Higher estimates use a broader definition of familial ALS and examine the family history of people with ALS more thoroughly.In sporadic ALS, there is no family history of the disease. Sporadic ALS and familial ALS appear identical clinically and pathologically and are similar genetically; about 10% of people with sporadic ALS have mutations in genes that are known to cause familial ALS. In light of these parallels, the term "sporadic ALS" has been criticized as misleading because it implies that cases of sporadic ALS are only caused by environmental factors; the term "isolated ALS" has been suggested as a more accurate alternative.More than 20 genes have been associated with familial ALS, of which four account for the majority of familial cases: C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARDBP (1–5%). The genetics of familial ALS are better understood than the genetics of sporadic ALS; as of 2016, the known ALS genes explained about 70% of familial ALS and about 15% of sporadic ALS. 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.ALS and frontotemporal dementia (FTD) are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities. Genetically, C9orf72 repeat expansions account for about 40% of familial ALS and 25% of familial FTD.
This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with ALS include ANG, SETX, and MATR3.C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72-ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRISPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination.Excitotoxicity, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter glutamate, is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor) that is more permeable to calcium.