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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 874-883. doi: 10.19723/j.issn.1671-167X.2022.05.015

• 论著 • 上一篇    下一篇

中国人群遗传性周围神经病的致病基因分布

刘小璇1,段晓慧2,张朔1,孙阿萍1,张英爽1,樊东升1,*()   

  1. 1. 北京大学第三医院神经内科，北京 100191
    2. 中日友好医院神经内科，北京 100029
  • 收稿日期:2022-07-02 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 樊东升 E-mail:dsfan@sina.com
  • 作者简介:樊东升，北京大学第三医院神经内科主任，北京大学医学部神经病学系主任，神经退行性疾病生物标志物研究及转化北京市重点实验室主任，国家卫生健康委员会神经科学重点实验室副主任及学术委员会副主任，神经科学教育部重点实验室学术委员会副主任，国家神经系统疾病医疗质量控制中心运动神经元疾病医疗质量工作组组长，中国残疾人康复协会罕见病康复专业委员会主任委员，《中华脑血管病杂志(电子版)》总编辑。
      曾获教育部科技进步一等奖、自然科学二等奖等，所承担的北京大学《神经病学》获“国家精品课程”。发表论文600余篇，H指数46，被引9 321次；其中SCI论文总影响因子1 010.5。2017年当选第八届国家卫生和计划生育委员会(现为国家卫生健康委员会)突出贡献专家，2022年当选美国科学家荣誉学会(Sigma Xi)会员。荣获第四届“国之名医·卓越建树奖”(2020)、第六届“荣耀医者·人文情怀奖”(2021)、国家卫生健康委员会脑卒中防治工程委员会“杰出贡献奖”(2021)、中国微循环学会“中国神经变性病领域特殊贡献奖”(2021)等
  • 基金资助:
    北京大学临床医学+X青年专项(PKU2021LCXQ019);北京大学第三医院队列建设项目(BYSYDL2021007)

Genetic distribution in Chinese patients with hereditary peripheral neuropathy

Xiao-xuan LIU1,Xiao-hui DUAN2,Shuo ZHANG1,A-ping SUN1,Ying-shuang ZHANG1,Dong-sheng FAN1,*()   

  1. 1. Department of Neurology, Peking University Third Hospital, Beijing 100191, China
    2. Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
  • Received:2022-07-02 Online:2022-10-18 Published:2022-10-14
  • Contact: Dong-sheng FAN E-mail:dsfan@sina.com
  • Supported by:
    Peking University Clinical Medicine Plus X-Youth Scholars Project(PKU2021LCXQ019);Peking University Third Hospital Cohort Study Project(BYSYDL2021007)

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摘要：

目的: 分析中国汉族人群遗传性周围神经病(hereditary peripheral neuropathy，HPN)致病基因的分布特点，探讨HPN与相关疾病的潜在发病机制和治疗前景。方法: 收集2007年1月到2022年5月在北京大学第三医院和中日友好医院诊治的HPN先证者666个，用多重连接探针扩增技术确定PMP22重复和缺失突变后，用二代测序基因包或全外显子组测序，Sanger法进行一代验证，分析比较结果。结果: 腓骨肌萎缩症(Charcot-Marie-Tooth，CMT)在HPN中所占比例最高，为74.3%(495/666)，其中69.1%(342/495)的患者获得基因确诊。最常见的基因突变为PMP22重复、MFN2和GJB1突变，占CMT总体确诊患者的71.3%(244/342)。遗传性运动神经病(hereditary motor neuropathy，HMN)所占比例为16.1%(107/666)，43%(46/107)为基因确诊，最常见的基因突变为HSPB1、t-RNA合成酶相关基因(aminoacyl-tRNA synthetases)和SORD突变，占HMN总体确诊患者的50%(23/46)。HMN的部分基因可以合并多种临床表型，如HSPB1、GARS、IGHMBP2可同时引起HMN和CMT，HMN叠加综合征的患者与肌萎缩侧索硬化(KIF5A、FIG4、DCTN1、SETX、VRK1)、遗传性痉挛性截瘫(KIF5A、ZFYVE26、BSCL2)和脊肌萎缩症(MORC2、IGHMBP2、DNAJB2)有共同的致病基因。遗传性感觉自主神经病(hereditary sensory and autosomal neuropathy，HSAN)在HPN中所占的比例较小，为2.6%(17/666)，最常见的致病基因为SPTLC1突变。引起遗传性淀粉样周围神经病的基因主要是TTR，本研究中最常见的基因突变位点是p.A117S和p.V50M，表现为晚发和比较突出的自主神经受累。结论: CMT和HMN是最常见的HPN，HMN与CMT2的致病基因有很多交叉，部分HMN致病基因与肌萎缩侧索硬化、遗传性痉挛性截瘫和脊肌萎缩症有重叠，提示不同疾病之间可能存在潜在的共同致病通路。

