Journal of Peking University(Health Sciences) >
Genetic distribution in Chinese patients with hereditary peripheral neuropathy
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)
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
Xiao-xuan LIU , Xiao-hui DUAN , Shuo ZHANG , A-ping SUN , Ying-shuang ZHANG , Dong-sheng FAN . Genetic distribution in Chinese patients with hereditary peripheral neuropathy[J]. Journal of Peking University(Health Sciences), 2022 , 54(5) : 874 -883 . DOI: 10.19723/j.issn.1671-167X.2022.05.015
| 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. |
/
| 〈 |
|
〉 |