Though the exact cause of<unk>  is unknown, genetic and environmental factors are thought to be of roughly equal importance. The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause<unk> . A liability threshold model for<unk>  proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life. Genetics<unk>  can be classified as familial or sporadic, depending on whether or not there is a family history of the disease. There is no consensus among neurologists on the exact definition of familial<unk> . The strictest definition is that a person with<unk>  must have two or more first-degree relatives (children, siblings, or parents) who<unk> o have<unk> . A less strict definition is that a person with<unk>  must have at least one first-degree or second-degree relative (grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who<unk> o has<unk> . Familial<unk>  is usually said to account for 10% of all cases of<unk> , though estimates range from 5% to 20%. Higher estimates use a broader definition of familial<unk>  and examine the family history of people with<unk>  more thoroughly. In sporadic<unk> , there is no family history of the disease. Sporadic<unk>  and familial<unk>  appear identical clinically and pathologically and are similar genetically; about 10% of people with sporadic<unk>  have mutations in genes that are known to cause familial<unk> . In light of these parallels, the term "sporadic<unk> " has been criticized as misleading because it implies that cases of sporadic<unk>  are only caused by environmental factors; the term "isolated<unk> " has been suggested as a more accurate alternative. More than 20 genes have been associated with familial<unk> , 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<unk>  are better understood than the genetics of sporadic<unk> ; , the known<unk>  genes explained about 70% of familial<unk>  and about 15% of sporadic<unk> . Overall, first-degree relatives of an individual with<unk>  have a 1% risk of developing<unk> .<unk>  has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.<unk>  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<unk>  and 25% of familial FTD. Clinically, 50% of people with<unk>  have some cognitive or behavioral impairments and 5–15% have FTD, while 40% of people with FTD have some motor neuron symptoms and 12.5% have<unk> . Pathologically, abnormal aggregations of TDP-43 protein are seen in up to 97% of<unk>  patients and up to 50% of FTD patients. In December 2021 a paper found the TDP-43 proteinopathy is in turn caused by defective cyclophilin A which regulates TARDBP gene expression. Other genes known to cause FTD-ALS include CHCHD10, SQSTM1, and TBK1. Environmental factors Where no family history of the disease is present – around 90% of cases – no cause is known. Possible associations for which evidence is inconclusive include military service and smoking. Although studies on military history and<unk>  frequency are inconsistent, there is weak evidence for a positive correlation. Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service. A 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to lead; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-three fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid. In a 2017 study by the United States Centers for Disease Control and Prevention analyzing U.S. deaths from 1985 to 2011, occupations correlated with<unk>  deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs. Other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock. There is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene. Head injury A 2015 review found that moderate to severe traumatic brain injury is a risk factor for<unk> , but whether mild traumatic brain injury increases rates was unclear. A 2017 meta-analysis found an association between head injuries and<unk> ; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed<unk> , rather than the cause of<unk> . Physical activity A number of reviews prior to 2021 found no relationship between the amount of physical activity and the risk of developing<unk> . A 2009 review found that the evidence for physical activity as a risk factor for<unk>  was limited, conflicting, and of insufficient quality to come to a firm conclusion. A 2014 review concluded that physical activity in general is not a risk factor for<unk> , that soccer and American football are possibly associated with<unk> , and that there was not enough evidence to say whether or not physically demanding occupations are associated with<unk> . A 2016 review found the evidence inconclusive and noted that differences in study design make it difficult to compare studies, as they do not use the same measures of physical activity or the same diagnostic criteria for<unk> . However, research published in 2021 suggested that there was a positive causal relationship between<unk>  and intense physical exercise in those with a risk genotype. Sports Both soccer and American football have been identified as risk factors for<unk>  in several studies, although this association is based on small numbers of<unk>  cases. A 2012 retrospective cohort study of 3,439 former NFL players found that their risk of dying from neurodegenerative causes was three times higher than the general US population, and their risk of dying from<unk>  or Alzheimer's disease was four times higher. However, this increased risk was calculated on the basis of two deaths from Alzheimer's disease and six deaths from<unk>  out of 334 deaths total in this cohort, meaning that this study does not definitively prove that playing American football is a risk factor for<unk> . Some NFL players thought to have died from<unk>  may have actually had chronic traumatic encephalopathy (CTE), a neurodegenerative disorder associated with multiple head injuries that can present with symptoms that are very similar to<unk> . Soccer was identified as a possible risk factor for<unk>  in a retrospective cohort study of 24,000 Italian soccer players who played between 1960 and 1996. There were 375 deaths in this group, including eight from<unk> . Based on this information and the incidence of<unk> , it was calculated that the soccer players were 11 times more likely to die from<unk>  than the general Italian population. However, this calculation has been criticized for relying on an inappropriately low number of expected cases of<unk>  in the cohort. When the lifetime risk of developing<unk>  was used to predict the number of expected cases, soccer players were no more likely to die of<unk>  than the general population. Smoking Smoking is possibly associated with<unk> . A 2009 review concluded that smoking was an established risk factor for<unk> . A 2010 systematic review and meta-analysis concluded that there was not a strong association between smoking and<unk> , but that smoking might be associated with a higher risk of<unk>  in women. A 2011 meta-analysis concluded that smoking increases the risk of<unk>  versus never smoking. Among smokers, the younger they started smoking, the more likely they were to get<unk> ; however, neither the number of years smoked nor the number of cigarettes smoked per day affected their risk of developing<unk> .
Amyotrophic lateral sclerosis
Botulism
Tropical ataxic neuropathy
Juvenile primary lateral sclerosis
Vascular myelopathy
Multiple system atrophy
Surfer's myelopathy
Lambert–Eaton myasthenic syndrome