一个远端型遗传性运动神经病V型家系分析

Analysis of a Chinese family with distal hereditary motor neuropathy type V

目的报道1个远端型遗传性运动神经病V型家系的临床和电生理特点,筛查其致病基因。方法收集1个2017年7月就诊于郑州大学第一附属医院的遗传性周围神经病家系,完善体格检查、电生理检测,应用高通量靶向测序筛查其致病基因,并在家系内和正常人群中筛查候选突变。结果该家系共有4例患者。先证者男性,25岁,主要表现为缓慢进展的四肢远端肌肉萎缩、无力,上肢远端较早受累且上肢受累严重,不伴有明显感觉异常。肌电图显示神经源性改变,运动神经传导速度减慢伴神经复合肌肉动作电位波幅降低,感觉神经未见异常。先证者外公、舅舅和表弟有类似临床表现和肌电图表现。靶向测序发现先证者存在GARS基因c.880G>A(p.G294R)突变,其母亲及患病舅舅和表弟存在此突变,家系内其他正常人及300名正常对照者均不携带此变异。该突变为新发突变,在dbSNP、ExAC和1000G数据库中均未有报道。结论首次在远端型遗传性运动神经病V型家系中发现GARS基因c.880G>A(p.G294R)突变,扩大了GARS基因突变致病谱。

Objective To report the clinical,electrophysiological and genetic features in a Chinese family with distal hereditary motor neuropathy type V(dHMN-V)and screen the pathogenic mutant gene.Methods A family with the history of inherited peripheral neuropathy was recruited in the First Affiliated Hospital of Zhengzhou University in July 2017.The clinical features and electrophysiological data were investigated.Genetic testing on well-established genes associated with hereditary peripheral neuropathy was conducted by targeted high throughput sequencing and the candidate variant was screened in the family and normal controls.Results There were four affected individuals in the family.The proband,a 25-year-old male,was characterized by weakness and atrophy in the distal extremities primarily affected the upper extremities without sensory impairment.Electrophysiological study showed chronic neurogenic pattern in the upper and lower limb muscles.The motor conduction showed reduced velocity and compound muscle action potential amplitude,while the sensory conduction studies results were normal.The grandfather,a maternal uncle and a cousin of the proband exhibited similar clinical manifestations and electrophysiological abnormality.Genetic testing revealed a heterozygous mutation,c.880G>A(p.G294R),in the GARSgene in the proband.Proband′s mother and two other affected individuals carried the mutation which was confirmed by Sanger sequencing.The mutation site was not found in the unaffected members from the family and 300 unrelated normal controls.The variant is a novel mutation which has not been reported in dbSNP,ExAC and 1000 Genomes Project databases.Conclusion The results suggest that the novel c.880G>A(p.G294R)mutation of the GARS gene is responsible for the Chinese patients with dHMN-V,and the findings broaden the mutational spectrum of GARS gene.