腓骨肌萎缩症2A2A型家系的神经电生理及基因突变分析

Electrophysiological and gene mutation analysis of Charcot Marie Tooth disease type 2A2A family

目的探讨一个腓骨肌萎缩症(charcot-marie-tooth,CMT)家系的临床表现、神经电生理学和基因突变特点。方法收集家系先证者及其他成员的临床资料,对先证者进行神经电生理学检查和全外显子组基因测序,用Sanger测序技术对先证者及其家系进行突变位点验证。应用计算机软件预测突变位点氨基酸进化保守性和突变可能导致的蛋白质结构和功能变化,分析突变位点的性质。结果先证者儿童期发病,出现双下肢对称性肌肉无力伴跟腱反射消失及足部畸形,其母亲有类似症状。先证者神经电生理检查示运动和感觉神经纤维脱髓鞘及轴索性改变。基因检测发现先证者和母亲MFN2基因第11个外显子均检出c.1066A>G(p.T356A)杂合错义突变;先证者姐姐和父亲未检测到该突变。用PolyPhen-2和MutationTaster软件预测该突变为致病性,突变区域序列在不同物种间高度保守。结论儿童CMT2A2A患者的神经电生理、临床特点、发病机制及相关基因表型均有改变,此可为儿童CMT的临床诊断提供依据。

Objective To explore the clinical manifestations,electroneurophysiology and gene mutation characteristics of a Charcot Marie Tooth(CMT)family.Methods Clinical data of probands and other members of the family were collected and analyzed,and electroneurophysiological examination and total exome gene sequencing were performed on the probands.The gine mutation sites were verified by Sanger sequencing technology.Bioinformatic analysis was carried out to detect the effect of gine mutations on the structure and function of the protein product.Results The proband suffered from children’s onset of bilateral lower limb symmetrical muscle weakness accompanied by the disappearance of Achilles tendon reflex and foot deformity,and his mother had similar symptoms.Electrophysiologic examination of the proband’s nerves showed demyelination and axonal changes in motor and sensory nerve fibers and c.1066A>G(p.T356A)heterozygous missense mutation was detected from the 11th exon of MFN2 gene of both the proband and the mother by genetic testing,while such missense mutation could not be detected from the proband's sister and father.The mutation was predicted to be pathogenic by PolyPhen-2 and Mutation Taster software,and the sequence of mutation regions was highly conserved among different species.Conclusion This study shows the changes of neuroelectrophysiology,clinical features,pathogenesis and related gene phenotypes of children with CMT2A2A.It provides the basis for the clinical diagnosis of fibula atrophy in children with CMT.