Progress in clinical neurosciences: The evidence for ALS as a multisystemsdisorder of limited phenotypic expression

Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a un ique neurodegeneration disorder in which motor neurons are selectively vuln erable to a single disease process. Our current understanding of ALS, howev er, suggests that this is far too limited an approach. While motor neuron d egeneration remains the central component to this process, there is conside rable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial varian ts of ALS for which unique genetic linkage has been identified is increasin g, attesting further to the biological heterogeneity of the disorder. At th e cellular level, derangements in cytoskeletal protein and glutamate metabo lism, mitochondrial function, and in glial interactions are clearly evident . When considered in this fashion, ALS can be justifiably considered a diso rder of multiple biological processes sharing in common the degeneration of motor neurons.