Email Alert | RSS

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)

RICH HTML

   

PDF (PC)

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 √
1 Ghosh S , Tourtellotte WG . The complex clinical and genetic landscape of hereditary peripheral neuropathy[J]. Annu Rev Pathol, 2021, 16, 487- 509.
doi: 10.1146/annurev-pathol-030320-100822
2 Bansagi B , Griffin H , Whittaker RG , et al. Genetic heterogeneity of motor neuropathies[J]. Neurology, 2017, 88 (13): 1226- 1234.
doi: 10.1212/WNL.0000000000003772
3 Rossor AM , Polke JM , Houlden H , et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease[J]. Nat Rev Neurol, 2013, 9 (10): 562- 571.
doi: 10.1038/nrneurol.2013.179
4 Previtali SC , Zhao E , Lazarevic D , et al. Expanding the spectrum of genes responsible for hereditary motor neuropathies[J]. J Neurol Neurosurg Psychiatry, 2019, 90 (10): 1171- 1179.
doi: 10.1136/jnnp-2019-320717
5 Beijer D , Baets J . The expanding genetic landscape of hereditary motor neuropathies[J]. Brain, 2020, 143 (12): 3540- 3563.
doi: 10.1093/brain/awaa311
6 Klein CJ . Charcot-Marie-Tooth disease and other hereditary neuropathies[J]. Continuum (Minneap Minn), 2020, 26 (5): 1224- 1256.
7 Magy L , Mathis S , Le Masson G , et al. Updating the classification of inherited neuropathies: Results of an international survey[J]. Neurology, 2018, 90 (10): e870- e876.
doi: 10.1212/WNL.0000000000005074
8 Beaudin M , Klein CJ , Rouleau GA , et al. Systematic review of autosomal recessive ataxias and proposal for a classification[J]. Cerebellum Ataxias, 2017, 4, 3.
doi: 10.1186/s40673-017-0061-y
9 Murphy SM , Herrmann DN , McDermott MP , et al. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease[J]. J Peripher Nerv Syst, 2011, 16 (3): 191- 198.
doi: 10.1111/j.1529-8027.2011.00350.x
10 Padilha JPD , Brasil CS , Hoefel AML , et al. Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies[J]. Clin Genet, 2020, 98 (2): 185- 190.
doi: 10.1111/cge.13793
11 Richards S , Aziz N , Bale S , et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17 (5): 405- 424.
doi: 10.1038/gim.2015.30
12 Xie Y , Lin Z , Liu L , et al. Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth from central south China[J]. Eur J Neurol, 2021, 28 (11): 3774- 3783.
doi: 10.1111/ene.15024
13 Vaeth S , Christensen R , Dunϕ M , et al. Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform[J]. Eur J Med Genet, 2019, 62 (1): 1- 8.
doi: 10.1016/j.ejmg.2018.04.003
14 刘小璇, 孙阿萍, 段晓慧, 等. 中国人群腓骨肌萎缩症的致病基因分布对比研究——14年队列观察[J]. 中华神经科杂志, 2022, 55 (5): 481- 489.
doi: 10.3760/cma.j.cn113694-20211102-00762
15 Cortese A , Zhu Y , Rebelo AP , et al. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes[J]. Nat Genet, 2020, 2 (5): 473- 481.
16 Sevilla T , Lupo V , Martínez-Rubio D , et al. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease[J]. Brain, 2016, 139 (Pt 1): 62- 72.
