Clinical and Genetic Variant Profile of Asian Charcot‐Marie Tooth Patients: A Systematic Review
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Abstract
Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy by high clinical and genetic heterogeneity. Although many studies reported from East Asian countries, data from West/South Asia remain limited. The current study aimed to summarize available epidemiological, clinical and genetic data of CMT patients in Asia.
Methods: We searched PubMed, Scopus, Web of Sciences, Nature, Google Scholar, Science Direct, and Willey for relevant published articles between 2003 until Feb 2023, according to PRISMA guidelines. Articles were screened for epidemiological, clinical and genetic information. Inclusion required published mutation frequency or genetic variant in CMT patients. The Q-Genie tool and Newcastle-Ottawa (NOS) were used to evaluate the quality of genetics and observational studies, respectively.
Results: Out of 320, 32 screened articles met the inclusion criteria. Most studies were reported from China (n = 12), Japan (n=7), and Korea (n=6). The axonal CMT was the frequent type (50%), followed by demyelinating (28%) and intermediate (9%) types. Autosomal dominant (AD) inheritance was observed in 62% of genetically confirmed cases. Frequently mutated genes were GDAP1, MPZ, and JGB1, which have been found mostly in the East Asia.
Conclusion: This systematic review reports substantial knowledge gap in West/South Asian CMT research. The review emphasized the urgent need to use comprehensively of next-generation sequencing (NGS) to uncover new mutations and improve diagnostics in West/South Asian. Future region-specific cohort studies and registries can be essential to identify frequent variants and fill the diagnostic gaps.
1. Hsu YH, Lin KP, Guo YC, et al (2019). Mu-tation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Tai-wan. Ann Clin Transl Neurol, 6 (6): 1090–1101.
2. Ando M, Higuchi Y, Yuan J, et al (2022). Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease. Ann Clin Transl Neurol, 9 (7): 902–11.
3. Pakhrin PS, Xie Y, Hu Z, et al (2018). Geno-type–phenotype correlation and fre-quency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations. J Neurol, 265 (3): 637–46.
4. Nam DE, Park JH, Park CE, et al (2022). Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study. J Peripher Nerv Syst, 27 (1): 38–49.
5. Chen X, Zhang Y, Li J, Huang L, Wu Z (2019). Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease. Clin Genet, 96 (5): 439-448.
6. Yalcouyé A, Diarra S, Traoré F, et al 2022). Current profile of Charcot-Marie-Tooth disease in Africa: A systematic review. J Peripher Nerv Syst, 27 (2): 100-112.
7. Sohani ZN, Meyre D, de Souza RJ, et al (2015). Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies Q-Genie) tool. BMC Genet, 16: 50.
8. Lo CKL, Mertz D, Loeb M (2014). Newcas-tle-Ottawa Scale: comparing reviewers’ to authors’ assessments. BMC Med Res Methodol, 14: 45.
9. Xie Y, Hu Z, Li X, et al (2021). Genotype and phenotype distribution of 435 pa-tients with Charcot-Marie-Tooth disease from central south China. Eur J Neurol, 28 (11): 3774-3783.
10. Song S, Zhang Y, Chen B, et al (2006). Muta-tion frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic pa-tients. Genet Med, 8 (8): 532–5.
11. Yoshimura A, Yuan JH, Hashiguchi A, et al (2017). Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. Clin Genet, 92 (3): 274–80.
12. Ando M, Higuchi Y, Yoshimura A, et al (2017). Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. J Peripher Nerv Syst, 22 (3): 191-199.
13. Nguyen-Le T, Pham TT, Tran HQ, et al (2022). Genotype–phenotype character-istics of Vietnamese patients diagnosed with Charcot-Marie-Tooth disease. Brain Behav, 12 (9): e2744.
14. Chen C, Li J, Dong H, Liu G, Bai G, Wu Z (2020). Identification and functional characterization of novel GDAP1 vari-ants in Chinese patients with Charcot-Marie-Tooth disease. Ann Clin Transl Neurol, 7 (12): 2381–92.
15. Zhao X, Jiang MM, Yan YZ, et al (2018). Screening for SH3TC2, PMP2, and BSCL2 variants in a cohort of Chinese patients with Charcot-Marie-Tooth. Chin Med J (Engl), 131 (2): 151–5.
