PMP22基因重复致非典型腓骨肌萎缩症1A型一个家系的遗传学分析

Genetic analysis of a Chinese pedigree affected with atypical Charcot-Marie-Tooth disease type 1A due to duplication of PMP22 gene

目的探讨非典型腓骨肌萎缩症1A型(CMT1A)一个家系的临床表现及基因检测结果。方法收集空军军医大学附属西京医院神经内科2022年6月收治的1例PMP22基因重复致非典型CMT1A先证者的临床资料,并依据高足弓及非典型临床症状对其4代17名家系成员进行追溯,对部分家系成员进行神经超声检查和基因检测。对先证者及部分患病成员进行全外显子组测序(WES)与多重连接探针扩增(MLPA)检测。结果先证者为15岁男性,以发作性四肢神经痛伴无力为突出表现,伴高弓足,双腓肠肌形态饱满,无双下肢远端肌肉萎缩所致的"鹤腿"样改变,双小腿MRI未见肌肉脂肪浸润,神经传导检查提示四肢感觉及运动神经均受损,以脱髓鞘改变为主。家系成员中共7人存在高弓足,其中5例表现为发作性神经痛和肌无力,2例无临床症状。先证者及其弟弟、父亲和姑姑神经超声检查均提示四肢周围神经全程增粗,束状结构不清晰。基因检测提示部分患病成员PMP22基因第1~5外显子及其附近区域存在大片段的重复(chr17:15133768_15502298),评定为致病性。结论PMP22基因重复考虑为该CMT1A家系的遗传学病因。

Objective To explore the clinical manifestations and genetic basis for a Chinese pedigree affected with atypical Charcot-Marie-Tooth disease type 1 A(CMT1A).Methods A patient admitted to the Department of Neurology,Xijing Hospital Affiliated to Air Force Medical University in June 2022 was selected as the study subject.Clinical data of the patient was collected,and 17 family members from four generations of this pedigree were traced based on pes arcuatus and atypical clinical symptoms.Neuroultrasound and genetic testing were carried out on available family members.Whole exome sequencing and multiple ligation-dependent probe amplification assay were carried out for the proband and some of the affected members of the pedigree.Results The proband,a 15-year-old male,had presented with paroxystic limb pain with weakness,accompanied by pes cavus and hypertrophy of gastrocnemius muscles,without stork leg sign caused by muscles atrophy in the distal lower extremities.MRI has revealed no sign of fat infiltration in the muscles of both legs.Nerve conduction examination had indicated damages of the sensory and motor nerves of the limbs,mainly with demyelinating changes.Seven members of the pedigree had pes arcuatus,including 5 presenting with paroxysmal neuropathic pain and myasthenia in the limbs,whilst 2 were without any clinical symptoms.Neurosonography of the proband,his brother,father and aunt showed thickened peripheral nerves of the extremities with unclear bundle structure.Genetic analysis revealed a large repeat encompassing exons 1 to 5 of the PMP22 gene and flanking regions(chr17:15133768_15502298)in some of the affected members,which was predicted to be pathogenic.Conclusion The duplication of PMP22 gene was considered to be pathogenic for this CMT1A pedigree.