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Charcot-Marie-Tooth Disease (CMT)

CMTX

What is Charcot-Marie-Tooth disease type X (X-linked, CMTX)?

CMTX is a subtype of CMT, a genetic, neurological disorder that causes damage to the peripheral nerves — tracts of nerve cell fibers that connect the brain and spinal cord to muscles and sensory organs. There are X-linked dominant and X-linked recessive forms of CMT. 6 Together, the X-linked forms account for approximately 10% to 15% of all CMT cases.

What are the symptoms of CMTX?

CMTX has many of the same symptoms of CMT1 and CMT2, including muscle weakness and atrophy, and changes in sensation, mostly in the feet, lower part of the legs, hands and forearms.

Because of its linkage to the X chromosome, CMTX often affects males more severely than females (as females have two X chromosomes and males have only one X chromosome and one Y chromosome). See Signs and Symptoms and Causes/Inheritance for more.

What causes CMTX?

CMTX1 is caused by mutations in the gene for connexin 32 (also known as the GJB1 gene), in the chromosome X, which normally codes for a protein located in myelin, the insulating sheath that surrounds nerve fibers.63 This is the X-linked dominant form of CMT and the second most common form of CMT after CMT1A, accounting for 7% to 12% of all CMT cases.64,6,65 It is the most common X-linked form of CMT, accounting for approximately 50% of X-linked cases.

Other less-common forms of CMTX include:

  • CMTX2, an X-linked recessive form with no identified causative gene66
  • CMTX3, an X-linked recessive form67
  • Cowchock syndrome (also known as CMTX4; CMT with deafness and intellectual disability), caused by an altered AIFM1 gene68
  • CMTX5, an X-linked recessive disorder with deafness and optic neuropathy caused by alterations in the PRPS1 gene. This form has been reported in a Korean family69,70
  • CMTX6, an X-linked dominant disorder described in a family from Australia. The cause is a mutation in the PDK3 gene71

What is the progression of CMTX?

CMTX has its onset in childhood or adolescence, and progression is generally slow. Individuals affected by CMTX1 may loose ambulation function later in life.

What is the status of research on CMT?

CMT research is focused on exploring the effects of defects in genes related to the peripheral nervous system and devising strategies to combat these effects.

