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The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy

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Abstract

Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies caused by aberration of the intimate relationship between the myelin sheath and the axon; disorders causing demyelination are classified as CMT1 and those causing axonal loss as CMT2. The mechanisms by which mutations disturb the relationship of the myelin sheath and axon are not fully understood; however, we hypothesize that some mutations affect this relationship more profoundly than others, and thus account for the paradox that mutation of a "myelin gene" can present with electrophysiologic features of CMT2 and vice versa. Also, contrary to popular understanding, inherited neuropathies account for a substantial number of chronic peripheral neuropathies. Because of this observation, we propose that molecular diagnosis is a necessary adjunct for differentiating genetic and acquired peripheral neuropathies, even in sporadic chronic neuropathy.

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References and Recommended Reading

  1. Lupski JR, Garcia CA: Charcot-Marie-Tooth peripheral neuropathies and related disorders. In In The Metabolic and Molecular Bases of Inherited Disease, edn 8. Edited by Scriver CR, Beaudet AL, Sly WS, et al. New York: McGraw-Hill; 2001:5759–5788. An excellent recent review of the genetics of Charcot-Marie-Tooth syndrome and its pathophysiology.

    Google Scholar 

  2. Skre H: Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 1974, 6:98–118.

    Article  PubMed  CAS  Google Scholar 

  3. Allan W: Relation of hereditary pattern to clinical severity as illustrated by peroneal atrophy. Arch Intern Med 1939, 63:1123–1131.

    Google Scholar 

  4. Dyck PJ, Lambert EH: Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol 1968, 18:603–618.

    PubMed  CAS  Google Scholar 

  5. Dyck PJ, Lambert EH: Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations. Arch Neurol 1968, 18:619–625.

    PubMed  CAS  Google Scholar 

  6. Chou SM: Immunohistochemical and ultrastructural classification of peripheral neuropathies with onion-bulbs. Clin Neuropathol 1992, 11:109–114.

    PubMed  CAS  Google Scholar 

  7. Snipes GJ, Suter U: Molecular anatomy and genetics of myelin proteins in the peripheral nervous system. J Anat 1995, 186:483–494.

    PubMed  CAS  Google Scholar 

  8. Raeymaekers P, Timmerman V, Nelis E, et al.: Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscular Disord 1991, 1:93–97.

    Article  CAS  Google Scholar 

  9. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al.: DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991, 66:219–232.

    Article  PubMed  CAS  Google Scholar 

  10. Palau F, Lofgren A, De Jonghe P, et al.: Origin of the de novo duplication in Charcot-Marie-Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis. Hum Mol Genet 1993, 2:2031–2035.

    Article  PubMed  CAS  Google Scholar 

  11. Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR: Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet 1992, 2:292–300.

    Article  PubMed  CAS  Google Scholar 

  12. Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA: Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron 1996, 17:435–449.

    Article  PubMed  CAS  Google Scholar 

  13. Ekici AB, Fuchs C, Nelis E, et al.: An adhesion test system based on Schneider cells to determine genotype-phenotype correlations for mutated P0 proteins. Genet Analysis 1998, 14:117–119.

    Article  CAS  Google Scholar 

  14. Warner LE, Hiz MJ, Appel SH, et al.: Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron 1996, 17:451–460.

    Article  PubMed  CAS  Google Scholar 

  15. Nagarajan R, Svaren J, Le N, et al.: EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron 2001, 30:355–368. A study showing that expression of several genes causing demyelinating neuropathies is regulated by EGR2.

    Article  PubMed  CAS  Google Scholar 

  16. Musso M, Balestra P, Bellone E, et al.: The D355V mutation decreases EGR2 binding to an element within the Cx32 promoter. Neurobiol Dis 2001, 8:700–706.

    Article  PubMed  CAS  Google Scholar 

  17. Swiatek PJ, Gridley T: Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev 1993, 7:2071–2084.

    PubMed  CAS  Google Scholar 

  18. Schneider-Maunoury S, Topilko P, Seitanidou T, et al.: Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 1993, 75:1199–1214.

    Article  PubMed  CAS  Google Scholar 

  19. Topilko P, Schneider-Maunoury S, Levi G, et al.: Krox-20 controls myelination in the peripheral nervous system. Nature 1994, 371:796–799.

    Article  PubMed  CAS  Google Scholar 

  20. Roa BB, Garcia CA, Pentao L, et al.: Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nature Genet 1993, 5:189–194.

    Article  PubMed  CAS  Google Scholar 

  21. Numakura C, Lin C, Oka N, Akiguchi I, Hayasaka K: Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1. Ann Neurol 2000, 47:101–103.

    Article  PubMed  CAS  Google Scholar 

  22. Warner LE, Mancias P, Butler IJ, et al.: Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 1998, 18:382–384.

    Article  PubMed  CAS  Google Scholar 

  23. Bolino A, Muglia M, Conforti FL, et al.: Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000, 25:17–19.

    Article  PubMed  CAS  Google Scholar 

  24. Kalaydjieva L, Gresham D, Gooding R, et al.: N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 2000, 67:47–58.

    Article  PubMed  CAS  Google Scholar 

  25. Boerkoel CF, Takashima H, Stankiewicz P, et al.: Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 2001, 68:325–333.

