Hattori Naoki, Yamamoto Masahiko, Yoshihara Tsuyoshi, Koike Haruki, Nakagawa Masanori, Yoshikawa Hiroo, Ohnishi Akio, Hayasaka Kiyoshi, Onodera Osamu, Baba Masayuki, Yasuda Hitoshi, Saito Toyokazu, Nakashima Kenji, Kira Jun-ichi, Kaji Ryuji, Oka Nobuyuki, Sobue Gen
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Brain. 2003 Jan;126(Pt 1):134-51. doi: 10.1093/brain/awg012.
Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.
通常导致夏科-马里-图斯病（CMT）的三个基因编码与髓鞘相关的蛋白质：外周髓鞘蛋白22（PMP22）、髓鞘蛋白零（MPZ）和连接蛋白32（Cx32）。脱髓鞘与轴索性表型是CMT中与这些基因的突变相关的主要问题。我们对205例患有PMP22重复、MPZ突变或Cx32突变的日本患者的脱髓鞘和轴索性特征进行了电生理、病理和遗传学评估。PMP22重复主要导致脱髓鞘表型，运动神经传导速度（MCV）减慢以及脱髓鞘组织病理学改变，而轴索性特征则可变地存在。MPZ突变的患者存在两个不同的表型亚组：一组MCV保持正常且仅有轴索性病理特征，而另一组则仅有脱髓鞘改变。这些轴索性和脱髓鞘性表型在各个家族的兄弟姐妹中高度一致，并且这两个亚组之间的MPZ突变没有重叠，这表明MPZ突变的性质和位置主要决定了轴索性和脱髓鞘性表型。Cx32突变的患者表现出MCV中度减慢，主要为轴索性特征以及相对较轻的脱髓鞘病理改变。这些轴索性和脱髓鞘性特征在个体患者中以不同程度同时存在。轴索性和脱髓鞘性特征的相对严重程度与特定的Cx32突变无关。正中神经MCV和整体组织病理学表型随疾病进展变化不大。复合肌肉动作电位（CMAP）波幅降低、轴突丢失、轴突发芽和神经性肌肉萎缩等轴索性特征均随疾病进展而变化，尤其是在PMP22重复和Cx32突变患者中。正中神经MCV不受年龄、疾病病程以及临床和病理异常严重程度的影响而保持良好，这证实正中神经MCV是遗传决定的神经病变表型的一个出色标志物。在PMP22重复、MPZ突变和Cx32突变患者中，CMAP波幅与远端肌肉力量显著相关，而MCV减慢则不然，这表明临床肌无力是由于功能性大轴突数量减少所致，而非脱髓鞘所致。因此，这三种主要的与髓鞘相关的蛋白质突变根据特定基因突变以及疾病进展阶段诱导出不同程度的轴索性和脱髓鞘性表型特征，而临床上明显的肌肉萎缩归因于功能性大轴突的丧失。