References

  1. Dematteis, M. et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: A family study. Lancet (2001). doi:10.1016/S0140-6736(00)03614-X
  2. Dziewas, R. et al. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: A case control study. J. Neurol. Neurosurg. Psychiatry (2008). doi:10.1136/jnnp.2007.137679
  3. Sabet, A. et al. Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B. Neurology (2006). doi:10.1212/01.wnl.0000238499.37764.b1
  4. Bouhouche, A. et al. A Locus for an Axonal Form of Autosomal Recessive Charcot-Marie-Tooth Disease Maps to Chromosome 1q21.2-q21.3. Am. J. Hum. Genet. (1999). doi:10.1086/302542
  5. Bouhouche, A. et al. Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): Phenotype-genotype correlations in 13 Moroccan families. Brain (2007). doi:10.1093/brain/awm014
  6. Ouvrier, R., Geevasingha, N. & Ryan, M. M. Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. Muscle and Nerve (2007). doi:10.1002/mus.20776
  7. Barreto, L. C. L. S. et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology (2016). doi:10.1159/000443706
  8. Reilly, M. M. Axonal Charcot-Marie-Tooth disease: the fog is slowly lifting! Neurology (2005). doi:10.1212/01.wnl.0000173904.97549.94
  9. Bienfait HME, Verhamme C, Schaik IN, et al. Comparison of CMT1A and CMT2: similarities and differences. J Neurol. 2006;253(12):1572-1580. doi:10.1007/s00415-006-0260-6
  10. Thomas D Bird M. Charcot-Marie-Tooth Neuropathy Type 2.; 1998. https://www.ncbi.nlm.nih.gov/books/NBK1285/pdf/Bookshelf_NBK1285.pdf. Accessed January 23, 2020.
  11. Elliott, J. L., Kwon, J. M., Goodfellow, P. J. & Yee, W. C. Hereditary motor and sensory neuropathy IIB: Clinical and electrodiagnostic characteristics. Neurology (1997). doi:10.1212/WNL.48.1.23
  12. Verpoorten, N. et al. Mutations in the Small GTP-ase Late Endosomal Protein RAB7 Cause Charcot-Marie-Tooth Type 2B Neuropathy. Am. J. Hum. Genet. (2003). doi:10.1086/367847
  13. Auer-Grumbach, M. et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat. Genet. (2010). doi:10.1038/ng.508
  14. Chen, D. H. et al. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology (2010). doi:10.1212/WNL.0b013e3181ffe4bb
  15. Ionasescu, V. et al. Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V. Am. J. Hum. Genet. (2003). doi:10.1086/375039
  16. Mersiyanova, I. V et al. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am. J. Hum. Genet. (2000). doi:10.1086/302962
  17. De Jonghe, P. et al. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann. Neurol. (2001). doi:10.1002/1531-8249(20010201)49:2<245::AID-ANA45>3.0.CO;2-A
  18. Yum, S. W., Zhang, J., Mo, K., Li, J. & Scherer, S. S. A novel recessive NEFL mutation causes a severe, early-onset axonal neuropathy. Ann. Neurol. (2009). doi:10.1002/ana.21728
  19. Evgrafov, O. V. et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat. Genet. (2004). doi:10.1038/ng1354
  20. Senderek, J. et al. Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: Two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible ‘hotspot’ on Thr124Met. Brain Pathol. (2000). doi:10.1111/j.1750-3639.2000.tb00257.x
  21. Hattori, N. et al. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): A clinicopathological study of 205 Japanese patients. Brain (2003). doi:10.1093/brain/awg012
  22. De Jonghe, P. et al. The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. Brain (1999). doi:10.1093/brain/122.2.281
  23. Misu, K. et al. An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val). J. Neurol. Neurosurg. Psychiatry (2000).
  24. Birouk, N. et al. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Arch. Neurol. (2003). doi:10.1001/archneur.60.4.598
  25. Chung, K. W. et al. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. J. Hum. Genet. (2008). doi:10.1007/s10038-008-0249-3
  26. Crimella, C. et al. The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K. J. Med. Genet. (2010). doi:10.1136/jmg.2010.077909
  27. Irobi, J. et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat. Genet. (2004). doi:10.1038/ng1328
  28. Fabrizi, G. M. et al. Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease. Neurology (2007). doi:10.1212/01.wnl.0000265820.51075.61
  29. Gallardo, E. et al. Magnetic resonance imaging findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation. J. Neurol. (2008). doi:10.1007/s00415-008-0808-8
  30. Nelis, E. Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3. J. Med. Genet. (2004). doi:10.1136/jmg.2003.012633
  31. Peeters, K. et al. Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1. Ann. Neurol. (2016). doi:10.1002/ana.24775
  32. Cottenie, E. et al. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am. J. Hum. Genet. (2014). doi:10.1016/j.ajhg.2014.10.002
  33. Shi, C. H. et al. Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation. Neurology (2015). doi:10.1212/WNL.0000000000001747
  34. Higuchi, Y. et al. Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. Ann. Neurol. (2016). doi:10.1002/ana.24612
  35. Pitceathly, R. D. S. et al. Genetic dysfunction of MT-ATP6 causes axonal charcot-Marie-Tooth disease. Neurology (2012). doi:10.1212/WNL.0b013e3182698d8d
  36. Bolino, A. et al. Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy. Neurogenetics (2001). doi:10.1007/s100480000101
