This article will review genetics’ role in the development of ALS, types of ALS, genetic testing, and potential environmental causes.

Is ALS Genetic?

The vast majority of ALS cases are sporadic, meaning that the condition occurs randomly and without any knowns risk factors or family history of ALS.

About 5–10% of all ALS cases are genetic or “familial.” This means that the person inherits the disease from a parent. Familial ALS usually only requires one parent to carry the disease-causing gene. There are more than a dozen gene mutations known to cause familial ALS.

Those with family members with the sporadic form of the disease are at an increased risk for developing ALS. However, the overall risk is still very low, and most will never develop the disease.

Types of ALS

ALS is typically divided into two types: sporadic and genetic.

However, other forms of ALS are categorized by clinical onset, including:

Limb-onset: First symptoms include muscle weakness, muscle wasting in the arms and legs, and involuntary muscle contractions. Bulbar ALS: First symptoms affect the muscles involved in speaking, swallowing, and breathing. These symptoms cause slurred speech and difficulty swallowing.

Other forms of the disease include:

Guamanian ALS: Occurs more commonly in one location in the Pacific around the island of Guam. Juvenile ALS: Affects younger people under the age of 25. ALS-Parkinsonism-Dementia Complex (ALS-PDC): ALS-PDC is a rare disorder that includes the signs and symptoms of ALS. However, this disorder also includes movement abnormalities, known as parkinsonism, and worsening impaired cognition, called dementia.

ALS Genes and Mutations

An ALS gene mutation is an error in DNA that affects protein. This can result in the cell making too little protein, too much protein, or a defective protein. Effects on the gene depend on the type of mutation occurring. However, any change to a gene’s normal protein can harm the cell and cause disease, including ALS.

C9ORF72

C9ORF72 is the most frequent genetic cause of ALS in Europe and North America. This form is extremely rare in Asian and Middle Eastern populations.

SOD1

Over 200 mutations in the SOD1 gene have been found to cause ALS. About half of all Americans with ALS caused by SOD1 gene mutations have a mutation that replaces the amino acid alanine with the amino acid valine.

SPTLC1

Research has shown that mutations in the SPTLC1 gene are a cause of juvenile or childhood-onset ALS.

NEK1

One study found that genetic variants of the NEK1 gene appear to increase the odds of developing ALS. These patients are significantly more likely to experience weakness in their hands as a first symptom.

TDP-43

Research has found that changes to the TDP-43 protein cause gene proteins to misfold and form protein clumps. These clumps have been found in nerve cells that control muscle movement in some people with ALS.

FUS

At least 85 mutations in the FUS gene have been found to cause ALS. These mutations might prevent messenger RNA transport out of the cell’s nucleus, trapping the RNA inside the cell. This may form clumps, which have been found in nerve cells that control muscle movement in some people with ALS.

UBQLN2

Research shows that mutations in UBQLN2 cause ALS with frontotemporal dementia. The mechanism by which the UBQLN2 mutations cause disease remains unclear; however, researchers believe it involves the prevention of misfolded protein clearance.

KIF5A

Mutations in the KIF5A gene were recently identified as a genetic cause of ALS.  One recent study reports that ALS-linked mutant KIF5A leads to dysregulated motor activity and decreased survival of neurons.

Genetic Testing for ALS

Genetic testing for ALS exists to determine whether a person’s ALS has an underlying genetic cause. If the test identifies a disease-causing variant, other family members may have the option to test themselves to see if they have the same variant. This is called predictive genetic testing and can be discussed in further detail with a genetic counselor.

Some people with ALS may want to get tested to understand better why they got the disease, how it might progress, and the likelihood their children will develop ALS.

Environmental Triggers

Some environmental factors can increase the risk of developing ALS.

Smoking

Tobacco smoking points to an increased risk of developing ALS in several studies. However, it is unknown whether the association between ALS and smoking is caused by nicotine or another toxic substance in tobacco smoke.

Exposure to Environmental Toxins

There is some evidence that heavy metal exposure may increase ALS risk. These toxins include lead, mercury, and manganese.

Military Service

Several studies show a correlation between U.S. military service and an increased risk factor for ALS. However, the increased risk is very small, and no singular specific factor has been identified.

Summary

Current research suggests that both genetics and environment play a role in motor neuron degeneration and the development of ALS. The vast majority of ALS cases are sporadic cases, meaning they occur randomly and without any known risk factors or family history of ALS.

Researchers suspect that mutations in genes involved in protein quality control are linked to ALS. Environmental triggers such as smoking, military service, and exposure to environmental toxins may also have a link to ALS risk.