17 Liu X , Duan X , Zhang Y , et al. Molecular analysis and clinical diversity of distal hereditary motor neuropathy[J]. Eur J Neurol, 2020, 27 (7): 1319- 1326.
doi: 10.1111/ene.14260
18 Evgrafov OV , Mersiyanova I , Irobi J , et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy[J]. Nat Genet, 2004, 36 (6): 602- 606.
doi: 10.1038/ng1354
19 Antonellis A , Ellsworth RE , Sambuughin N , et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type Ⅴ[J]. Am J Hum Genet, 2003, 72 (5): 1293- 1299.
doi: 10.1086/375039
20 Latour P , Thauvin-Robinet C , Baudelet-Mery C , et al. A major determinant for binding and aminoacylation of tRNA (Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease[J]. Am J Hum Genet, 2010, 86 (1): 77- 82.
doi: 10.1016/j.ajhg.2009.12.005
21 Gonzalez M , McLaughlin H , Houlden H , et al. Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2[J]. J Neurol Neurosurg Psychiatry, 2013, 84 (11): 1247- 1249.
doi: 10.1136/jnnp-2013-305049
22 Vester A , Velez-Ruiz G , McLaughlin HM , et al. A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo[J]. Hum Mutat, 2013, 34 (1): 191- 199.
doi: 10.1002/humu.22210
23 Tsai PC , Soong BW , Mademan I , et al. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy[J]. Brain, 2017, 140 (5): 1252- 1266.
doi: 10.1093/brain/awx058
24 Yuan RY , Ye ZL , Zhang XR , et al. Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease[J]. Ann Clin Transl Neurol, 2021, 8 (1): 266- 270.
doi: 10.1002/acn3.51268
25 Scarlino S , Domi T , Pozzi L , et al. Burden of rare variants in ALS and axonal hereditary neuropathy genes influence survival in ALS: Insights from a next generation sequencing study of an Italian ALS cohort[J]. Int J Mol Sci, 2020, 21 (9): 3346.
doi: 10.3390/ijms21093346
26 Montecchiani C , Pedace L , Giudice TL , et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease[J]. Brain, 2016, 139 (Pt 1): 73- 85.
27 Brenner D , Yilmaz R , Muller K , et al. Hot-spot KIF5A mutations cause familial ALS[J]. Brain, 2018, 141 (3): 688- 697.
doi: 10.1093/brain/awx370
28 He J , Liu X , Tang L , et al. Whole-exome sequencing identified novel KIF5A mutations in Chinese patients with amyotrophic lateral sclerosis and Charcot-Marie-Tooth type 2[J]. J Neurol Neurosurg Psychiatry, 2020, 91 (3): 326- 328.
doi: 10.1136/jnnp-2019-320483
29 Stavrou M , Sargiannidou I , Georgiou E , et al. Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies[J]. Int J Mol Sci, 2021, 22 (11): 6048.
doi: 10.3390/ijms22116048
30 Bejaoui K , Wu C , Scheffler MD , et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1[J]. Nat Genet, 2001, 27 (3): 261- 262.
doi: 10.1038/85817
31 Eichler FS , Hornemann T , McCampbell A , et al. Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1[J]. J Neurosci, 2009, 29 (46): 14646- 14651.
