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

TLDR

Charcot‑Marie‑Tooth disease type 1A is caused by a 1.5 Mb duplication on chromosome 17 q and is characterized by slowed nerve conduction, reduced motor and sensory potentials, distal weakness, sensory loss, and decreased reflexes. The study evaluated the clinical and electrophysiological phenotype of 42 CMT1A patients to identify features that correlate with neurological dysfunction and could be therapeutic targets. Muscle weakness, CMAP amplitudes, motor unit number estimates, loss of joint position sense, and reduced SNAP amplitudes all correlated with clinical disability, whereas motor and sensory NCVs did not, indicating that large‑calibre axonal loss drives CMT1A dysfunction and that therapies should aim to prevent degeneration or promote regeneration.

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients 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 understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.