16. Jamiri Z, Khosravi R, Heidari MM, et al (2022). A nonsense mutation in MME gene associates with autosomal recessive late-onset Charcot-Marie-Tooth disease. Mol Genet Genomic Med, 10 (5): e1913.
17. Hattori N, Yamamoto M, Yoshihara T, et al (2003). Demyelinating and axonal fea-tures of Charcot-Marie-Tooth disease with mutations of myelin-related pro-teins PMP22, MPZ and Cx32): a clinico-pathological study of 205 Japanese pa-tients. Brain, 126 (Pt 1): 134–51.
18. Duan X, Liu X, Wang G, et al (2021). Char-acterization of genotype-phenotype cor-relation with MORC2 mutated axonal Charcot-Marie-Tooth disease in a co-hort of Chinese patients. Orphanet J Rare Dis, 16 (1): 244.
19. Liu X, He J, Yilihamu M, et al (2021). Clini-cal and genetic features of biallelic mu-tations in SORD in a series of Chinese patients with Charcot-Marie-Tooth and distal hereditary motor neuropathy. Front Neurol, 12: 733926.
20. Sharma S, Govindaraj P, Chickabasaviah YT, et al (2022). Genetic spectrum of in-herited neuropathies in India. Ann Indi-an Acad Neurol, 25 (3): 407–16.
21. Yoshimura A, Yuan JH, Hashiguchi A, et al (2019). Genetic profile and onset fea-tures of 1005 patients with Charcot-Marie-Tooth disease in Japan. J Neurol Neurosurg Psychiatry, 90 (2): 195–202.
22. Hao X, Li C, Lv Y, et al (2022). MPZ gene variant site in Chinese patients with Charcot-Marie-Tooth disease. Mol Genet Genomic Med, 10 (4): e1890.
23. Wang X, Han C, Liu W, et al (2014). A novel RAB7 mutation in a Chinese family with Charcot-Marie-Tooth type 2B disease. Gene, 534 (2): 431–4.
24. Liu Y, Xue J, Li Z, et al (2020). A novel GJB1 mutation associated with X-linked Charcot-Marie-Tooth disease in a large Chinese family pedigree. Mol Genet Ge-nomic Med, 8 (3): e1127.
25. Kim Y, Choi KG, Park KD, et al (2012). X-linked dominant Charcot-Marie-Tooth disease with connexin 32 Cx32) muta-tions in Koreans. Clin Genet, 81 (2): 142–9.
26. Hyun YS, Lee J, Kim HJ, et al (2015). Char-cot-Marie-Tooth disease type 4H result-ing from compound heterozygous muta-tions in FGD4 from nonconsanguine-ous Korean families. Ann Hum Genet, 79 (6): 460–9.
27. Taniguchi T, Ando M, Okamoto Y, et al (2021). Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Ja-pan. Clin Genet, 99 (3): 359–75.
28. Lin Y, Chen Y, Wang J, Huang Z, Wu Y (2016). Clinical and molecular character-ization of BSCL2 mutations in a Tai-wanese cohort with hereditary neuropa-thy. PLoS One, 11 (1): e0147677.
29. Kanwal S, Choi YJ, Lim SO, et al (2021). Novel homozygous mutations in Paki-stani families with Charcot-Marie-Tooth disease. BMC Med Genomics, 14 (1): 174.
30. Bakhshandeh M, Ghorbani A (2023). Muta-tional spectrum and clinical symptoms of Iranian patients with Charcot-Marie-Tooth disease: a study of 23 patients. J Iran Med Counc, 6 (3): 488–503.
31. Megarbane A, Bizzari S, Deepthi A, et al (2022). A 20-year clinical and genetic neuromuscular cohort analysis in Leba-non: an international effort. J Neuromus-cul Dis, 9 (1): 193–210.
32. Hong YB, Park JM, Yu JS, et al (2017). Clin-ical characterization and genetic analy-sis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1. J Peripher Nerv Syst, 22 (3): 172–81.
33. Choi BO, Lee MS, Shin SH, et al (2004). Mu-tational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat, 24 (2): 185–6.
34. Sun B, He ZQ, Li YR, et al (2022). Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients. Acta Neurol Belg, 122 (5): 1169–75.
35. Fu J, Dai S, Lu Y, et al (2017). Similar clini-cal, pathological, and genetic features in Chinese patients with autosomal reces-sive and dominant Charcot-Marie-Tooth disease type 2K. Neuromuscul Disord, 27 (8): 760–5.
