{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:11:29Z","timestamp":1792069889126,"version":"4.4.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Charcot\u2013Marie 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, 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\u2010stimulated muscle force after partially inhibiting ClC\u20101 chloride channels with the novel small molecule NMD670.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010one CMT patients (46.4\u2009\u00b1\u200914.4\u2009years) and 10 HC (43.3\u2009\u00b1\u200912.7\u2009years) were enrolled. SFEMG jitter (NMJ variability) was higher [median (range)] in the CMT patients [56\u2009\u03bcs (35; 197\u2009\u03bcs)] vs. HC [29\u2009\u03bcs (19; 36\u2009\u03bcs)], (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Blocking (NMJ failure) was higher in the CMT patients (13.4% (0.0; 90.9%)) vs. HC (0.0% (0.0; 4.5%)), (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study suggests that NMJ dysfunction contributes to muscle dysfunction in patients with CMT 1 and 2. Furthermore, our preclinical data provide proof\u2010of\u2010mechanism for recovery of muscle function with ClC\u20101 inhibition in CMT mouse models. Collectively, these findings suggest that targeting NMJ dysfunction with ClC\u20101 inhibitors could enhance muscle function in CMT patients, warranting further clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52252","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T10:41:34Z","timestamp":1734086494000},"page":"320-331","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuromuscular transmission deficits in patients with <scp>CMT<\/scp> and <scp>ClC<\/scp>\u20101 inhibition in <scp>CMT<\/scp> animal models"],"prefix":"10.1002","volume":"12","author":[{"given":"Thomas Skj\u00e6rlund","family":"Gr\u00f8nneb\u00e6k","sequence":"first","affiliation":[{"name":"NMD Pharma A\/S  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Haahr\u2010Lillevang","sequence":"additional","affiliation":[{"name":"Department of Neurology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4449-472X","authenticated-orcid":false,"given":"Martin","family":"Skov","sequence":"additional","affiliation":[{"name":"NMD Pharma A\/S  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2151-0873","authenticated-orcid":false,"given":"Kristina","family":"Kelly","sequence":"additional","affiliation":[{"name":"NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Department of Physical Medicine and Rehabilitation University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan R.","family":"Kerr","sequence":"additional","affiliation":[{"name":"NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Department of Physical Medicine and Rehabilitation University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Viteri","sequence":"additional","affiliation":[{"name":"NextGen Precision Health University of Missouri  Columbia Missouri USA"},{"name":"Department of Physical Medicine and Rehabilitation University of Missouri  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Jaworek","sequence":"additional","affiliation":[{"name":"Department of Neurology The Ohio State University  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Department of Neurology The Ohio State University  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Bold","sequence":"additional","affiliation":[{"name":"NMD Pharma A\/S  Aarhus 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