关键词: 遗传性感觉和运动神经病, 基因, 中国

Abstract:

Objective: To analyze the distribution characteristics of hereditary peripheral neuropathy (HPN) pathogenic genes in Chinese Han population, and to explore the potential pathogenesis and treatment prospects of HPN and related diseases. Methods: Six hundred and fifty-six index patients with HPN were enrolled in Peking University Third Hospital and China-Japan Friendship Hospital from January 2007 to May 2022. The PMP22 duplication and deletion mutations were screened and validated by multiplex ligation probe amplification technique. The next-generation sequencing gene panel or whole exome sequencing was used, and the suspected genes were validated by Sanger sequencing. Results: Charcot-Marie-Tooth (CMT) accounted for 74.3% (495/666) of the patients with HPN, of whom 69.1% (342/495) were genetically confirmed. The most common genes of CMT were PMP22 duplication, MFN2 and GJB1 mutations, which accounted for 71.3% (244/342) of the patients with genetically confirmed CMT. Hereditary motor neuropathy (HMN) accounted for 16.1% (107/666) of HPN, and 43% (46/107) of HPN was genetically confirmed. The most common genes of HMN were HSPB1, aminoacyl tRNA synthetases and SORD mutations, which accounted for 56.5% (26/46) of the patients with genetically confirmed HMN. Most genes associated with HMN could cause different phenotypes. HMN and CMT shared many genes (e.g. HSPB1, GARS, IGHMBP2). Some genes associated with dHMN-plus shared genes associated with amyotrophic lateral sclerosis (KIF5A, FIG4, DCTN1, SETX, VRK1), hereditary spastic paraplegia (KIF5A, ZFYVE26, BSCL2) and spinal muscular atrophy (MORC2, IGHMBP, DNAJB2), suggesting that HMN was a continuum rather than a distinct entity. Hereditary sensor and autosomal neuropathy (HSAN) accounted for a small proportion of 2.6% (17/666) in HPN. The most common pathogenic gene was SPTLC1 mutation. TTR was the main gene causing hereditary amyloid peripheral neuropathy. The most common types of gene mutations were p.A117S and p.V50M. The symptoms were characterized by late-onset and prominent autonomic nerve involvement. Conclusion: CMT and HMN are the most common diseases of HPN. There is a large overlap between HMN and motor-CMT2 pathogenic genes, and some HMN pathogenic genes overlap with amyotrophic lateral sclerosis, hereditary spastic hemiplegia and spinal muscular atrophy, suggesting that there may be a potential common pathogenic pathway between different diseases.

Key words: Hereditary sensory and motor neuropathy, Genes, China

中图分类号: 

  • R741

图1

遗传性周围神病的疾病构成分布"

表1

HPN各临床类型的流行病学资料"

Phenotype n (%) Age of onset/years Age of examination/years Disease course/years CMTNS-v2
HPN 666 (100) 24.9±17.6 34.3±17.8 9.0±9.4 11.3±5.3
  CMT 495 (74.3) 24.6±18.0 33.4±17.2 8.7±9.0 12.2±5.6
  HMN 107 (16.1) 25.6±17.0 35.4±18.2 9.4±9.5 8.9±5.0
  HNPP 39 (5.9) 27.6±11.0 32.4±12.2 4.4±2.5 8.4±2.9
  HSAN 17 (2.6) 31.5±11.0 38.4±15.2 10.4±9.5 11.8±9.4
  FAP 7 (1.1) 52 (11-78) 55 (12-83) 5.4±2.5 16.8±9.5
  Refsum 1 25 35 10 16

图2

CMT1A患者的神经活检"

图3

CMT(A)和HMN(B)的基因分布图"

图4

HMN患者的神经活检"

图5

HNPP患者的神经活检"

图6

FAP患者的神经活检"

表2

可以引起多种临床表型的基因"

Gene CMT1 CMT2 HMN ALS HSP SMA
PMP22 CMT1A, CMT1E, DSS, HNPP
MPZ CMT1B, DSS CMT2J
HSPB1 CMT2F HMN2B
GARS CMT2D HMN5A
IGHMBP2 CMT2S HMN6
HSPB8 CMT2L HMN2A
KIF5A √ √ √
DCTN1 √ √
FIG4 CMT4J √
MORC2 CMT2Z √ √
DYNC1H1 CMT2O √
SPTLC1 HSAN1 √
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