Background

Charcot-Marie-Tooth disease (CMT) is a family of rare inherited peripheral nerve disorders resulting in lifelong disability, with no disease-modifying therapies available. Patients usually present with muscle weakness and wasting, as well as sensory deficits, in the hands and feet, indicating that motor and sensory neurons with the longest axons are generally the most susceptible to neuropathy.

Compromised axonal transport has been identified in several CMT subtypes and is hypothesized to be a major driver of axon and synaptic degeneration. The subtype CMT type 2D (CMT2D) manifests during adolescence because of dominantly inherited mis-sense mutations in the widely and constitutively expressed GARS1 gene, which encodes glycyl-tRNA synthetase (GlyRS), an enzyme essential for protein synthesis.