About 5 to 10 percent of ALS is familial — meaning it arises in families in which there is a history of ALS. Several genes associated with ALS have been identified or at least mapped to a specific region of a chromosome.
The other 90 to 95 percent of ALS is sporadic, meaning it occurs without a family history (in other words, "sporadically"). There appear to be genetic variations that influence one's susceptibility to sporadic ALS, even if they don't actually cause the disease by themselves.
Below you will find an examination of possible causes of both sporadic and familial ALS currently under investigation by MDA researchers:
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 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 only FDA-approved drug for ALS, riluzole  (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. However, the evidence for this link is not strong.
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, although they can be toxic to the nervous system, haven't been shown to be causative agents in ALS.
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.
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The term "familial" ALS means that there is more than one occurrence of the disease in a family. The term "sporadic" applies when there is no known history of other family members with the disease. 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."
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 TDP43 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  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.
A database of genes  that are or may be associated with ALS provides more information.
For more about inheritance patterns, see Facts About Genetics and Neuromuscular Diseases .
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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.
To learn more about the causes of ALS, see Research .
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