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Journal of Peking University (Health Sciences) ›› 2022, Vol. 54 ›› Issue (5): 874-883. doi: 10.19723/j.issn.1671-167X.2022.05.015

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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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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

CLC Number: 

  • R741

Figure 1

Constitute distribution of different types of hereditary peripheral neuropathy CMT, Charcot-Marie-Tooth; HMN, hereditary motor neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autosomal neuropathy; FAP, familiar amyloid neuropathy."

Table 1

Epidemiological data of clinical types of HPN"

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

Figure 2

Sural nerve biopsy in a patient with CMT1A A, the number of normal myelinated nerve fibers is reduced, and some myelin are lost and regenerated, showing a typical "onion" like structure (thin arrow), and occasionally regenerative cluster like structure (thick arrow, semi-thin sections, toluidine blue staining ×200); B, the concentric round collagen layer structure formed by Schwann cell proliferation, namely the "onion" structure (electron micrography). CMT, Charcot-Marie-Tooth."

Figure 3

Genetic distribution of CMT (A) and HMN (B) The number of examples is in the bracket, followed by the percentage. CMT, Charcot-Marie-Tooth; HMN, hereditary motor neuropathy."

Figure 4

Sural nerve biopsy in a patient with HMN A, mild loss of large myelinated fibers, unmyelinated nerves had thinned axons (HE ×40); B, patial loss of large myelinated fibers, some Schwann cells showed swollen cytoplasm and degeneration (electron micrography). HMN, hereditary motor neuropathy."

Figure 5

Sural nerve biopsy in a patient with HNPP A, Part of the fiber myelin sheath is folded and thickened (semi-thin sections, toluidine blue staining ×100); B, Concentric myelin thickening formed a "sausage like" structure, named tomaculum (electron micrography). HMN, hereditary motor neuropathy."

Figure 6

Sural nerve biopsy in a patient with FAP A, homogeneous eosinophilic deposit has been found in sural nerve (arrow, HE staining ×40); B, amyloid deposition (arrow, Congo red staining ×100). FAP, familiar amyloid neuropathy."

Table 2

Multiple disease-causing gene with divergent phenotypes"

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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