Charcot-Marie-Tooth disease and related neuropathies

Charcot-Marie-Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated.