上海交通大学学报（医学版）

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2022 , Vol. 42 >Issue 5: 609 - 616

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.05.008

论著 · 临床研究

PMP22基因相关性周围神经病的遗传学和临床特点分析

  • 朱啸巍 ,
  • 詹飞霞 ,
  • 张超 ,
  • 刘时华 ,
  • 钟平 ,
  • 曹立 ,
  • 栾兴华
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  • 1.上海交通大学医学院附属第六人民医院神经内科，上海 200030
    2.安徽医科大学附属宿州医院神经内科，宿州 234000
朱啸巍（1997—），女，硕士生；电子信箱：zhuxw@rjlab.cn。
栾兴华，电子信箱：green_lxh@sina.com。

收稿日期: 2021-12-06

  录用日期: 2022-05-06

  网络出版日期: 2022-05-28

基金资助

国家自然科学基金(81870889)

收起

Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy

  • Xiaowei ZHU ,
  • Feixia ZHAN ,
  • Chao ZHANG ,
  • Shihua LIU ,
  • Ping ZHONG ,
  • Li CAO ,
  • Xinghua LUAN
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  • 1.Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
    2.Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China
LUAN Xinghua, E-mail: green_lxh@sina.com.

Received date: 2021-12-06

  Accepted date: 2022-05-06

  Online published: 2022-05-28

Supported by

National Natural Science Foundation of China(81870889)

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摘要

目的·研究周围髓鞘蛋白22（peripheral myelin protein-22，PMP22）基因相关性周围神经病患者的遗传学特点和临床特征，并探讨基因型和临床表型的相关性。方法·收集2006年—2022年就诊于上海交通大学医学院附属第六人民医院神经内科的162例周围神经病患者，应用多重连接依赖的探针扩增（multiplex ligation-dependent probe amplification，MLPA）、全外显子测序（whole exon sequencing，WES）和Sanger测序技术等分子诊断技术综合分析筛选出26例PMP22基因相关性周围神经病先证者及其33例家系成员患者的基因变异情况，包括重复突变、缺失突变及点突变。进一步分析26例PMP22基因相关性周围神经病患者的遗传学和临床特点，临床特点包括人口学数据、临床表现、神经电生理特点、病理学特点等。结果·PMP22基因相关性周围神经病患者共59例（男性37例，女性22例），其中46例为家系病例（来自13个家系），余13例为散发病例。所有患者发病年龄34.0（14.0，49.5）岁，首发症状为肢体无力或肢体麻木。51例为PMP22重复突变，临床表型为腓骨肌萎缩症1A型（Charcot-Marie-Tooth type-1A，CMT1A）；6例PMP22缺失突变，临床表型为遗传性压迫易感性神经病（hereditary neuropathy with liability to pressure palsies，HNPP）；2例PMP22点突变（p.S72L和p.G100V），表型为Dejerine-Sottas综合征（Dejerine-Sottas syndrome，DSS）。16例PMP22基因相关性周围神经病患者进行神经电生理检测，12例PMP22重复突变患者的运动神经传导速度（motor nerve conduction velocity，MCV）、复合肌肉动作电位波幅（compound muscle action potential，CMAP）和感觉传导速度（sensory nerve conduction velocities，SCV）较4例PMP22缺失突变患者明显降低（均P<0.05），2种突变类型均可出现传导阻滞现象。12例PMP22基因相关性周围神经病患者进行腓肠神经活检，包括8例PMP22重复突变、3例PMP22缺失突变和1例PMP22点突变，可见不同程度有髓神经纤维变薄、“洋葱球样”变及神经纤维密度减低等病理改变。结论·PMP22基因相关性周围神经病可表现为CMT1A、HNPP及DSS等表型，具有临床异质性。对于电生理检测和腓肠神经活检呈脱髓鞘表现的患者，排除获得性病因后，应予以PMP22基因重复、缺失和点突变的基因检测，有助于该病的优化诊断以及遗传咨询。

关键词： 腓骨肌萎缩症1A型; 遗传性压迫易感性神经病; Dejerine-Sottas综合征; PMP22基因; 突变

本文引用格式

朱啸巍 , 詹飞霞 , 张超 , 刘时华 , 钟平 , 曹立 , 栾兴华 . PMP22基因相关性周围神经病的遗传学和临床特点分析[J]. 上海交通大学学报（医学版）, 2022 , 42(5) : 609 -616 . DOI: 10.3969/j.issn.1674-8115.2022.05.008

Abstract

Objective

·To investigate the genetic and clinical features of peripheral neuropathy patients with PMP22 gene variations and the association between genotype and clinical phenotype.

Methods

·A total of 162 patients with peripheral neuropathy who were treated in Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine from 2006 to 2022 were collected. Molecular detecting techniques including combining multiplex ligation-dependent probe amplification (MLPA), whole exon sequencing (WES) and Sanger sequencing were used to comprehensively analyze the genetic variation of 162 patients, and 26 probands with PMP22 gene variations and their 33 family members were screened out. The genetic variations included duplication, deletion and point mutations. The clinical and genetic characteristics of 26 patients with PMP22-associated peripheral neuropathy were further analyzed. The clinical characteristics included clinical demographic data, clinical manifestations, electrophysiological and pathological characteristics.

Results

·There were a total of 59 (37 male and 22 female) individuals with PMP22-associated peripheral neuropathy, among whom 46 patients in 13 families had positive family histories and 13 did not. The median age at onset of neuropathy was 34.0 (14.0, 49.5) years old. The initial symptom was limb weakness or limb numbness. There were 51 Charcot-Marie-Tooth type-1A (CMT1A) patients with PMP22 duplication, 6 hereditary neuropathy with liability to pressure palsies (HNPP) patients with PMP22 deletion and 2 Dejerine-Sottas syndrome (DSS) patients with PMP22 point mutations (p.S72L and p.G100V). Sixteen patients underwent electrophysiological detections. Compared with the 4 PMP22 deletion patients, the motor nerve conduction velocity (MCV), compound muscle action potential (CMAP) and sensory nerve conduction velocities (SCV) of 12 PMP22 duplication patients were obviously decreased (all P<0.05). Conduction block was found in both kinds of mutation types. Sural nerve biopsies were performed in 12 patients, including 8 PMP22 duplication, 3 PMP22 deletion and 1 PMP22 point mutation, and pathological changes such as thinning of myelinated nerve fibers, “onion bulbs” and decreased nerve fiber density were observed in varying degrees.

Conclusion

·PMP22 gene-associated neuropathies can be characterized by CMT1A, HNPP and DSS with high clinical heterogeneity. Patients with demyelinating manifestations on electrophysiological detections and sural nerve biopsy need genetic testing for PMP22 gene duplication, deletion and point mutation after ruling out acquired etiology. It is available to help optimize diagnosis and genetic counseling of the disease.

Key words： Charcot-Marie-Tooth type-1A (CMT1A); hereditary neuropathy with liability to pressure palsies (HNPP); Dejerine-Sottas syndrome (DSS); PMP22 gene; mutation

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