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Amyotrophic comes from the Greek language: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophy of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening (sclerosis) in the region.

In ALS, the progressive weakness that develops is due to selective death of motor neurons, the nerve cells that carry messages telling the muscles to contract. Motor neurons are unique cells, the longest in the body. All neurons extend a connecting fiber, the axon, to the next neuron or end organ. Some motor neurons in the spinal cord must extend their axon up to a meter, to reach the toes, for example, yet the cell body maintaining this extraordinary fiber is only of ordinary size. Metabolic demands on the motor neurons must be correspondingly extraordinary.