期刊
CLINICAL NEUROPHYSIOLOGY
卷 131, 期 10, 页码 2440-2451出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.clinph.2020.06.034
关键词
Axon excitability; Demyelination; Charcot-Marie Tooth neuropathy; Mouse model; Voltage-gated Na plus currents
资金
- Lundbeck Foundation
- Danish Foundation for Independent Research
Objective: The myelin impairment in demyelinating Charcot-Marie-Tooth (CMT) disease leads to various degrees of axonal degeneration, the ultimate cause of disability. We aimed to assess the pathophysiological changes in axonal function related to the neuropathy severity in hypo-/demyelinating CMT patients associated with myelin protein zero gene (MPZ) deficiency. Methods: We investigated four family members (two parents and two sons) harboring a frameshift mutation (c.306delA, p.Asp104ThrfsTer14) in the MPZ gene, predicted to result in a nonfunctional P0, by conventional conduction studies and multiple measures of motor axon excitability. In addition to the conventional excitability studies of the median nerve at the wrist, we tested the spinal accessory nerves. Control measures were obtained from 14 healthy volunteers. Results: The heterozygous parents (aged 56 and 63) had a mild CMT1B whereas their two homozygous sons (aged 31 and 39 years) had a severe Dejerine-Sottas disease phenotype. The spinal accessory nerve excitability could be measured in all patients. The sons showed reduced deviations during depolarizing threshold electrotonus and other depolarizing features which were not apparent in the accessory and median nerve studies of the parents. Mathematical modeling indicated impairment in voltage-gated sodium channels. This interpretation was supported by comparative modeling of excitability measurements in MPZ deficient mice. Conclusion: Our data suggest that axonal depolarization in the context of abnormal voltage-gated sodium channels precedes axonal degeneration in severely hypo-/demyelinating CMT as previously reported in the mouse models. Significance: Measures of the accessory nerve excitability could provide pathophysiological markers of neurotoxicity in severe demyelinating neuropathies. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.
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