Observational studyAnnals of clinical and translational neurology2025
Neuromuscular transmission deficits in patients with CMT and ClC-1 inhibition in CMT animal models.
Observational study in Annals of clinical and translational neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.The Journal of clinical investigation · 2026Article
- Ten years of disease-modifying therapy in spinal muscular atrophy: lessons learned and future directions.Nature reviews. Neurology · 2026Review
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveCharcot-Marie Tooth (CMT) is a hereditary neuropathy characterized by muscle weakness and fatigue with no approved therapies. Preclinical studies implicate neuromuscular junction (NMJ) transmission deficits in muscle dysfunction in CMT. This study aimed to evaluate NMJ function in patients with CMT types 1 and 2, and to determine whether enhancing NMJ transmission can improve muscle function in preclinical CMT models.
methodsFirst, an observational study involving single fiber electromyography (SFEMG) and clinical testing in patients with CMT 1 and 2 and healthy controls (HC) was conducted. Next, preclinical studies examined muscle function, specifically nerve-stimulated muscle force after partially inhibiting ClC-1 chloride channels with the novel small molecule NMD670.
resultsTwenty-one CMT patients (46.4 ± 14.4 years) and 10 HC (43.3 ± 12.7 years) were enrolled. SFEMG jitter (NMJ variability) was higher [median (range)] in the CMT patients [56 μs (35; 197 μs)] vs. HC [29 μs (19; 36 μs)], (p < 0.05). Blocking (NMJ failure) was higher in the CMT patients (13.4% (0.0; 90.9%)) vs. HC (0.0% (0.0; 4.5%)), (p < 0.05). In CMT, jitter and blocking correlated inversely with muscle strength, mobility, balance, and endurance. In CMT 1A and 2D mice, NMD670 increased both peak force and contractile endurance in vivo.
interpretationOur study suggests that NMJ dysfunction contributes to muscle dysfunction in patients with CMT 1 and 2. Furthermore, our preclinical data provide proof-of-mechanism for recovery of muscle function with ClC-1 inhibition in CMT mouse models. Collectively, these findings suggest that targeting NMJ dysfunction with ClC-1 inhibitors could enhance muscle function in CMT patients, warranting further clinical trials.
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