Neuromuscular junction dysfunction in a subset of Charcot-Marie Tooth and related peripheral neuropathies mouse...

Charcot-Marie Tooth (CMT) disease is a clinically and genetically heterogeneous inherited peripheral neuropathy for which there is no treatment. CMT patients often present with weakness, fatigue, and muscle atrophy in the distal limbs. Improving function at the neuromuscular junction (NMJ) may improve function in some CMT patients. Using mouse models, we investigated eight CMT subtypes for NMJ phenotypes by morphology and functional deficits assessed by electromyography (EMG). We did not find NMJ abnormalities in mice with mutations in Gjb1^Y/Δ2 (CMT1X), or Yars1^E196K/E196K (diCMTC). Mice with mutations in Ighmbp2^Y918S/Y918S (CMT2S) and Pla2g6^M1J/M1J (Infantile Neuroaxonal Dystrophy) have neuromuscular phenotypes that could imply NMJ dysfunction, but we did not find defects in synaptic transmission or anatomy. A transgenic model of PMP22 overexpression (CMT1A) had EMG deficits with high frequency stimulation that are consistent with NMJ involvement. Three models showed indications of altered NMJ morphology and/or function. Gars^+/ΔETAQ mice, modeling CMT2D, displayed robust synaptic deficits morphologically and by EMG. Nadk2^S330P/S330P mice, modeling an ultrarare neuromuscular disease, had an EMG phenotype coinciding with symptom onset. Nefl^+/N98S mice, modeling CMT2E, had normal EMG; but pre-synaptic axon terminals were dysmorphic, with large varicosities, which were more pronounced in proximal muscles. Across multiple models, we found that the extensor digitorum longus was resistant to disease phenotypes based on NMJ innervation status and/or muscle weight and atrophy. Our results indicate that some subtypes of CMT have NMJ deficits, and that assessing neuromuscular disease patients for NMJ dysfunction may reveal a population that could benefit from therapies that enhance transmission.