There are more than 25 genes known to be associated with amyotrophic lateral sclerosis (ALS) as of June 2018, which collectively account for about 70% of cases of familial ALS (fALS) and 10% of cases of sporadic ALS (sALS). About 5–10% of cases of ALS are directly inherited. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease. C9orf72 is the most common gene associated with ALS, causing 40% of familial cases of ALS, as well as a small percentage of sporadic cases; it also causes about 25% of familial cases of frontotemporal dementia. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); the more repeats in C9orf72, the more pathogenic the mutation. People without ALS tend to have fewer than 25 repeat units, while people with ALS due to a mutation in C9orf72 tend to have hundreds or thousands of repeat units. It is not clear exactly how many repeat units are needed to cause disease. SOD1, which codes for superoxide dismutase 1, is the second most common gene associated with ALS and causes about 12% of familial cases and about 2% of sporadic cases. More than 150 mutations in SOD1 have been described, almost all of which have an autosomal dominant mode of inheritance. TARDBP, which codes for TAR DNA-binding protein (TDP-43), is associated with 1–5% of familial ALS and less than 1% of sporadic ALS. While TARDBP mutations are somewhat rare in ALS, pathological aggregations of TDP-43 are seen in up to 97% of ALS patients and up to 50% of FTD patients. TDP-43 is involved in the repair of DNA double-strand breaks. It is recruited to DNA damage sites and interacts with proteins involved in the repair process of non-homologous end joining. FUS, which codes for "Fused in sarcoma" protein, is associated with 1–5% of familial ALS and less than 1% of sporadic ALS. FUS is an RNA-binding protein with a similar function to TDP-43. Some people have both ALS and frontotemporal dementia (FTD–ALS). The four main genes associated with FTD–ALS are C9orf72, CHCHD10, SQSTM1, and TBK1. C9orf72 repeat expansions explain about 40% of familial ALS and 25% of familial FTD; thus, C9orf72 provides a genetic explanation for most of the overlap between the two diseases. While about half of the people with ALS have some degree of cognitive impairment, only 10–15% have cognitive impairment severe enough to meet the criteria for frontotemporal dementia (FTD). Additionally, about 15% of people with FTD have symptoms of motor neuron dysfunction that resemble ALS. Mutations in TARDBP, FUS, C9orf72, and other genes can cause ALS as well as related forms of frontotemporal dementia (FTD–ALS). Proteins made by these genes appear to have prion-like activity and form inclusion bodies in some instances of ALS.
Genes As of May 2017 more than 20 genes have been associated with various types of ALS. As of 2016 these genes explained about 70% of familial ALS (fALS) and 15% of sporadic ALS (sALS). These associations include:
Other genes The following genes associated with ALS have been discussed in a June 2018 literature review, but have not yet been added to the Online Mendelian Inheritance in Man database.
SOD1 In 1993, scientists discovered that mutations in the gene (SOD1) that produces the Cu-Zn superoxide dismutase (SOD1) enzyme were associated with around 20% of familial ALS and 5% of sporadic ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can cause damage to DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disorder, some of which (such as H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated. To date, 180 different mutations in SOD1 gene are known to cause familial ALS. A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of DNA damage. A gain of SOD1 function could be toxic in other ways. Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins. Hypotheses proposed in explaining structural instability causing the misfold in the mutant SOD1 include, (1) glutamate excitotoxicity caused by reduced astroglial glutamate transporter EAAT2; (2) abnormalities of mitochondria in which increased misfolded SOD1 are deposited in the spinal cord mitochondria leading to defects in mitochondrial transport causing energy depletion, disruption in Ca2+ buffering, activating synaptic dysfunction, and loss of neurons; (3) impaired axonal structure or transport defects, in which neurotrophic signaling is lost, with defective anterograde and retrograde axonal transport observed in early pathogenesis, and (4) free radical-mediated oxidative stress causing cytotoxicity. A 2016 paper proposed that SOD1 maturation and proteins regulating intracellular copper levels are potential therapeutic targets of SOD1-ALS. The DNA oxidation product 8-oxoG is a well-established marker of oxidative DNA damage. 8-oxoG accumulates in the mitochondria of spinal motor neurons of persons with ALS. In transgenic ALS mice harboring a mutant SOD1 gene, 8-oxoG accumulates in mitochondrial DNA of spinal motor neurons. Thus oxidative damage to mitochondrial DNA of motor neurons due to altered SOD1 may be a significant factor in the etiology of ALS.
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