The complex relation between genotype and phenotype in motor neuron disease



The success in mapping genetic loci and identifying mutant genes in familial neurodegenerative disease has outpaced our ability to understand the linkage between genotype and phenotype of disease. The results have led to a backlog of genetic information with limited clarification of underlying disease mechanisms. A major dilemma is how mutations in widely expressed proteins lead to degeneration or dysfunction of small subsets of neurons. The problem raises fundamental questions as to the nature and interrelation of pathways that maintain the homeostasis of differentiated neurons. The issue also bears on the pathogenesis of sporadic forms of disease and prospective efficacy of therapeutic applications. This review examines the problem as it relates to motor neuron disease. Ann Neurol 2007