ALS.

Scientists have identified at least 40 genes linked to ALS. A gene variation can occur due to changes in the cell’s DNA. Certain gene alterations may cause ALS.

Researchers do not always know the specific physiological effect of the gene variation. However, it appears gene alterations may affect the production of certain proteins that become toxic and may cause ALS. Each specific gene mutation may increase the risk for ALS a little differently.

Some of the genes associated with ALS include:

  • C9ORF72: Variations in the gene C9ORF72 are the most common genetic cause of ALS and account for 25–40% of familial ALS.
  • SOD1: This is the second most common gene linked to ALS. It accounts for about 10–20% of familial ALS cases. A mutation in the SOD1 gene may produce a defective protein that has a toxic function and leads to ALS.
  • FUS: This gene appears to be associated with familial ALS in about 5% of cases. It may impair typical RNA processing from a variety of genes and lead to ALS.
  • TARDBP: Similar to FUS, TARDBP appears to alter the RNA of varied genes. It has a link with about 4% of familial ALS cases.
  • NEK1: A 2021 meta-analysis found the NEK1 mutation may account for about 3.1% of cases of familial ALS.
  • UBQLN2: A 2019 review found that alterations in the UBQLN2 gene were linked to the impaired clearing of damaged cells and neuroinflammation, increasing the risk of ALS.
  • KIF5A: A variation in KIF5A appears to cause altered nerve fiber transport, among other changes linked to the development of familial ALS.

The development of ALS may occur due to a combination of genetics and environmental factors. Anyone can develop ALS, but experts have identified some factors that increase a person’s risk of developing it.

According to the National Institute of Neurological Disorders and Stroke, the following factors may increase an individual’s risk of ALS:

  • Age: Most people develop symptoms between the ages of 55–75 years.
  • Biological sex: Males are slightly more likely to develop ALS than females.
  • Race and ethnicity: Anyone of any race or ethnicity can develop ALS. However, non-Hispanic and Caucasian individuals are most likely to develop the disease.
  • Veteran status: Military veterans appear to develop ALS up to two times more than the general population. This may occur due to exposure to encountering environmental exposures.

Testing for familial ALS involves giving a blood or saliva sample. Technicians analyze the sample, isolate an individual’s DNA, and test for genes linked to ALS.

Genetic testing helps determine if someone has a variation in a specific gene that may increase the risk of ALS. About 60–70% of people with familial ALS have a positive genetic test with an identified gene mutation.

Some people may still have familial ALS even without a positive result from genetic testing. In those instances, familial ALS may have developed due to a gene alteration not yet discovered.

Doctors classify the majority of cases of ALS as sporadic. In most instances, the cause remains unknown. Researchers continue to study potential causes of ALS to determine any factors connected with the condition.

A 2018 review indicates that possible factors which may contribute toward ALS include:

  • immune system changes
  • viral exposures
  • smoking
  • exposures to heavy metals
  • pesticides
  • glutamate toxicity
  • solvents
  • oxidative stress

However, evidence also suggests there is not a definitive relationship with the above factors. Additionally, according to the Centers for Disease Control and Prevention (CDC), studies have not found a definite environmental cause.

ALS may have a genetic link in some cases. About 10% of cases of ALS appear to be related to inheriting specific gene variations. Several different gene alterations may affect the development of familial ALS. The genes may alter protein development in the cells and affect motor function.

But most instances of ALS are sporadic, and the exact cause remains unclear. Possible factors associated with ALS include exposure to pesticides, heavy metals, and oxidative stress.