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北京大学学报（医学版） >

2022 , Vol. 54 >Issue 5: 874 - 883

DOI: https://doi.org/10.19723/j.issn.1671-167X.2022.05.015

论著

中国人群遗传性周围神经病的致病基因分布

  • 刘小璇 ,
  • 段晓慧 ,
  • 张朔 ,
  • 孙阿萍 ,
  • 张英爽 ,
  • 樊东升
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  • 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
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

收稿日期: 2022-07-02

  网络出版日期: 2022-10-14

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)

收起

Genetic distribution in Chinese patients with hereditary peripheral neuropathy

  • Xiao-xuan LIU ,
  • Xiao-hui DUAN ,
  • Shuo ZHANG ,
  • A-ping SUN ,
  • Ying-shuang ZHANG ,
  • Dong-sheng FAN
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  • 1. Department of Neurology, Peking University Third Hospital, Beijing 100191, China
    2. Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China

Received date: 2022-07-02

  Online published: 2022-10-14

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

本文引用格式

刘小璇 , 段晓慧 , 张朔 , 孙阿萍 , 张英爽 , 樊东升 . 中国人群遗传性周围神经病的致病基因分布[J]. 北京大学学报（医学版）, 2022 , 54(5) : 874 -883 . DOI: 10.19723/j.issn.1671-167X.2022.05.015

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

参考文献

1 Ghosh S , Tourtellotte WG . The complex clinical and genetic landscape of hereditary peripheral neuropathy[J]. Annu Rev Pathol, 2021, 16, 487- 509.
2 Bansagi B , Griffin H , Whittaker RG , et al. Genetic heterogeneity of motor neuropathies[J]. Neurology, 2017, 88 (13): 1226- 1234.
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.
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.
5 Beijer D , Baets J . The expanding genetic landscape of hereditary motor neuropathies[J]. Brain, 2020, 143 (12): 3540- 3563.
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.
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.
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.
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.
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.
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.
13 Vaeth S , Christensen R , Dun? 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
35 Buxbaum JN . Oligonucleotide drugs for transthyretin amyloidosis[J]. N Engl J Med, 2018, 379 (1): 82- 85.
36 Visser AC , Klein CJ . Wild-type TTR neuropathy with cardiomyo-pathy presenting with burning feet[J]. Neurology, 2017, 88 (11): 1101- 1102.
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ISSN 1671-167X
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