36. Abe A, Numakura C, Kijima K, et al (2011). Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Ja-pan. J Hum Genet, 56 (5): 364–8.
37. Kim HS, Kim HJ, Nam SH, et al (2021). Clinical and neuroimaging features in Charcot-Marie-Tooth patients with GDAP1 mutations. J Clin Neurol, 17 (1): 52–62.
38. Ma M, Li Y, Dai S, et al (2023). A meta-analysis on the prevalence of Charcot-Marie-Tooth disease and related inher-ited peripheral neuropathies. J Neurol, 270 (5): 2468–82.
39. Pisciotta C, Bertini A, Tramacere I, et al (2023). Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: data from the National CMT Registry. Eur J Neurol, 30 (8): 2461–70.
40. Manzoor U, Ali A, Ali SL, et al (2023). Muta-tional screening of GDAP1 in dyspho-nia associated with Charcot-Marie-Tooth disease: clinical insights and phenotypic effects. J Genet Eng Biotechnol, 21 (1): 119.
41. Auranen M, Ylikallio E, Toppila J, et al (2013). Dominant GDAP1 founder mu-tation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. Neurogenetics, 14 (2): 123–32.
42. Crimella C, Tonelli A, Airoldi G, et al (2010). The GST domain of GDAP1 is a frequent target of mutations in the dom-inant form of axonal Charcot-Marie-Tooth type 2K. J Med Genet, 47 (10): 712–6.
43. Zimoń M, Battaloğlu E, Parman Y, et al (2015). Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozy-gosity mapping approach. Neurogenetics, 16 (1): 33–42.
44. Lee JH, Kim JH, Park JS, Shin JH, Jung WS (2022). Clinical genetics of Charcot-Marie-Tooth disease. J Clin Med, 11 (5): 1284–93.
45. Shu XM, Tian MQ, Li J, Peng LY, Yu XH (2015). X-linked hereditary motor senso-ry neuropathy type 1 CMTX1) in a three-generation Gelao Chinese family. Neuropediatrics, 46 (6): 424–7.
46. Sun B, Chen Z, Ling L, Yang F, Huang X (2017). Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. J Peripher Nerv Syst, 22 (1): 13–8.
47. Sakaguchi H, Yamashita S, Miura A, et al (2011). A novel GJB1 frameshift muta-tion produces a transient CNS symptom of X-linked Charcot-Marie-Tooth dis-ease. J Neurol, 258 (2): 284–90.
48. Wang R, He J, Li JJ, et al (2015). Clinical and genetic spectra in a series of Chi-nese patients with Charcot-Marie-Tooth disease. Clin Chim Acta, 451 (Pt 2): 263–70.
49. Nakagawa M (2011). A commentary on mo-lecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. J Hum Genet, 56 (5): 341–2.
2. Ando M, Higuchi Y, Yuan J, et al (2022). Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease. Ann Clin Transl Neurol, 9 (7): 902–11.
3. Pakhrin PS, Xie Y, Hu Z, et al (2018). Geno-type–phenotype correlation and fre-quency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations. J Neurol, 265 (3): 637–46.
4. Nam DE, Park JH, Park CE, et al (2022). Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study. J Peripher Nerv Syst, 27 (1): 38–49.
5. Chen X, Zhang Y, Li J, Huang L, Wu Z (2019). Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease. Clin Genet, 96 (5): 439-448.
6. Yalcouyé A, Diarra S, Traoré F, et al 2022). Current profile of Charcot-Marie-Tooth disease in Africa: A systematic review. J Peripher Nerv Syst, 27 (2): 100-112.
7. Sohani ZN, Meyre D, de Souza RJ, et al (2015). Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies Q-Genie) tool. BMC Genet, 16: 50.
8. Lo CKL, Mertz D, Loeb M (2014). Newcas-tle-Ottawa Scale: comparing reviewers’ to authors’ assessments. BMC Med Res Methodol, 14: 45.
9. Xie Y, Hu Z, Li X, et al (2021). Genotype and phenotype distribution of 435 pa-tients with Charcot-Marie-Tooth disease from central south China. Eur J Neurol, 28 (11): 3774-3783.
10. Song S, Zhang Y, Chen B, et al (2006). Muta-tion frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic pa-tients. Genet Med, 8 (8): 532–5.
11. Yoshimura A, Yuan JH, Hashiguchi A, et al (2017). Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. Clin Genet, 92 (3): 274–80.
