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Charcot-Marie-Tooth Disease (CMT)

CMT4

What is Charcot-Marie-Tooth disease type 4 (CMT4)?

CMT4 is a rare 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. CMT4 is a subtype of CMT that is inherited in an autosomal recessive pattern. Individuals with CMT4 present a typical CMT phenotype, such as foot deformities, sensory loss, atrophy, and distal muscle weakness.36

What are the symptoms of CMT4?

CMT4 causes weakness, usually mostly distal but sometimes involving proximal (near the center of the body) muscles. Impairment or changes in sensations (such as the sense of touch or ability to perceive temperature changes) also can occur. When CMT4 begins in infancy, it is characterized by low muscle tone. CMT4 patients may also develop other symptoms such as cataracts or deafness. Generally, cases of CMT4 present with more severe symptoms compared to CMT1 or CMT2. Since some of the symptoms are severe and the onset can be early, some subtypes of CMT4 may also be called Severe, Early-Onset CMT. See Signs and Symptoms for more.

What causes CMT4?

In general, CMT4 is caused by defects in the myelin sheath that insulates the axon.

Diagnosis Associated Gene
CMT4A GDAP1 37
CMT4B1 MTMR2 38,39
CMT4B2 SBF2 40,41,42,43,44
CMT4B3 SBF145
CMT4C SH3TC2 46 ,47,48,49,50
CMT4D NDRG1 51,52
CMT4E EGR2 53
CMT4F PRX 54,55
CMT4G HK1 57
CMT4H FDG4 58,59,60
CMT4J FIG4 61,62

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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