Insight into the sporadic form of the disease has been afforded by analyses of the approximately 10 percent of ALS cases that are familial and those caused by identifiable sporadic mutations. These genetic and molecular influences are summarized by Brown and Al-Chalabi. They are inherited mainly in an autosomal dominant pattern (Table 38-6). Of these forms with a known family history, approximately 40 percent are associated with a hexanucleotide expansion in the C9orf  72 gene. Provocatively, 5 to 10 percent of presumably sporadic cases also have mutations in the gene, however, these numbers are derived from studies that excluded nonmotor manifestations in family members, namely frontotemporal dementia; therefore, the number of sporadic cases of ALS explained by the mutation is probably less than the 5 to 10 percent given above. The mechanism of motor neuron death that results from this mutation is not known but may be associated with mishandling of RNA-binding proteins.
Of similar interest are the TARDBP and FUS genes that each has an association with approximately 5 percent of familial cases and 2 percent of sporadic ones. They may damage motor neurons through mechanisms of altered protein degradation. The SOD1 mutation, the first to be found in familial ALS, codes for the cytosolic enzyme Cu-Zn superoxide dismutase (SOD1; Rosen et al); it has also been implicated in a small proportion of sporadic cases. There are yet other mutations in this group that have associations, not necessarily causal, with small numbers of both sporadic and inherited cases (Table 38-7). As already alluded to, all 3 of the aforementioned genes have also been implicated in degenerative frontotemporal dementia and in the combination of this dementia with ALS.
A rare and recessively inherited childhood form of motor neuron disease (affecting corticospinal more than spinal motor neurons) has been attributed to mutations in a gene whose protein (alsin) is a component of the neuronal cell-signaling pathways. Yet another rare childhood-onset form of disease arises from mutations in the senataxin gene, a DNA helicase that probably assists in chromatin folding and unfolding. (It is of interest that a recessively inherited mutation in the same gene transmits a form of ataxia with oculomotor disorder.) In several families, a mutation has been detected in a protein that is involved in the transport of vesicles in neurons. Table 38-6 summarizes some of the known genetic forms of motor neuron disease.
Trauma, particularly traction injury of an arm, but also repetitive head and spine injury has been reported occasionally as an antecedent event in patients with ALS, but a causative relationship has not been established. Younger and coworkers have found a higher incidence of paraproteinemia in patients with motor system disease than can be accounted for by chance. Many other examples of disordered immune function have been described but a coherent explanation of ALS as an autoimmune disease has not emerged. It has never been proved that intoxication with heavy metals (lead, mercury, aluminum) can cause motor system disease, although there are reports of concurrent myelopathic and radicular motor signs in patients with lead intoxication. There is little evidence that ALS represent a reactivation of a virus or the presence of some other infectious agent. The progressive weakness that occurs some 30 to 40 years after recovery from polio should not be confused with PMA, as already indicated. Finally, we have had occasion to see patients who, many years after a severe electrical injury that passed through the region of the cervical cord, developed a progressive and severe amyotrophy of the arms; other such extraordinary cases are known but the concordance is considered coincidental by most authorities (see Chap. 42).