Such mutations can increase a person’s risk of developing ALS, also known as Lou Gehrig’s disease, which affects motor neurons, the nerve cells that control muscle movements.
Genetic, environmental, and lifestyle factors all are believed to play a role in causing ALS.
Genetic mutations associated with ALS
The C9ORF72 gene is the most frequently mutated gene in ALS patients. Mutations in this gene account for an estimated 40-50% of familial ALS cases and about 5-10% of sporadic cases.
Mutations in C9ORF72 also can cause another neurodegenerative disease called frontotemporal dementia or FTD, which is characterized by problems with cognition and memory, as well as personality changes. Some individuals with a mutation in the C9ORF72 gene develop ALS, some develop FTD, and some have symptoms of both conditions.
It is not entirely clear how mutations in C9ORF72 cause ALS or FTD, or why some people with mutations in this gene will develop one disease, the other, or both. It’s possible that the mutant gene leads to too-low levels of the protein encoded by C9ORF72. Another possible explanation is that the mutation may end up disrupting normal protein production in cells.
Mutations in the SOD1 gene account for about 12-20% of familial ALS cases and 1-2% percent of sporadic cases. This gene provides instructions to build an enzyme called superoxide dismutase (SOD1).
The SOD1 enzyme neutralizes free radicals, which are byproducts of normal cellular processes that are harmful to the cells. It’s not fully understood how SOD1 mutations cause ALS; possible explanations include abnormally high levels of free radicals causing cellular damage, and abnormal clumps of mutant SOD1 protein forming in cells.
Mutations in the TARDBP gene are found in about 4% of familial ALS cases and about 1% of sporadic cases. Similar to C9ORF72, mutations in TARDBP also have been linked with FTD – people with TARDBP mutations may develop ALS, FTD, or both.
The TARDBP gene provides the instructions to build a protein called TDP-43, which is normally located in the nucleus (where genetic information is stored in cells) and involved in various steps of protein production. Mutations in the TARDBP gene cause the TDP-43 protein to form aggregates (clumps) outside the nucleus, which are damaging to cells.
Of note, TDP-43 aggregates are found in about 97% of ALS patients, including in people who do not have mutations in the TARDBP gene.
The FUS gene is mutated in about 5% of familial ALS and about 1% of sporadic ALS cases. Like TARDBP and C9ORF72, this gene also is linked with FTD.
It is thought that mutations in FUS lead the protein encoded by this gene — also called FUS — to form clumps in motor neurons that disrupt their function and ultimately kill them.
Other genes associated with ALS
Other genetic mutations may be linked to ALS, and researchers are actively working to fully understand how a person’s genetics affects this complicated disease. Among the genes linked to ALS are the VCP, ATXN2, ANG, TBK1, VAPB, and SQSTM1 genes.
Inheritance of ALS
In familial cases, ALS can be inherited — that is, passed from parents to their children. For the majority of genes, everyone inherits two copies, one from each parent. The specific pattern of disease inheritance depends on the particular gene that is mutated.
In most cases, ALS is inherited in an autosomal dominant manner. This means that a person with just one mutated copy of the gene in question can develop the disease. An individual with an autosomal dominant disease has a 50% risk of passing the mutated gene to a biological child.
Less commonly, ALS can be inherited in an autosomal recessive manner, which means that both copies of the gene must be mutated for the disease to develop. People with just one mutated copy are said to be “carriers,” as they will not develop the disease themselves, but may pass the disease-causing mutation to their biological children.
In very rare cases, ALS is inherited in an X-linked dominant manner. Sexual development is determined by two pieces of DNA called the X chromosome and the Y chromosome. In general, females have two X chromosomes, while males have one X chromosome and one Y chromosome. In X-linked dominant inheritance, males who inherit a disease-causing mutation on their sole X chromosome will develop the disease, while females who inherit the mutation — but also have another X-chromosome that carries a non-mutant form of the gene — will not.
Testing for ALS-linked mutations is typically done using a sample of blood or saliva. Because the genetics of ALS are complex, and new disease-causing mutations are continually being discovered, it is difficult to clearly diagnose ALS with a genetic test.
There are various different kinds of genetic tests, ranging from specific tests to look for mutations in a particular gene, to sequencing all of a person’s genetic material.
Notably, people with clinical ALS symptoms may test negative if their disease-causing mutation has not yet been identified and linked to the disease. At the same time, an asymptomatic individual with a family history of ALS may receive positive results on a genetic test, but there is still a chance that the person will never develop disease symptoms in his or her lifetime.
Asymptomatic individuals with a family history of ALS may be advised, or decide, to undergo genetic testing. Family planning is a frequent reason for this.
Last updated: Nov. 30, 2021
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