doi: 10.1523/JNEUROSCI.2536-09.2009
32 Fridman V , Suriyanarayanan S , Novak P , et al. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1[J]. Neurology, 2019, 92 (4): e359- e370.
doi: 10.1212/WNL.0000000000006811
33 Mohassel P , Donkervoort S , Lone MA , et al. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis[J]. Nat Med, 2021, 27 (7): 1197- 1204.
doi: 10.1038/s41591-021-01346-1
34 Zhang Y , Liu Z , Zhang Y , et al. Corneal sub-basal whorl-like nerve plexus: A landmark for early and follow-up evaluation in transthyretin familial amyloid polyneuropathy[J]. Eur J Neurol, 2021, 28 (2): 630- 638.
doi: 10.1111/ene.14563
35 Buxbaum JN . Oligonucleotide drugs for transthyretin amyloidosis[J]. N Engl J Med, 2018, 379 (1): 82- 85.
doi: 10.1056/NEJMe1805499
36 Visser AC , Klein CJ . Wild-type TTR neuropathy with cardiomyo-pathy presenting with burning feet[J]. Neurology, 2017, 88 (11): 1101- 1102.
doi: 10.1212/WNL.0000000000003721
[1] 殷昊明, 王子杰, 舒帆, 张展奕, 梁会, 张树栋. 肾透明细胞癌FABP6基因长转录本的表达及意义[J]. 北京大学学报（医学版）, 2026, 58(2): 393-398.
[2] 耿芸玲, 刘超, 杨萍, 郑佳佳, 沈宁, 杜毅鹏. 医院获得性肺炎患者肺炎克雷伯菌多部位感染的临床特征及毒力基因分布[J]. 北京大学学报（医学版）, 2026, 58(1): 201-207.
[3] 刘艳华, 陆敏, 赵旭阳, 张宽根, 武睿, 梅放, 戴志豪, 由江峰, 裴斐. 肿瘤转移抑制基因LASS2去磷酸化对液泡型ATP酶活性及前列腺癌侵袭性的影响[J]. 北京大学学报（医学版）, 2025, 57(6): 1113-1123.
[4] 董琪, 何菁, 贾园, 姚海红, 张霞. 模拟复发性多软骨炎的VEXAS综合征1例[J]. 北京大学学报（医学版）, 2025, 57(6): 1180-1183.
[5] 张展奕, 陆敏, 孙悦皓, 董靖晗, 侯小飞, 肖春雷, 王国良, 田晓军, 马潞林, 张洪宪, 张树栋. TFE3重排肾细胞癌合并静脉癌栓患者的临床病理特征及生存分析[J]. 北京大学学报（医学版）, 2025, 57(4): 650-661.
[6] 李梦迪, 雷蕾, 刘中宁, 李健, 姜婷. siRNA沉默NLK基因促进神经化组织工程骨再生[J]. 北京大学学报（医学版）, 2025, 57(2): 227-236.
[7] 张真伟, 徐欣然, 高学军, 董艳梅, 田华. RELT基因移码突变导致遗传性釉质发育不全[J]. 北京大学学报（医学版）, 2025, 57(1): 13-18.
[8] 马民英, 晁晓芹, 赵扬, 赵国廷. LncRNA SNHG20靶向调控miR-520c-3p/RAB22A通路对人口腔鳞状细胞癌细胞上皮间质转化及微管形成的影响[J]. 北京大学学报（医学版）, 2025, 57(1): 26-32.
[9] 帅婷, 郭艳艳, 林春平, 侯晓玫, 金婵媛. 敲减NPTX1促进人骨髓间充质干细胞成骨分化[J]. 北京大学学报（医学版）, 2025, 57(1): 7-12.
[10] 金银姬, 刘蕊. 以肠系膜静脉血栓为突出表现的遗传性蛋白S缺乏症1例[J]. 北京大学学报（医学版）, 2024, 56(6): 1106-1109.
[11] 李炳乐, 朱凌妍, 王永福, 白力. 褪黑素调控节律基因表达及其缓解间质性肺纤维化的机制[J]. 北京大学学报（医学版）, 2024, 56(6): 963-971.
[12] 焦莶如, 龚潘, 牛悦, 徐兆, 周宗朴, 杨志仙. 以婴儿癫痫性痉挛综合征为表型的吡哆醇依赖性癫痫[J]. 北京大学学报（医学版）, 2024, 56(5): 781-787.
[13] 武志慧, 胡明智, 赵巧英, 吕凤凤, 张晶莹, 张伟, 王永福, 孙晓林, 王慧. miR-125b-5p修饰脐带间充质干细胞对系统性红斑狼疮的免疫调控机制[J]. 北京大学学报（医学版）, 2024, 56(5): 860-867.
[14] 郭煌达,彭和香,王斯悦,侯天姣,李奕昕,章涵宇,王梦莹,武轶群,秦雪英,唐迅,李劲,陈大方,胡永华,吴涛. 短期大气颗粒物暴露和MTNR1B基因多态性对甘油三酯-葡萄糖指数影响的家系研究[J]. 北京大学学报（医学版）, 2024, 56(3): 375-383.
[15] 侯天姣,周治波,王竹青,王梦莹,王斯悦,彭和香,郭煌达,李奕昕,章涵宇,秦雪英,武轶群,郑鸿尘,李静,吴涛,朱洪平. 转化生长因子β信号通路与非综合征型唇腭裂发病风险的基因-基因及基因-环境交互作用[J]. 北京大学学报（医学版）, 2024, 56(3): 384-389.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
ISSN 1671-167X
CN 11-4691/R
主管单位：中华人民共和国教育部
主办单位：北京大学
地址： 北京市海淀区学院路38号 北京大学医学部 《北京大学学报（医学版）》
邮编：100191
电话：010-82801551
Email： xbbjb2@bjmu.edu.cn

《北京大学学报（医学版）》
微信公众号
版权所有 © 2018 《北京大学学报（医学版）》编辑部