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xi Introduction ALS, or amyotrophic lateral sclerosis, is a rare neuromuscular disease in which muscles controlling movement of the legs, arms, hands, face, jaw, and diaphragm progressively atrophy, leaving the individual unable to stand, use their arms or hands, walk, talk, chew, swallow, and, eventually, breathe. The onset is insidious—a highly localized weakness so subtle that it is often overlooked or a muscle that suddenly stops working. Spreading of muscle weakness and lack of response among connected body regions are hallmarks of ALS, which lead to death over a period averaging 3–5 years. For a few people, the decline is more rapid, in others slower. The physicist Stephen Hawking survived a remarkable 53 years after being told at age 21 that he had only 2 years to live. His story has heartened the ALS field, because it indicates that the disease can be slowed and perhaps some- day even stopped. The primary defect is the degeneration of a specific type of nerve cell, the motor neurons, which control voluntary muscle movement. Other types of neurons such as those responsible for cognition, sensation, and most other mental functions in the brain, sphincter activity, or eye blink do not degenerate. ALS affects primarily middle-aged and older adults, as well as younger individuals who have inheritable forms of the disease. In many ways, it is a mysterious disease with no clear cause in most cases. It only affects voluntary muscles, those controlled by the individual. The cause(s) of ALS are unknown. Most cases of ALS appear for the first time in a family with no apparent connection to any particular environ- mental exposure, occupation, or activity, and they are defined as sporadic. ALS affects slightly more men than women. About 10 percent of all cases are inherited forms of ALS, genetic mutations in one of a small number of genes for proteins passed along in families. Most individuals carrying one of these mutant genes will develop ALS, frequently at an earlier age than for the sporadic disease. There are no cures for ALS. Currently there are