The causes of the vast majority of ALS cases are still unknown. Although most cases of the disease are sporadic, meaning there is no family history of the disease, about 5 to 10 percent of cases are familial, meaning the disease runs in the family.
The term “genetic” can apply to both familial and sporadic ALS. In some sporadic cases, the family history may not be known. In others, parents may have died before showing signs of the disease. In still others, an ALS-causing genetic mutation may not have been present in either parent but may have occurred for the first time in the person with the disease. Once an ALS-causing mutation has occurred in someone, his or her children can inherit it, and their disease would be considered “familial.”
Scientists have been studying many factors that could be linked with ALS such as heredity and environmental exposures. Other scientists have looked at diet or injury. Although no cause has been found for most cases of ALS, a number of inherited factors have been found to cause familial ALS. In the future, scientists may find that many factors together cause ALS.
Possible causes of sporadic ALS
Oxidative stress is a phenomenon that occurs when there’s an imbalance between the production of oxygen-containing molecules that carry an electrical charge, which can be toxic, and a biological system’s ability to readily detoxify them. Oxygen-containing charged particles are common byproducts of cellular metabolism.
The FDA-approved drug for ALS, edaravone (brand name Radicava), is thought to work by relieving the effects of oxidative stress, which has been suspected to play a role in the death of motor neurons. Targeting this pathway could potentially preserve motor neuron health, which could, in turn, keep muscles functional for a longer period of time.
The mitochondria are microscopic energy “factories” inside cells. They resemble miniature cells themselves and have their own DNA. Abnormalities of the mitochondria may be involved in ALS causation and/or progression.
Abnormalities of the immune system
There is evidence that the immune system, particularly immunologic cells in the nervous system known as microglia, can be both beneficial and harmful in ALS. Microglia may be protective up to a certain point and then become damaging. Modifying the actions of the immune system is an active area of ALS research.
Glutamate carries signals between neurons (nerve cells), and there may be too much of it in ALS.
Glutamate is one of many neurotransmitter chemicals in the nervous system that carries signals between nerve cells. There is some evidence that in ALS glutamate accumulates in the spaces around a nerve cell after it has completed its signaling function, causing problems for the nerve cells in its vicinity. The problem could be caused by inadequate transport of glutamate away from the cells.
The FDA-approved drug for ALS, riluzole (brand name Rilutek), is based on reducing glutamate levels. Riluzole has a modest effect on slowing disease progression and prolonging survival.
For years, experts have tried to find factors common to people who develop ALS, such as environmental toxins, occupational hazards, places of work or residence, exposure to chemicals and so forth. So far, the evidence for such risk factors and triggers has been frustratingly unclear, although a recent finding of an association between developing ALS and having served in the military is one of the strongest of these proposed risk factors.
In particular, the association of military service in the Gulf War with ALS may yield some clues.
Cyanobacteria, microorganisms that live in desert sands and which can be inhaled when they’re kicked up in dust, could be among the reasons for the elevated risk of ALS in those who served in the Gulf War, some experts believe.
Cyanobacteria are also found in some bodies of water. In 2009, some experts suggested water contamination of a lake in New Hampshire as a possible cause of an apparent increase in ALS risk in the surrounding area. Additional studies are ongoing to determine whether links exist between ALS and a person’s proximity to contaminated bodies of water.
Higher-than-average rates of ALS on the island of Guam have led scientists to suspect a possible toxic factor may have been involved there, at least historically. Recent evidence suggests that inclusion in the native peoples’ diet of poisonous nuts from the indigenous cycad trees could be an explanation.
The heavy metals lead, mercury and arsenic, which can be toxic to the nervous system, have also been suggested as causative agents in ALS, but additional studies are needed.
Genetic influences on sporadic ALS
There are some variants of genes that may increase susceptibility to the development of ALS. These may work in concert with other factors such as environmental exposures.
Causes of familial ALS
With an explosion in ALS gene discovery over the past 10 years, scientists have now identified the majority of the causes of inherited forms of ALS. To date, more than 40 genes have been identified to cause familial ALS; some of them also have been found in sporadic ALS patients.
Mutations in the SOD1 (superoxide dismutase 1) gene account for about 20 percent of familial ALS and also perhaps 1 to 3 percent of sporadic ALS. SOD1 was the first gene found to be associated with familial ALS, and a mouse model of SOD1-associated ALS is widely used in research today. Mutations in the SOD1 gene were identified as a cause of familial ALS in 1993. Since then, many more genes have been found that, when flawed, can cause familial ALS.
Mutations in the gene for the TDP-43 protein have been found to be a cause of a small percentage of familial ALS. In 2009, scientists determined that mutations in the FUS gene (a similar gene to TDP-43) also account for some cases of familial ALS.
In 2011, mutations in the gene for the ubiquilin 2 protein were identified as a cause of familial ALS. And at around the same time, a mutation in the C9ORF72 gene involving an expansion of repeated DNA sequences was found to account for more ALS cases than any previously identified genetic abnormality. Data from two independent research studies showed that the C9ORF72 mutation is more than twice as common as mutations in the SOD1 gene as a cause of familial ALS, and more than three times as common as mutations in TDP43, FUS and two other genes — optineurin and valosin-containing protein (VCP) gene — combined.
The discovery of the C9ORF72 DNA expansion highlighted the overlap between ALS and another disorder, frontotemporal dementia (FTD). In families with the C9ORF72 expansion, some affected members may develop ALS while others may develop FTD. Some patients can develop symptoms of both diseases.
Genetic testing is available for many ALS-causing gene mutations. A genetic counselor can help interpret test results and discuss their implications for the person with ALS and his or her family. Genetic testing may be important to determine whether or not a person is eligible to participate in certain clinical trials.
Registries are helping scientists learn about ALS
A disease registry is a collection of information (a database) about people with a particular disease or condition.
The Muscular Dystrophy Association-supported U.S. Neuromuscular Disease Registry and the U.S. government-supported National ALS Registry collect different information from different sources, but both are important for people with ALS. Both registries share the goals of learning more about ALS; better understanding the onset and progression of the disease; finding ways of predicting how ALS may change over time in specific people; learning more about ALS-related genes; identifying which treatments lead to better outcomes; helping doctors and other professionals improve care; providing information to families; and creating a privacy-protected database of people who can take part in clinical trials.
There is a lot scientists still don’t know about ALS. For those living with the disease, participation in a registry is a way to actively participate in the research that could lead to treatments and cures.