Amyotrophic lateral sclerosis (ALS) is a rare neurological condition that is characterized by the deterioration of nerve cells that are involved in voluntary muscle movement. There are two types of ALS – sporadic and familial.
Understanding the cause of ALS or what factors impact survival rates is important for the development of effective treatments. However, the causes of ALS are largely unknown.
Researchers have been investigating the potential causes of ALS and there are some risk factors, particularly genetics and environment, that have emerged as contributors to the development of the disease.
1. Genetics and ALS
Approximately 10% of ALS patients have a first-degree family member (parents, sibling) that also has ALS. This is known as familial ALS. Furthermore, more thorough genealogical studies that encompass distant relatives and include ALS-related diseases have proposed that more than 20% of ALS patients have a familial component to the disease.
To date, studies have revealed the involvement of more than 25 genes in the development of ALS. The genes that are involved in ALS have been identified in 70% of patients with familial ALS.
Researchers have also identified that, even in patients that have sporadic ALS, there is a significant genetic component to the disease. In sporadic ALS, patients will randomly have mutations in the same genes that contribute to familial ALS. Hence, almost every familial ALS gene has also been implicated in sporadic ALS.
Three genes, in particular, have been identified as the most common contributors to the development of ALS:
- C9orf72 gene –the most frequent cause of ALS as it is responsible for about 30% of familial and up to 10% of sporadic cases
- SOD1 gene
- TARDBP gene
2. Environmental risk factors
In contrast to genetics, environmental risk factors for ALS have been more difficult to identify. These are the following environmental risk factors that have been identified to date:
- Smoking: Smoking has been linked to a higher risk of ALS in some studies. Additionally, smoking may confer a higher risk to particular subgroups of patients with ALS.
- Occupation: In particular, individuals that have undergone military service and have been deployment were found to have a higher risk of ALS. However, the evidence largely comes from the United States, as they have large military datasets.
- Physical activity: As several high-profile sports players have been known to develop ALS and patients that present with ALS tend to be leaner, have a lower BMI and higher levels of participation in recreational sports, researchers have been investigating the effect of physical activity on the development of the disease. However, the link has not yet been established.
- Electric shock: While electric shock has not been shown to be a risk factor in some analyses, it has been in others.
- Chemical exposure: Studies have shown conflicting results for whether exposure to chemicals – such as heavy metals, ambient aromatic hydrocarbons, pesticides, and cyanotoxins – leads to ALS.
- Injury: Trauma, such as head injury, has been shown to be a risk factor in a large scale study.
3. Inflammation and ALS
Sometimes, a person's immune system starts to attack some the normal, healthy cells within the body. This can lead to a process called inflammation.
There are several lines of evidence that point to inflammation as a major component in ALS. Generally, immune cells are not present in large numbers with the central nervous system. However, research has shown that there are immune cells in the nervous system of patients with ALS and these cause neuroinflammation (inflammation of the central nervous system, including the brain).
Therefore, at this point, researchers are conducting studies to investigate therapies that target the immune system in order to improve survival of ALS patients.
4. Retroviruses, poliovirus, HIV and ALS
Research has shown that certain viruses such as poliovirus and others can cause a disease known as post-infectious myelitis which is associated with eventual paralysis. Furthermore, HIV infection can also lead to an ALS-like syndrome. Hence, some researchers have postulated that the presence of these retroviruses in the body can predispose an individual into developing ALS.
Further evidence for this theory comes from studies that have been conducted using serum and cerebrospinal fluid from ALS patients which suggested that there are activated retroviruses that are associated with ALS.
Currently, there is no direct evidence that retroviruses cause ALS in humans. However, there are studies underway to investigate whether anti-retrovirals slow progression and improve survival in patients with ALS.
5. Oxidative stress
Oxidative stress refers to a process that takes place due to an increase in free radicals, a type of molecule that is toxic to the body. Studies have implicated a role for oxidative stress in ALS, particularly in familial ALS such as patients with the SOD1 mutation.
6. Mitochondrial dysfunction
Abnormalities of the mitochondria, which are small energy-producing factories inside cells, have also been implicated in causing ALS or contributing to its progression.
7. Glutamate toxicity
Glutamate is a chemical in the nervous system that carries signals between nerve cells. Some studies have shown that in ALS, glutamate accumulates around a nerve, which causes issues for nerve cell signaling.
The one FDA-approved drug for ALS, called Rilutek, works by decreasing levels of glutamate.
8. Demographics and ALS
There are certain demographic factors that are risk factors for the development of ALS:
- Sex: Approximately 60% of all patients that develop ALS are of the male gender
- Age: ALS generally develops between 40 and 60 years of age and most people get the disease in their 50s. While it is possible to develop the disease earlier, it is unlikely to get it before 30.
- Race: The vast majority of individuals that develop ALS (93%) are Caucasian.