  37. Othmane, K. Ben et al. Linkage of a locus (CMT4A) for autosomal recessive charcot-marie-tooth disease to chromosome 8q. Hum. Mol. Genet. (1993). doi:10.1093/hmg/2.10.1625
  38. Bolino, A. et al. Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Hum. Mol. Genet. (1996). doi:10.1093/hmg/5.7.1051
  39. Bolino, A. et al. Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22. Genomics (2000). doi:10.1006/geno.1999.6088
  40. Ben Othmane, K. et al. Identification of a new locus for autosomal recessive Charcot-Marie- Tooth disease with focally folded myelin on chromosome 11p15. Genomics (1999). doi:10.1006/geno.1999.6028
  41. Hirano, R. et al. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology (2004). doi:10.1212/01.WNL.0000133211.40288.9A
  42. Senderek, J. et al. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy tye 4B2/11p15. Hum. Mol. Genet. (2003). doi:10.1093/hmg/ddg030
  43. Bouhouche, A. et al. Mutations in MTMR13, a New Pseudophosphatase Homologue of MTMR2 and Sbf1, in Two Families with an Autosomal Recessive Demyelinating Form of Charcot-Marie-Tooth Disease Associated with Early-Onset Glaucoma. Am. J. Hum. Genet. (2003). doi:10.1086/375034
  44. Kiwaki, T. et al. Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma. Neurology (2000). doi:10.1212/WNL.55.3.392
  45. Nakhro, K. et al. SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology (2013). doi:10.1212/WNL.0b013e31829a3421
  46. Guilbot, A. et al. Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: Exclusion of candidate genes including EGR1. Eur. J. Hum. Genet. (1999). doi:10.1038/sj.ejhg.5200382
  47. Varley, T. L., Bourque, P. R. & Baker, S. K. Phenotypic variability of CMT4C in a French-Canadian kindred. Muscle and Nerve (2015). doi:10.1002/mus.24640
  48. Laššuthová, P. et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin. Genet. (2011). doi:10.1111/j.1399-0004.2011.01640.x
  49. Colomer, J. et al. Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2. Neuromuscul. Disord. (2006). doi:10.1016/j.nmd.2006.05.005
  50. Jerath, N. U. et al. Charcot–Marie–Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle and Nerve (2018). doi:10.1002/mus.25981
  51. Kalaydjieva, L. et al. Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat. Genet. (1996). doi:10.1038/ng1096-214
  52. Kalaydjieva, L. et al. N-myc Downstream-Regulated Gene 1 Is Mutated in Hereditary Motor and Sensory Neuropathy–Lom. Am. J. Hum. Genet. (2000). doi:10.1086/302978
  53. Warner, L. E. et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat. Genet. (1998). doi:10.1038/ng0498-382
  54. Guilbot, A. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum. Mol. Genet. (2002). doi:10.1093/hmg/10.4.415
  55. Boerkoel, C. F. et al. Periaxin Mutations Cause Recessive Dejerine-Sottas Neuropathy. Am. J. Hum. Genet. (2001). doi:10.1086/318208
  56. Rogers, T. et al. A Novel Locus for Autosomal Recessive Peripheral Neuropathy in the EGR2 Region on 10q23. Am. J. Hum. Genet. (2000). doi:10.1086/303053
  57. Sevilla, T. et al. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: The hereditary motor and sensory neuropathy-Russe in depth. Clin. Genet. (2013). doi:10.1111/cge.12015
  58. De Sandre-Giovannoli, A. et al. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. J. Med. Genet. (2005). doi:10.1136/jmg.2004.024364
  59. Stendel, C. et al. Peripheral Nerve Demyelination Caused by a Mutant Rho GTPase Guanine Nucleotide Exchange Factor, Frabin/FGD4. Am. J. Hum. Genet. (2007). doi:10.1086/518770
  60. Fabrizi, G. M. et al. Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H. Neurology (2009). doi:10.1212/01.wnl.0000345373.58618.b6
  61. Chow, C. Y. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature (2007). doi:10.1038/nature05876
  62. Zhang, X. et al. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain (2008). doi:10.1093/brain/awn114
  63. Shy, M. E. et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology (2007). doi:10.1212/01.wnl.0000256709.08271.4d
  64. Fridman, V. et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: A cross-sectional analysis. J. Neurol. Neurosurg. Psychiatry (2015). doi:10.1136/jnnp-2014-308826
  65. Pareyson, D. & Marchesi, C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. The Lancet Neurology (2009). doi:10.1016/S1474-4422(09)70110-3
  66. Wang, Y. & Yin, F. A review of X-linked Charcot-Marie-Tooth disease. Journal of Child Neurology (2016). doi:10.1177/0883073815604227
  67. Huttner, I. G., Kennerson, M. L., Reddel, S. W., Radovanovic, D. & Nicholson, G. A. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology (2006). doi:10.1212/01.wnl.0000247271.40782.b7
  68. Cowchock, F. S., Duckett, S. W., Streletz, L. J., Graziani, L. J. & Jackson, L. G. X-linked motor-sensory neuropathy type II with deafness and mental retardation: A new disorder. Am. J. Med. Genet. (1985). doi:10.1002/ajmg.1320200214
  69. Kim, H. J. et al. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology (2005). doi:10.1212/01.WNL.0000163768.58168.3A
  70. Kim, H.-J. et al. Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral Neuropathy with Hearing Loss and Optic Neuropathy (CMTX5). Am. J. Hum. Genet. (2007). doi:10.1086/519529
  71. Kennerson, M. L. et al. A new locus for X-linked dominant charcot-marie-tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum. Mol. Genet. (2013). doi:10.1093/hmg/dds557

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