12. Ando M, Higuchi Y, Yoshimura A, et al (2017). Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. J Peripher Nerv Syst, 22 (3): 191-199.
13. Nguyen-Le T, Pham TT, Tran HQ, et al (2022). Genotype–phenotype character-istics of Vietnamese patients diagnosed with Charcot-Marie-Tooth disease. Brain Behav, 12 (9): e2744.
14. Chen C, Li J, Dong H, Liu G, Bai G, Wu Z (2020). Identification and functional characterization of novel GDAP1 vari-ants in Chinese patients with Charcot-Marie-Tooth disease. Ann Clin Transl Neurol, 7 (12): 2381–92.
15. Zhao X, Jiang MM, Yan YZ, et al (2018). Screening for SH3TC2, PMP2, and BSCL2 variants in a cohort of Chinese patients with Charcot-Marie-Tooth. Chin Med J (Engl), 131 (2): 151–5.
16. Jamiri Z, Khosravi R, Heidari MM, et al (2022). A nonsense mutation in MME gene associates with autosomal recessive late-onset Charcot-Marie-Tooth disease. Mol Genet Genomic Med, 10 (5): e1913.
17. Hattori N, Yamamoto M, Yoshihara T, et al (2003). Demyelinating and axonal fea-tures of Charcot-Marie-Tooth disease with mutations of myelin-related pro-teins PMP22, MPZ and Cx32): a clinico-pathological study of 205 Japanese pa-tients. Brain, 126 (Pt 1): 134–51.
18. Duan X, Liu X, Wang G, et al (2021). Char-acterization of genotype-phenotype cor-relation with MORC2 mutated axonal Charcot-Marie-Tooth disease in a co-hort of Chinese patients. Orphanet J Rare Dis, 16 (1): 244.
19. Liu X, He J, Yilihamu M, et al (2021). Clini-cal and genetic features of biallelic mu-tations in SORD in a series of Chinese patients with Charcot-Marie-Tooth and distal hereditary motor neuropathy. Front Neurol, 12: 733926.
20. Sharma S, Govindaraj P, Chickabasaviah YT, et al (2022). Genetic spectrum of in-herited neuropathies in India. Ann Indi-an Acad Neurol, 25 (3): 407–16.
21. Yoshimura A, Yuan JH, Hashiguchi A, et al (2019). Genetic profile and onset fea-tures of 1005 patients with Charcot-Marie-Tooth disease in Japan. J Neurol Neurosurg Psychiatry, 90 (2): 195–202.
22. Hao X, Li C, Lv Y, et al (2022). MPZ gene variant site in Chinese patients with Charcot-Marie-Tooth disease. Mol Genet Genomic Med, 10 (4): e1890.
23. Wang X, Han C, Liu W, et al (2014). A novel RAB7 mutation in a Chinese family with Charcot-Marie-Tooth type 2B disease. Gene, 534 (2): 431–4.
24. Liu Y, Xue J, Li Z, et al (2020). A novel GJB1 mutation associated with X-linked Charcot-Marie-Tooth disease in a large Chinese family pedigree. Mol Genet Ge-nomic Med, 8 (3): e1127.
25. Kim Y, Choi KG, Park KD, et al (2012). X-linked dominant Charcot-Marie-Tooth disease with connexin 32 Cx32) muta-tions in Koreans. Clin Genet, 81 (2): 142–9.
26. Hyun YS, Lee J, Kim HJ, et al (2015). Char-cot-Marie-Tooth disease type 4H result-ing from compound heterozygous muta-tions in FGD4 from nonconsanguine-ous Korean families. Ann Hum Genet, 79 (6): 460–9.
27. Taniguchi T, Ando M, Okamoto Y, et al (2021). Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Ja-pan. Clin Genet, 99 (3): 359–75.
28. Lin Y, Chen Y, Wang J, Huang Z, Wu Y (2016). Clinical and molecular character-ization of BSCL2 mutations in a Tai-wanese cohort with hereditary neuropa-thy. PLoS One, 11 (1): e0147677.
29. Kanwal S, Choi YJ, Lim SO, et al (2021). Novel homozygous mutations in Paki-stani families with Charcot-Marie-Tooth disease. BMC Med Genomics, 14 (1): 174.
30. Bakhshandeh M, Ghorbani A (2023). Muta-tional spectrum and clinical symptoms of Iranian patients with Charcot-Marie-Tooth disease: a study of 23 patients. J Iran Med Counc, 6 (3): 488–503.
