Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy arising from mutations in diverse genes that principally disrupt axons and Schwann cells. As the most distal synaptic interface of motor neurons, the neuromuscular junction (NMJ) represents a plausible but underexplored site at which such disruptions may converge to confer selective peripheral neuropathy. This review synthesises current evidence for NMJ involvement in CMT, focusing on mammalian systems, and evaluates how localised synaptic pathology relates to distal nerve dysfunction across genetic models. We outline the organisation of the mammalian NMJ and experimental approaches used to assess its dysregulation, emphasising the distinction between structural and functional denervation. Appraisal of NMJ abnormalities reported across axonal and demyelinating CMT models reveals evidence for impaired synaptic maturation, transmission and conduction failure, often prior to subsequent structural denervation and axonal degeneration. Emerging patterns indicate well-studied axonal subtypes show early, length-dependent synaptic dysfunction, whereas demyelinating forms often exhibit secondary NMJ destabilisation with ineffective axonal sprouting and reinnervation attempts. We also address methodological and interpretive considerations in NMJ studies, and consider the translational relevance of NMJ disruption as a functional readout of pathology and potential therapeutic target. Collectively, this review clarifies the NMJ as an informative, active and selective site of vulnerability in CMT, while demonstrating both the need and relevance for additional investigation in mammalian systems.