Charcot-Marie-Tooth病(CMT)是最常见的遗传性神经系统疾病之一,可由100多种不同基因的突变引起。致病基因之一是8号染色体上的NEFL,它编码神经丝光蛋白(NEFL),共组装形成神经丝的五种蛋白质之一。据报道,NEFL中至少有34种引起CMT的突变跨越头部,杆,和蛋白质的尾部结构域。这些突变大多数是显性遗传的,但有些是隐性遗传。所产生的疾病在临床报告中根据电诊断研究分为轴突(2型;CMT2E),脱髓鞘(1型;CMT1F),或介于两者之间的中间形式(主要中间;DI-CMTG)。在这篇文章中,我们首先简要介绍CMT和神经丝。然后,我们整理和分析疾病分类的临床文献中的数据,各种突变的发病年龄和电诊断测试结果。我们发现头部的突变,杆,和尾部结构域都可以导致疾病的早期发作和严重的神经功能缺损,头部结构域突变有更严重的趋势。我们还发现疾病分类与特定突变或结构域无关。事实上,具有相同突变的不同个体可以归类为具有轴突,脱髓鞘,或疾病的显性中间形式。这表明该疾病的分类为CMT2E,CMT1F或DI-CMTG更多地与可变的疾病表现有关,而不是与潜在疾病机制的差异有关。在所有情况下,这很可能主要是轴突。
Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders and can be caused by mutations in over 100 different genes. One of the causative genes is NEFL on chromosome 8 which encodes
neurofilament light protein (NEFL), one of five proteins that co-assemble to form neurofilaments. At least 34 different CMT-causing mutations in NEFL have been reported which span the head, rod, and tail domains of the protein. The majority of these mutations are inherited dominantly, but some are inherited recessively. The resulting disease is classified variably in clinical reports based on electrodiagnostic studies as either axonal (type 2; CMT2E), demyelinating (type 1; CMT1F), or a form intermediate between the two (dominant intermediate; DI-CMTG). In this article, we first present a brief introduction to CMT and neurofilaments. We then collate and analyze the data from the clinical literature on the disease classification, age of onset and electrodiagnostic test results for the various mutations. We find that mutations in the head, rod, and tail domains can all cause disease with early onset and profound neurological impairment, with a trend toward greater severity for head domain mutations. We also find that the disease classification does not correlate with specific mutation or domain. In fact, different individuals with the same mutation can be classified as having axonal, demyelinating, or dominant intermediate forms of the disease. This suggests that the classification of the disease as CMT2E, CMT1F or DI-CMTG has more to do with variable disease presentation than to differences in the underlying disease mechanism, which is most likely primarily axonal in all cases.