儿童早发型腓骨肌萎缩症2型21例线粒体融合蛋白2基因型和表型分析

Analysis of mitofusin 2 genotype and phenotype in 21 children with charact-marry-tooth type Ⅱ

目的分析儿童腓骨肌萎缩症2型(CMT2)线粒体融合蛋白2(MFN2)基因型与临床表型。方法纳入1998至2012年首都医科大学附属北京儿童医院临床诊断的CMT2患儿为研究对象,采用直接测序方法检测MFN2突变基因,并描述分析突变和未突变患儿的临床表型、神经电生理、实验室和病理学检查特征。结果 21例CMT2患儿进入分析。①未检出MFN2基因突变18例(男14例,女4例),起病年龄平均3.3岁。其中9例累及下肢近端和远端,7例累及四肢,2例无法行走,8例下肢近端和远端肌肉萎缩,4例可见轻微感觉障碍。MFN2基因突变3例(男2例,女1例),起病年龄1.5～8岁,1例有家族史。均可见下肢近端和远端肌肉萎缩,2例足下垂并内翻,均有感觉障碍表现。②21例运动和(或)感觉神经传导速度≥38m·s-1或波幅降低,MFN2基因突变患儿腓总神经和胫神经复合肌肉动作电位波幅较正常值的下降幅度高于未突变患儿;③10例行腓肠神经活检检查,其中MFN2基因突变1例,未检出MFN2突变9例,均符合慢性轴索神经病病理改变,电镜下可见轴索线粒体聚集排列和肿胀。结论 MFN2基因突变是CMT2的致病原因之一,携带该突变患儿多为早发型,临床表型可能重于未突变者,仍需扩大样本量进一步分析。

Objective To analyze MFN2 mutations and associated phenotypes in patients with charact-marry-tooth （CMT） type Ⅱ. Methods Children diagnosed as CMT 2 in Beijing Childreng Hospital from 1998 to 2012 were included. Direct sequencing of the MFN2 gene and clinical investigations were performed in patients with MFN2 mutations. The clinical features, electrophysiological finding, labortory test and pathology of paitients with and without MFN2 mutations were analyzed. Results Twenty one cases with CMT 2 were included in the study. ①No gene mutation was detected in 18 cases （male 14 cases, female 4 cases）. The average age of the onset of the disease was 3.3 years. Nine of them involved in both proximal end and distal end of lower limb, seven cases involved in limbs, two cases could not walk, eight cases were with myophagism of proximal and distal ends of lower limb, mild sensory disturbance could be detected in four cases. Three different missense mutations were identified in 3 patients （ male 2 cases, female 1 case）. The age of onset ranged from 1.5 to 8 years, one had a family history of autosomal dominant inheritance. Myophagism of proximal and distal ends of lower limb could be found in all cases, foot drop with strephenopodia were observed in two cases, and all with sensory disturbance. ②Conduction velocity great than 38 m · s^-1 of motor nerve and/or sensory nerve, or decreased amplitude could be detected in all cases. The decreased value of CAMP of common peroneal nerve and tibial nerve was higher in MFN2 gene mutation children than that in children without MFN2 mutation. ③Sural nerve examination was performed in ten cases, one of them with MFN2 gene mutation, nine without MFN2 gene mutation, prominent mitochondrial abnormalities in both myelinated and unmyelinated nerve fibers were observed under electronic microscope. Conclusions MFN2 mutations was one of the causes of CMT2 with either dominant or recessive inheritance. The age of onset of patients with MFN2 gene mutation usually was before 10 years old.