What causes amyotrophic lateral sclerosis?

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; motor neuron disease; neurodegenerative disease.

Figure 1.. The time course of amyotrophic lateral sclerosis (ALS).

Time is represented along the x-axis; physical health and molecular damage are represented along the y-axis. With time, molecular damage increases in a step-wise way until it reaches a threshold, at which point physical health declines, representing disease onset. People with a family history of ALS may have a large genetic predisposition to ALS and so need fewer steps to reach the level of molecular damage that causes disease, corresponding to a younger age of onset. Lack of exposure to sufficient risk factors means that the disease does not manifest, even if a genetic cause is present, explaining reduced penetrance. There is not a 1:1 mapping of risk factors and steps, as the steps represent molecular hits that lead to cellular damage rather than actual exposures. Once physical symptoms have started, progression shows a log-linear decline until the onset of respiratory symptoms, where decline is exponential. Clinical and functional involvement can be measured by the King’s clinical staging and Milano-Torino staging (MiToS) systems. A dotted line represents the hypothetical trajectory in an unaffected individual. Black arrows represent genetic and environmental risk factors. Numbers indicate remaining molecular hits until disease onset.