    Article  PubMed  CAS  Google Scholar 

  26. Baxter RV, Ben Othmane K, Rochelle JM, et al.: Novel mutations in the GDAP1 gene are responsible for Charcot-Marie-Tooth disease type 4A. Am J Hum Genet 2001, 69:626.

    Google Scholar 

  27. LeGuern E, Guilbot A, Kessali M, et al.: Homozygosity mapping of an autosomal recessive form of demylinating Charcot-Marie-Tooth disease to chromosome 5q23-q33. Hum Mol Genet 1996, 5:1685–1688.

    Article  PubMed  CAS  Google Scholar 

  28. Ben Othmane K, Johnson E, Menold M, et al.: Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15. Genomics 1999, 62:344–349.

    Article  CAS  Google Scholar 

  29. Rogers T, Chandler D, Angelicheva D, et al.: A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23. Am J Hum Genet 2000, 67:664–671.

    Article  PubMed  CAS  Google Scholar 

  30. Verhoeven K, Villanova M, Rossi A, et al.: Localization of the gene for the intermediate form of Charcot-Marie-Tooth to chromosome 10q24.1-q25.1. Am J Hum Genet 2001, 69:889–894.

    Article  PubMed  CAS  Google Scholar 

  31. Cui X, De Vivo I, Slany R, et al.: Association of SET domain and myotubularin-related proteins modulates growth control. Nat Genet 1998, 18:331–337.

    Article  PubMed  CAS  Google Scholar 

  32. Gillespie CS, Sherman DL, Fleetwood-Walker SM, et al.: Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 2000, 26:523–531. An excellent recent study providing new insights into possible mechanisms of demyelinating neuropathies.

    Article  PubMed  CAS  Google Scholar 

  33. Palau F, Cuesta A, Pedrola L, et al.: Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene cause axonal Charcot-Marie-Tooth disease. Am J Hum Genet 2001, 69:196.

    Google Scholar 

  34. Bergoffen J, Scherer SS, Wang S, et al.: Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 1993, 262:2039–2042.

    Article  PubMed  CAS  Google Scholar 

  35. Bone LJ, Deschenes SM, Balice-Gordon RJ, Fischbeck KH, Scherer SS: Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis 1997, 4:221–230.

    Article  PubMed  CAS  Google Scholar 

  36. Scherer SS, Bone LJ, Deschenes SM, et al.: The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease. Novartis Found Symp 1999, 219:175–185.

    Article  PubMed  CAS  Google Scholar 

  37. Ressot C, Gomes D, Dautigny A, Pham-Dinh D, Bruzzone R: Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci 1998, 18:4063–4075.

    PubMed  CAS  Google Scholar 

  38. Abrams CK, Freidin MM, Verselis VK, Bennett MV, Bargiello TA: Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res 2001, 900:9–25.

    Article  PubMed  CAS  Google Scholar 

  39. Omori Y, Mesnil M, Yamasaki H: Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects. Mol Biol Cell 1996, 7:907–916.

    PubMed  CAS  Google Scholar 

  40. Ionasescu VV, Trofatter J, Haines JL, et al.: Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet 1991, 48:1075–1083.

    PubMed  CAS  Google Scholar 

  41. Erwin WG: A pedigree of sex-linked recessive peroneal atrophy. J Heredity 1944, 35:24–26.

    Google Scholar 

  42. Ionasescu VV, Trofatter J, Haines JL, et al.: X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 1992, 15:368–373.

    Article  PubMed  CAS  Google Scholar 

  43. Mersiyanova IV, Perepelov AV, Polyakov AV, et al.: A new variant of Charcot-Marie-Tooth disease type 2 (CMT2E) is probably the result of a mutation in the neurofilament light gene. Am J Hum Genet 2000, 67:37–46.

    Article  PubMed  CAS  Google Scholar 

  44. Zhao C, Takita J, Tanaka Y, et al.: Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bâ. Cell 2001, 105:587–597. An excellent recent comprehensive study implicating abnormalities of axonal transport as a cause of Charcot-Marie-Tooth (CMT) disease. as well as reporting the discovery of the molecular cause of CMT2A.

    Article  PubMed  CAS  Google Scholar 

  45. Kwon JM, Elliott JL, Yee WC, et al.: Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet 1995, 57:853–858.

    PubMed  CAS  Google Scholar 

  46. Ellsworth RE, Ionasescu V, Searby C, et al.: The CMT2D locus: refined genetic position and construction of a bacterial clone-based physical map. Genome Res 1999, 9:568–574.

