Accrued somatic mutations (nucleic acid changes) trigger ALS: 2005-2015 update.

Amyotrophic lateral sclerosis (ALS) is a multilevel disease of the motor neuron system. The mechanisms triggering disease onset should be considered separately from those facilitating its spread and motor neuron death. In 2005, I brought together clinical and epidemiological evidence to support the hypothesis that acquired nucleic acid changes may trigger sporadic ALS. Since 2005, the conceptual foundations for this hypothesis have been strengthened. The journal Amyotrophic Lateral Sclerosis was renamed Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. The focal onset, with simultaneous initial maximal upper and lower motor neuron involvement in the region of onset, and patterns of spread, were characterized further. Clues from the epidemiology of sporadic ALS were affirmed by quantitative analysis, including the increase in disease incidence with age, suggesting accrual of time-dependent changes, and the confirmation of smoking as an established risk factor. Additional observations support the conclusion that accrued somatic mutations trigger onset of ALS. Muscle Nerve 53: 842-849, 2016.