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.

中文翻译：

---

Charcot-Marie-Tooth病家系髓鞘蛋白零基因剂量依赖性轴突离子通道功能障碍

目的 脱髓鞘 Charcot-Marie-Tooth (CMT) 病中的髓鞘损伤会导致不同程度的轴索变性，这是导致残疾的最终原因。我们旨在评估与髓鞘蛋白零基因 (MPZ) 缺乏相关的低/脱髓鞘 CMT 患者的神经病变严重程度相关的轴突功能的病理生理变化。方法我们调查了四个家庭成员（两个父母和两个儿子）在 MPZ 基因中携带移码突变（c.306delA，p.Asp104ThrfsTer14），通过传统的传导研究和运动轴突兴奋性的多种测量，预测会导致无功能的 P0 . 除了腕部正中神经的常规兴奋性研究外，我们还测试了脊髓副神经。控制措施来自 14 名健康志愿者。结果 杂合子父母（56 岁和 63 岁）具有轻度 CMT1B，而他们的两个纯合子儿子（31 岁和 39 岁）具有严重的 Dejerine-Sottas 病表型。所有患者均可测量脊髓副神经兴奋性。儿子在去极化阈值电紧张和其他去极化特征期间表现出减少的偏差，这在父母的副神经和正中神经研究中并不明显。数学模型表明电压门控钠通道受损。这种解释得到了 MPZ 缺陷小鼠兴奋性测量比较模型的支持。结论我们的数据表明，如先前在小鼠模型中报道的那样，在严重低/脱髓鞘 CMT 中，异常电压门控钠通道背景下的轴突去极化先于轴突变​​性。