31. Megarbane A, Bizzari S, Deepthi A, et al (2022). A 20-year clinical and genetic neuromuscular cohort analysis in Leba-non: an international effort. J Neuromus-cul Dis, 9 (1): 193–210.
32. Hong YB, Park JM, Yu JS, et al (2017). Clin-ical characterization and genetic analy-sis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1. J Peripher Nerv Syst, 22 (3): 172–81.
33. Choi BO, Lee MS, Shin SH, et al (2004). Mu-tational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat, 24 (2): 185–6.
34. Sun B, He ZQ, Li YR, et al (2022). Screening for SH3TC2 variants in Charcot-Marie-Tooth disease in a cohort of Chinese patients. Acta Neurol Belg, 122 (5): 1169–75.
35. Fu J, Dai S, Lu Y, et al (2017). Similar clini-cal, pathological, and genetic features in Chinese patients with autosomal reces-sive and dominant Charcot-Marie-Tooth disease type 2K. Neuromuscul Disord, 27 (8): 760–5.
36. Abe A, Numakura C, Kijima K, et al (2011). Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Ja-pan. J Hum Genet, 56 (5): 364–8.
37. Kim HS, Kim HJ, Nam SH, et al (2021). Clinical and neuroimaging features in Charcot-Marie-Tooth patients with GDAP1 mutations. J Clin Neurol, 17 (1): 52–62.
38. Ma M, Li Y, Dai S, et al (2023). A meta-analysis on the prevalence of Charcot-Marie-Tooth disease and related inher-ited peripheral neuropathies. J Neurol, 270 (5): 2468–82.
39. Pisciotta C, Bertini A, Tramacere I, et al (2023). Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: data from the National CMT Registry. Eur J Neurol, 30 (8): 2461–70.
40. Manzoor U, Ali A, Ali SL, et al (2023). Muta-tional screening of GDAP1 in dyspho-nia associated with Charcot-Marie-Tooth disease: clinical insights and phenotypic effects. J Genet Eng Biotechnol, 21 (1): 119.
41. Auranen M, Ylikallio E, Toppila J, et al (2013). Dominant GDAP1 founder mu-tation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. Neurogenetics, 14 (2): 123–32.
42. Crimella C, Tonelli A, Airoldi G, et al (2010). The GST domain of GDAP1 is a frequent target of mutations in the dom-inant form of axonal Charcot-Marie-Tooth type 2K. J Med Genet, 47 (10): 712–6.
43. Zimoń M, Battaloğlu E, Parman Y, et al (2015). Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozy-gosity mapping approach. Neurogenetics, 16 (1): 33–42.
44. Lee JH, Kim JH, Park JS, Shin JH, Jung WS (2022). Clinical genetics of Charcot-Marie-Tooth disease. J Clin Med, 11 (5): 1284–93.
45. Shu XM, Tian MQ, Li J, Peng LY, Yu XH (2015). X-linked hereditary motor senso-ry neuropathy type 1 CMTX1) in a three-generation Gelao Chinese family. Neuropediatrics, 46 (6): 424–7.
46. Sun B, Chen Z, Ling L, Yang F, Huang X (2017). Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. J Peripher Nerv Syst, 22 (1): 13–8.
47. Sakaguchi H, Yamashita S, Miura A, et al (2011). A novel GJB1 frameshift muta-tion produces a transient CNS symptom of X-linked Charcot-Marie-Tooth dis-ease. J Neurol, 258 (2): 284–90.
48. Wang R, He J, Li JJ, et al (2015). Clinical and genetic spectra in a series of Chi-nese patients with Charcot-Marie-Tooth disease. Clin Chim Acta, 451 (Pt 2): 263–70.
49. Nakagawa M (2011). A commentary on mo-lecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. J Hum Genet, 56 (5): 341–2.
| Files | ||
| Issue | Vol 54 No 10 (2025) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v54i10.20138 | |
| Keywords | ||
| Asian Charcot-Marie-tooth disease Clinical Epidemiology Genetics | ||
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How to Cite
1.
Kavoosi S, Karimi Z, Moghaddam N, Ashtari F. Clinical and Genetic Variant Profile of Asian Charcot‐Marie Tooth Patients: A Systematic Review. Iran J Public Health. 2025;54(10):2199-2211.
