Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of GAIT , is caused by a 1.5 Mb duplication on the short arm of chromosome 17, Pati ents with CMT1A typically. have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs ), distal weakness, sensory loss and decreased reflexes, In order to unders tand further the molecular pathogenesis of CMT1A, as well as to determine w hich features correlate with neurological dysfunction and might thus be ame nable to treatment, we evaluated the clinical and electrophysiological phen otype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP a mplitudes and regeneration, motor unit number estimates correlated with cli nical disability, while motor NCV did not, In addition, loss of joint posit ion sense and reduction in SNAP amplitudes also correlated with clinical di sability, while sensory NCV did not, Taken together, these data strongly su pport the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to targe calibre motor and sensory ax ons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotr ophic lateral sclerosis and other neurodegenerative diseases, should thus b e directed towards preventing axonal degeneration and/or promoting axonal r egeneration.