    PubMed  CAS  Google Scholar 

  47. Carpenter DA, Ip W: Neurofilament triplet protein interactions: evidence for the preferred formation of NF-L-containing dimers and a putative function for the end domains. J Cell Sci 1996, 109:2493–2498.

    PubMed  CAS  Google Scholar 

  48. Xu Z, Marszalek JR, Lee MK, et al.: Subunit composition of neurofilaments specifies axonal diameter. J Cell Biol 1996, 133:1061–1069.

    Article  PubMed  CAS  Google Scholar 

  49. Ohara O, Gahara Y, Miyake T, Teraoka H, Kitamura T: Neurofilament deficiency in quail caused by nonsense mutation in neurofilament-L gene. J Cell Biol 1993, 121:387–395.

    Article  PubMed  CAS  Google Scholar 

  50. Lee MK, Marszalek JR, Cleveland DW: A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron 1994, 13:975–988.

    Article  PubMed  CAS  Google Scholar 

  51. Fernyhough P, Gallagher A, Averill SA, et al.: Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes 1999, 48:881–889. A study correlating abnormalities of the axonal cytoskeleton to diabetic neuropathy in a model system.

    Article  PubMed  CAS  Google Scholar 

  52. Sahenk Z, Chen L, Mendell JR: Effects of PMP22 duplication and deletions on the axonal cytoskeleton. Ann Neurol 1999, 45:16–24. A study correlating abnormalities of the axonal cytoskeleton with abnormalities of PMP22 dosage.

    Article  PubMed  CAS  Google Scholar 

  53. Bomont P, Cavalier L, Blondeau F, et al.: The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet 2000, 26:370–374.

    Article  PubMed  CAS  Google Scholar 

  54. Bouhouche A, Benomar A, Birouk N, 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, 65:722–727.

    Article  PubMed  CAS  Google Scholar 

  55. Leal A, Morera B, Del Valle G, et al.: A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am J Hum Genet 2001, 68:269–274.

    Article  PubMed  CAS  Google Scholar 

  56. Casaubon LK, Melanson M, Lopes-Cendes I, et al.: The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet 1996, 58:28–34.

    PubMed  CAS  Google Scholar 

  57. Timmerman V, De Jonghe P, Spoelders P, et al.: Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type families with chromosomes 1p35-p36 and Xq13. Neurology 1996, 46:1311–1318.

    PubMed  CAS  Google Scholar 

  58. Priest JM, Fischbeck KH, Nouri N, Keats BJ: A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics 29:409–412.

  59. Nelis E, Timmerman V, De Jonghe P, Van Broeckhoven C, Rautenstrauss B: Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics 1999, 2:137–148.

    Article  PubMed  CAS  Google Scholar 

  60. Lewis RA: The challenge of CMTX and connexin 32 mutations. Muscle Nerve 2000, 23:147–149. An editorial on the difficulties of electrophysiologically and clinically diagnosing X-linked Charcot-Marie-Tooth disease because of the overlap with demyelinating and axonal neuropathies.

    Article  PubMed  CAS  Google Scholar 

  61. Timmerman V, Jonghe PD, Spoelders P, et al.: Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type families with chromosomes 1p35-p36 and Xq13. Neurology 1996, 46:1311–1318.

    PubMed  CAS  Google Scholar 

  62. Scherer S: Axonal pathology in demyelinating diseases. Ann Neurol 1999, 45:6–7. review of the effects of demyelination on axonal pathology.

    Article  PubMed  CAS  Google Scholar 

  63. de Waegh SM, Lee VM, Brady ST: Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 1992, 68:451–463.

    Article  PubMed  Google Scholar 

  64. Scherer SS: The biology and pathobiology of Schwann cells. Curr Opin Neurol 1997, 10:386–397.

    Article  PubMed  CAS  Google Scholar 

  65. Boerkoel CF, Takashima H, Garcia CA, et al.: CMT and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 2001, in press. A recent study documenting the high incidence of de novo mutations as a cause of sporadic Charcot-Marie-Tooth (CMT) syndrome and defining the relative incidences of various mutations as a cause of CMT.

  66. Hoogendijk JE, Hensels GW, Gabreels-Festen AA, et al.: De-novo mutation in hereditary motor and sensory neuropathy type I. Lancet 1992, 339:1081–1082.

    Article  PubMed  CAS  Google Scholar 

  67. Nelis E, Van Broeckhoven C, De Jonghe P, et al.: Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet 1996, 4:25–33.

    PubMed  CAS  Google Scholar 

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  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, 77030, Houston, TX, USA

    Cornelius F. Boerkoel MD, PhD, Hiroshi Takashima MD, PhD & James R. Lupski MD, PhD

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  1. Cornelius F. Boerkoel MD, PhD
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  2. Hiroshi Takashima MD, PhD
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  3. James R. Lupski MD, PhD
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Boerkoel, C.F., Takashima, H. & Lupski, J.R. The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy. Curr Neurol Neurosci Rep 2, 70–77 (2002). https://doi.org/10.1007/s11910-002-0056-8

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