Qiao Xiao-hui, Li Yue-xing, Chang Xing-zhi, Luan Xing-hua, Chen Bin, Bu Ding-fang, Yuan Yun
Department of Neurology, Peking University First Hospital, Beijing 100034, China.
Zhonghua Yi Xue Za Zhi. 2009 Dec 22;89(47):3328-31.
To analyze the relationship between phenotype and genotype and the role of immune cells in the pathogenesis of X-linked Charcot-Marie-Tooth disease (CMT1X).
The probands of the two families with X-linked dominant inherited peripheral neuropathy were evaluated clinically, electrophysiologically, pathologically and genetically. The available family members were genetic analyzed and the novel mutations were compared with other known ones.
(1) In both families, affected members presented progressive weakness and wasting of distal extremities and it seems that males suffered more severely than affected females with onset in the first decade of their life. Proband of family 1 showed moderately elevated CSF protein and marked increase of IgG-syn in CSF.(2) Nerve conduction velocity (NCV) of the peripheral nerves was intermediately slow in both motor and sensory nerves exhibiting the features of demyelination. Brain-stem auditory evoked potentials (BAEPs) was abnormal in the proband of family 1: delayed I-III interpeak intervals were recorded but with normal III-V interpeak intervals. (3) Sural nerve biopsy in the probands of the two families showed a prominent distinguished loss of myelinated fibers and a few clusters of regenerating axons without conspicuous onion-bulb formations. Thinly myelinated fibers was prominent in family 2 but not in family 1. Immunohistochemical staining showed that there were positive CD68 cells in the endoneurial space and lamellar sheath. (4) By genetic testing, we identified two novel missense mutations of GJB1 gene, which resulted in Ile127Phe amino acid substitution in family 1(located in the intracellular loop of connexin 32) and Asp178Gly amino acid substitution in family 2 (located in the 2(nd) extracellular loop of CX32), respectively. Both mutations were highly conserved in low species and were predicted to be possibly damaging through Polyphen prediction tool.
The two novel GJB1 gene mutations cause a spectrum of clinical manifestations of CMT1X in both families. However, the mutations site of CX32 alone cannot predict these phenotypic variations in CMT1X fully. The immune system may be involved in the pathogenesis of the disease.
分析X连锁遗传性夏科-马里-图斯病（CMT1X）发病机制中表型与基因型的关系以及免疫细胞的作用。
对两个X连锁显性遗传性周围神经病家系的先证者进行临床、电生理、病理及遗传学评估。对家系中可获取的成员进行基因分析，并将新发现的突变与其他已知突变进行比较。
（1）在两个家系中，受累成员均表现为进行性远端肢体无力和萎缩，男性似乎比受累女性病情更严重，发病于生命的第一个十年。家系1的先证者脑脊液蛋白中度升高，脑脊液中IgG-syn显著增加。（2）两个家系外周神经的神经传导速度（NCV）在运动和感觉神经中均中度减慢，呈现脱髓鞘特征。家系1的先证者脑干听觉诱发电位（BAEP）异常：记录到I-III峰间期延迟，但III-V峰间期正常。（3）两个家系先证者的腓肠神经活检显示有髓纤维明显显著丢失，有少量再生轴突簇，但无明显的洋葱球样结构形成。薄髓鞘纤维在2号家系中突出，但在1号家系中不突出。免疫组化染色显示神经内膜间隙和板层鞘中有CD68阳性细胞。（4）通过基因检测，我们鉴定出GJB1基因的两个新的错义突变，分别导致家系1中Ile127Phe氨基酸替换（位于连接蛋白32的细胞内环）和家系2中Asp178Gly氨基酸替换（位于CX32的第二个细胞外环）。这两个突变在低等物种中高度保守，通过Polyphen预测工具预测可能具有损害性。
两个新的GJB1基因突变导致两个家系出现一系列CMT1X的临床表现。然而，单独的CX32突变位点不能完全预测CMT1X中的这些表型变异。免疫系统可能参与了该疾病的发病机制。
