Most cases of ALS are “sporadic,” meaning they are due to no known cause. Approximately 5-10% of cases are due to known genetic mutations. In most of those cases, another family member also has ALS or a related disease (see C9ORF72 below). Such cases are called “familial.” Cases of familial ALS (FALS) are presumed to be due to genes, although the gene may not be known in all cases.
In some cases of ALS, the disease may be due to a faulty gene, but there may be no other affected family members. In such cases, the person may be diagnosed with sporadic ALS, when in fact the cause is genetic. As the number of genes known for ALS grows, physicians are beginning to appreciate that an apparently sporadic case of ALS may in fact be due to a gene mutation. It is likely that as new genes are discovered, more cases of sporadic ALS will be attributable to genetics.
Genes are strings of DNA that provide instructions, or code, for making proteins. Proteins are the principle components of all types of cells, controlling reactions and providing structure. Genes are linked together to form chromosomes, which reside in the nucleus of each cell. Chromosomes and the genes they contain are inherited, passing from parent to child.
A mutation is a mistake in the DNA instructions, usually causing the cell to make either too little protein, or too much protein, or a defective protein. Different mutations may cause different effects. Any change in the normal protein can be harmful to the cell, and may cause disease. For instance, loss of function of the angiogenin protein due to mutation in the gene causes some cases of ALS. A gain of a new and toxic function of the superoxide dismutase 1(SOD1) protein is probably how mutation of the SOD1 gene causes ALS.
A mutation may also be harmful not because it changes the protein encoded by the gene, but due to its effect on RNA. RNA is an intermediary, or messenger, between gene and protein. To make a protein, the cell first uses the DNA gene to form an RNA copy. That copy is then used to provide the “working instructions” to make the protein. After it is formed and before it is used to make protein, RNA is processed in several different ways. Mistakes in RNA processing may cause disease. For instance, the C9ORF72 gene may cause ALS due to accumulations of RNA that occur when the gene is mutated. FUS and TDP43 mutations may impair the normal processing of RNA from a wide variety of genes, leading to ALS.
Genes are present in pairs, one copy inherited from each parent. For most ALS genes, only one mutated copy is needed to cause disease. This is called a “dominant” gene. For other genes, both copies must be mutated to cause disease. This is called a “recessive” gene.
During formation of eggs and sperm, gene pairs split up, so that an egg (or sperm) contains only one gene copy. If a parent carries one copy of the disease gene, there is a 50-50 chance of passing along that disease gene to any one child. If the disease gene is dominant, the child will develop the disease (since only one copy is needed). If the gene is recessive, the child would need to inherit two disease genes, one from each parent. If both parents carry one copy of this gene, the chances of any one child inheriting two copies and developing disease is 25%.
This gene, discovered in 2011, is the most common genetic cause of ALS. (Its name refers to the position of an “open reading frame” on chromosome 9). Mutations in this gene account for between 25% and 40% of all familial ALS cases (depending on the population), and also approximately 4% to 6% of sporadic cases. As noted above, these apparently sporadic cases are in fact genetic. The gene mutation appears to act in a dominant manner. This gene also causes another neurodegenerative disease, called frontotemporal dementia (FTD). Some people with this gene will develop symptoms only of ALS, some only of FTD, and some will have symptoms of both disorders. How this gene causes ALS is unknown, and is the subject of a great deal of intense research.
Mutations in SOD1 were first described in 1993, and SOD1 was the first gene known for ALS. It accounts for about 10% of familial ALS, or 1.5% to 2% of all ALS. It is inherited in a dominant manner. How SOD1 mutations cause ALS is unknown. It is clear that disease is not due to lack of function of the protein, since deleting the gene in animal models doesn’t cause ALS. Instead, it appears to take on some new toxic function, possibly related to an increase in the tendency of mutant SOD1 molecules to aggregate and form clumps in motor neurons. It is also possible that SOD1 causes ALS through actions in nearby cells called astrocytes, not in motor neurons themselves. Astrocytes help maintain motor neurons, and SOD1 mutation may impair their ability to do so. Read more about SOD1
TAR DNA binding protein 43 (TDP-43) was linked to ALS in 2008. Mutations in TDP-43 cause a dominant form of ALS. The normal role of the TDP-43 protein includes binding to RNA, the genetic messenger molecule. Mutations in the TDP-43 gene cause the TDP-43 protein to mislocalize in motor neurons, away from the nucleus where it is normally found, and into the cytoplasm (the material surrounding the nucleus), where it aggregates into clumps that can be seen under the microscope. Even in ALS not caused by TDP-43 mutations, the protein is found in these aggregates, suggesting it may play a pivotal role in many forms of ALS.
Fused in sarcoma (FUS) was also discovered to play a role in ALS in 2008. Like TDP-43, it is inherited in a dominant manner. It is also an RNA binding protein, and may play a similar normal role in the cell. FUS and TDP-43 may in fact interact as part of their normal function.Ubiquilin-2
Ubiquilin-2 was linked to ALS in 2011. Unlike all other known ALS genes, the ubiquilin-2 gene resides on the X chromosome, one of the chromosomes that determine sex. Men carry only one X chromosome, while women carry two. Despite this, both men and women develop ALS due to ubiquilin-2 mutations. The normal function of the protein is to help degrade damaged or defective proteins in the cell. It is likely that mutations in the gene interfere with this function, and may lead to accumulation of harmful material within the cell.
Other genetic causes of ALS affect relatively few people. Nonetheless, understanding how they cause the disease may offer large insights into the disease process. These genes include VCP (valosin-containing protein), alsin, senataxin, and angiogenin and optineurin.
ALS is remarkably similar whether it is inherited or appears in a person spontaneously with no family history of the disease. Therefore, insights gained from studying genetic forms of the disease are likely to benefit those with sporadic ALS as well. Therapies aimed at correcting the consequences of gene mutations may lead to treatment for all cases of ALS.
Updated November 2013