Models of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) hereditary neuropathies are the most common inherited neuromuscular disorder. They are inherited as dominant or recessive traits and consist of demyelinating or axonal types. To decipher thepathomechanisms of CMT neuropathy, animal models have taken center stage, as it is there that the normal three-dimensional and reciprocal relationships between Schwann cells and axons are obtained, and that chronic secondary changes may be followed. There are four types of animal models of CMT: those resulting from naturally occurring mutations, those resulting from alterations produced through random chemical mutagenesis, those resulting from targeted mutations introduced by homologous recombination in mouse embryonic stem cells, and random insertion transgenes. This chapter characterizes animal models relevant to 8 of 14 CMT genes. The majority are behaviorally, electrophysiologically, and pathologically similar to the corresponding human diseases. These models have produced new information about the normal function of CMT genes, as well as the natural history of CMT neuropathies, and emphasize that the pathogenesis usually begins cell autonomously and is often mutation specific, even for diverse alterations of the same gene.