[Genetic distribution in Chinese patients with hereditary peripheral neuropathy]

Beijing Da Xue Xue Bao Yi Xue Ban. 2022 Oct 18;54(5):874-883. doi: 10.19723/j.issn.1671-167X.2022.05.015.
[Article in Chinese]


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.

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、MFN2GJB1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HSPB1GARSIGHMBP2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(KIF5AFIG4DCTN1SETXVRK1)、遗传性痉挛性截瘫(KIF5AZFYVE26BSCL2)和脊肌萎缩症(MORC2IGHMBP2DNAJB2)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。

Keywords: China; Genes; Hereditary sensory and motor neuropathy.

MeSH terms

  • Amyotrophic Lateral Sclerosis*
  • Charcot-Marie-Tooth Disease* / genetics
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Flavoproteins
  • HSP40 Heat-Shock Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kinesins
  • Ligases / genetics
  • Molecular Chaperones
  • Multifunctional Enzymes
  • Muscular Atrophy, Spinal* / genetics
  • Mutation
  • Phosphoric Monoester Hydrolases
  • Protein Serine-Threonine Kinases
  • RNA Helicases / genetics
  • RNA, Transfer
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • DNAJB2 protein, human
  • Flavoproteins
  • HSP40 Heat-Shock Proteins
  • IGHMBP2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • KIF5A protein, human
  • MORC2 protein, human
  • Molecular Chaperones
  • Multifunctional Enzymes
  • Transcription Factors
  • RNA, Transfer
  • Protein Serine-Threonine Kinases
  • VRK1 protein, human
  • FIG4 protein, human
  • Phosphoric Monoester Hydrolases
  • SETX protein, human
  • DNA Helicases
  • RNA Helicases
  • Kinesins
  • Ligases

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