There are more than 25 genes known to be associated with<unk><unk><unk>  (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 from a person's parents. 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<unk> explanation for most of the overlap between the two diseases. While about half of 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.
Genetics of amyotrophic lateral sclerosis
Charcot–Marie–Tooth disease classifications
Biochemistry of Alzheimer's disease
Amyotrophic lateral sclerosis research
Multiple sclerosis functional composite
Pathology of multiple sclerosis
Alzheimer's disease biomarkers
Multiple sclerosis biomarkers