Causes of ALS

The exact causes of amyotrophic lateral sclerosis (ALS) are largely unknown, but a number of factors, including genetics, environmental exposures, and lifestyle habits, have been linked to an increased risk of developing the neurodegenerative condition.

Also known as Lou Gehrig’s disease, for the famous baseball player diagnosed with the disorder in 1939, ALS is characterized by the progressive death of motor neurons — the specialized nerve cells that control muscle movement — leading to muscle weakness and other symptoms.

Scientists don’t entirely understand why motor neuron death happens, but ongoing research is focused on better understanding what causes ALS and identifying better treatment targets.

Genetics and ALS

There is strong evidence that genetic factors influence the risk of developing ALS. Mutations in more than a dozen genes have been definitively linked with ALS, and many more genes have shown potential associations with disease risk. There are four major genes most commonly linked to ALS:

• C9ORF72
• SOD1
• TARDBP
• FUS

ALS can broadly be divided into two types: familial, meaning the disease affects more than one person in a family, and sporadic, when there’s no family history. Mutations in these genes are mostly found in people with familial ALS, but a minority of people with sporadic ALS also carry a known ALS-associated mutation.

Importantly, most ALS-associated mutations have incomplete penetrance and genetic pleiotropy. Essentially, that means that even if a person has a certain mutation, it doesn’t ensure they are guaranteed to develop ALS; other factors also play a role.

If a person has ALS symptoms or a family member who has received an ALS diagnosis, genetic testing can identify disease-related mutations, which could inform treatment options and family planning decisions. However, testing positive for a mutation does not mean ALS will necessarily develop, and a negative result does not completely rule it out.

Familial ALS

ALS can run in families, with parents passing disease-associated mutations on to their biological children. A family history of ALS is one of the strongest risk factors associated with the disease. About 5%-10% of all ALS cases are considered familial.

Familial ALS mutations are most often inherited in an autosomal dominant manner, meaning that a person with an ALS-associated mutation has a 50% chance of passing it on to any biological children. A child who inherits a single mutation from one parent is at risk of developing ALS, but the likelihood that will occur is influenced by which gene is involved and other risk factors.

Specific genetic causes of ALS have been identified in approximately two-thirds of familial ALS cases, most often involving C9ORF72  (25%-40%), SOD1 (10%-20%), TARDBP (4%), or FUS (5%).

Scientists have not yet identified all possible ALS-associated mutations, so in some cases, a disease-causing mutation cannot be identified. If there is a well-established family history, familial ALS can still be diagnosed. Research to uncover these mutations could reveal new ALS causes.

Sporadic ALS

When a case of ALS is isolated without a clear family history, as is true for about 90%-95% of patients, it is referred to as sporadic ALS. Genetics are still thought to play a role in determining disease risk for these individuals, though sporadic ALS genetics are incompletely understood.

Approximately 1 in 10 people with sporadic ALS have a known ALS-associated mutation, most commonly in C9ORF72 (5%-10%) or SOD1 (1%-2%). These mutations may be inherited from a parent who never developed the disease, or may have occurr spontaneously in the affected individual during early development.

Genetics likely interacts with various other risk factors to inform disease risk. Because of this complexity and the lack of a clear inheritance pattern, it can be difficult to predict who will develop sporadic ALS.

Environmental and lifestyle factors

While the genetic basis of ALS is relatively well established, gene mutations are not the sole determinants of disease risk. The likelihood of developing the disease is thought to result from interactions between genetic, environmental, and lifestyle factors.

Among the lifestyle and environmental risk factors most strongly linked to ALS are:

• Military service: Studies have suggested that veterans are more likely to develop ALS than people in the general population, with a reportedly higher risk seen for those who deployed more recently.
• Smoking: Studies have suggested that the risk of ALS is increased among people who have ever smoked cigarettes compared with those who have never smoked. Other studies showed that the risk is particularly high in current smokers and women.
• Head injury and trauma: Head injuries are linked with a greater likelihood of developing ALS, especially when such injuries are severe or recurrent.
• Toxic chemical exposure: Exposure to certain toxic chemicals is linked to an increased ALS risk. This includes heavy metals (e.g. lead, mercury, zinc, and copper), pesticides, herbicides, and insecticides, organic solvents (e.g., benzene, formaldehyde), and beta-methylamino-L-alanine, a toxic compound made by algae.

These factors may in part explain why people in certain occupations have been found to be at an increased risk of developing ALS. For example, professional athletes or those who served in combat could be at an increased risk due to the higher likelihood of head injuries. People exposed to toxic chemicals through their jobs, such as military personnel and those who work in manufacturing, welding, construction, or mining, could also be at an increased risk.

Various other factors have been associated with a potentially increased risk of ALS, although there is generally less data to support them. These include:

• Electric shock and exposure to electromagnetic fields: A history of electric shock and/or exposure to electromagnetic fields could possibly increase ALS risk, particularly among people exposed through work, such as electricians, mechanics, or train drivers.
• Viral infections: A history of infection with certain viruses — in particular enteroviruses, a group that includes the virus that causes polio — has been linked with an increased risk of ALS. Also, viruses like HIV can trigger ALS-like symptoms that resolve after the viral infection is controlled. However, the association between any infection and ALS risk remains unproven.
• Excessive exercise: Studies have suggested that people who are very physically active and regularly engage in strenuous exercise, such as professional athletes, are more likely to develop ALS.

Biological factors

Beyond genetics, biological traits that may influence disease risk include:

• Age: ALS can develop in people of any age, but it is very rare in children. Most people who develop ALS do so between the ages of 55 and 75.
• Sex: The disease is about 20% more common in males than in females — a difference that is more pronounced among younger patients. This difference may be related to a combination of hormonal, environmental, and occupational factors.

In ALS, genetic and environmental risk factors can cause a number of biological systems in the body to become dysregulated, which contributes to the onset and gradual progression of the disease. Biological processes that may contribute to motor neuron damage in ALS include:

• Chemical imbalance: People with ALS generally have higher than normal levels of the chemical messenger glutamate in the brain and spinal fluid. This can be toxic to nerve cells, known as glutamate toxicity, and contribute to neurodegeneration.
• Immune overactivity: Neuroinflammation, driven by nervous system support cells that become proinflammatory, affects nerve function. A few studies have sugg suggested that people with autoimmune diseases may be at an increased risk of developing ALS, though the data have been inconsistent.
• Protein and RNA processing defects: Dysfunction of the cellular machinery that regulates protein production and recycling, as well as the processing of genetic material, may contribute to nerve cell damage.
• Impaired neuronal transport: The systems that move cargo within nerve cells can become compromised, leaving the cells unable to work as they should to send signals and perform other functions.
• Mitochondrial problems: In people with ALS, mitochondria, the cellular structures that produce energy, can become dysfunctional, starving nerve cells of the energy they need to function and survive. This can also contribute to a form of cellular damage called oxidative stress, in which oxygen-containing molecules called free radicals further harm nerve cells.