Amyotrophic Lateral Sclerosis (ALS)

Causes/Inheritance

About 5-10% of ALS is familial — meaning it arises in families in which there is a history of ALS. A number of genes associated with ALS have been identified or at least mapped to a specific region of a chromosome.

The other 90-95% 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 do not necessarily cause the disease by themselves. Additionally, some of the same genes identified to cause familial ALS have been found in patients with sporadic ALS. A genetic counselor can help advise on the risk of passing along the disease to others within the family.

Caucasians have higher rates of ALS than other races. Prior to the age of 65-70, the incidence of ALS is higher in men than in women, but thereafter the gender incidence is equal. The only established risk factors for ALS are age and family history.

Below, you will find an examination of possible causes of both sporadic and familial ALS currently under investigation by MDA researchers.

Possible causes of sporadic ALS

Oxidative stress

Oxidative stress is a phenomenon that occurs when there is 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.

Though the exact mechanism is not known, the therapeutic effect of edaravone (Radicava) is thought to be a result of its antioxidant properties, which combat oxidative stress.

Mitochondrial dysfunction

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 immune 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 toxicity

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.

Riluzole (Rilutek) is based on reducing glutamate levels. (Rilutek) has a modest effect on slowing disease progression and prolonging life.

Toxic exposures

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 others. 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. The incidents of ALS cases among Gulf War veterans is two times higher than expected.

Cyanobacteria, microorganisms that live in desert sands and that 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, more studies are needed to establish a clear link.

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, aluminum, and arsenic, although they can be toxic to the nervous system, have not been shown to be causative agents in ALS.

Genetic influences on ALS

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." At least 25 different loci¹ are thought to harbor ALS-causing mutations. Loci is the plural form of locus, which refers to the position of a gene or other significant sequence on a chromosome.

Although most familial ALS cases follow an autosomal dominant inheritance, recessive and X-linked forms have been described. Autosomal means that the mutation occurs in a chromosome other than X or Y. Dominant means that only one copy (normally, a person has two copies of each gene, one inherited from the father and one inherited from the mother) of a gene is enough to cause a disease. A person who inherits the defective gene from a parent will have the disease, as will the parent. In the recessive pattern of inheritance, two copies of a defective gene are required for expressing the disease. One copy is inherited from each parent, neither of whom would normally have the disease. An X-linked form of ALS means that the genetic defect (or mutation) is located on the X chromosome. In females, who have two X chromosomes, a normal copy of the gene on one chromosome can often compensate (at least partially) for the defective copy. Therefore, X-linked diseases usually affect males more severely than females, because males have only one X chromosome.

SOD1 and C9orf72 are the most common genetic causes for ALS. However, as described above, additional genes are associated with the disease.

ALS1 is associated with a mutation in SOD1 (superoxide dismutase 1) gene. Mutations in the SOD1 gene account for about 15% of familial ALS within European populations, 30% among Asian populations, and some cases 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, scientists have discovered many more flawed genes that can cause familial ALS.

C9orf72 gene (Chromosome 9 open reading frame 72) provides instructions for a protein that is highly abundant in nerve cells, and mainly located at the tip of the axons, an area called the presynaptic terminal. C9orf72-related ALS is the most common autosomal dominantly inherited form of familial ALS (34% of the cases in European population), together with SOD1-related ALS as described above. Repeat expansions in the C9orf72 gene are causally linked to classical ALS and frontotemporal dementia (FTD).¹

ALS types 2	Associated with gene 2	Type of inheritance- Autosomal Dominant (AD), Autosomal Recessive (AR), or X-linked (XD)2
ALS1	SOD1	AD,AR
ALS2	ALS2	AR
ALS3	Chromosome 18	AR
ALS4	SEXT	AD
ALS5	SPG11	AD
ALS6	FUS	AD
ALS7	Chromosome 20	AD
ALS8	VAPB	AD
ALS9	ANG	AD
ALS10	TARDBP/TDP-43	AD
ALS11	FIG4	AD
ALS12	OPTN	AD,AR
ALS13	ATXN2	AD
ALS14	VCP	AD
ALS15	UBQLN2	XD
ALS16	SIGMAR1	AR
ALS17	CHMP2B	AD
ALS18	PFN1	AD
ALS19	ERBB4	AD
ALS20	HNRNPA1	AD
ALS21	MATR3	AD
ALS22	TUBA4A	AD
ALS23	ANXA11	AD
ALS24	NEK1	----
ALS25	KIF5A	AD
FTDALS1	C9orf72	AD
FTDALS2	CHCHD10	AD
FTDALS3	SQSTM1	AD
FTDALS4	TBK1	AD
ALS	LRP10	AD
ALS	SPTLC1	AD

Other genes associated with ALS1 are NEFH, PRPH, DCTN1.

Genetic testing and counseling

Genetic testing is available for many ALS-causing gene mutations. Genetic testing for specific ALS-causing mutations is most useful for establishing the diagnosis. A genetic counselor can help interpret test results and discuss their implications for the person with ALS and his or her family. The most common use of genetic testing for ALS is to provide risk information and subsequent counseling for unaffected at-risk family members. There are also ongoing clinical trials testing therapies targeted to specific genetic subtypes of ALS (e.g. SOD1 and C9ORF72) and genetic testing can provide information about whether someone with ALS is eligible for these trials.

Anyone diagnosed with ALS or any adult with a family history of ALS who is considering genetic testing should first meet with a genetic counselor or a physician knowledgeable about familial ALS before undergoing any test.

Genetic testing can be done on a blood, saliva, or tissue sample. The sample is then analyzed for mutations in the specific gene of interest.

For more information, please speak with your MDA Care Center team.

To learn more about the causes of ALS, see Research.

References

1. Nguyen, H. P., Van Broeckhoven, C. & van der Zee, J. ALS Genes in the Genomic Era and their Implications for FTD. Trends in Genetics (2018). doi:10.1016/j.tig.2018.03.001
2. Benarroch, L., Bonne, G., Rivier, F., & Hamroun, D. The 2023 version of the gene table of neuromuscular disorders (nuclear genome), Neuromuscular Disorders, (2023). doi.org/10.1016/j.nmd.2022.12.002.