UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis

Author
Peter B Kang, MD, FAAP, FAAN
Section Editors
Douglas R Nordli, Jr, MD
Helen V Firth, DM, FRCP, DCH
Jeremy M Shefner, MD, PhD
Deputy Editor
John F Dashe, MD, PhD

INTRODUCTION

The hereditary peripheral neuropathies have been classified based upon clinical characteristics, mode of inheritance, electrophysiologic features, metabolic defects, and specific genetic markers. The primary hereditary neuropathies predominantly affect peripheral nerves and produce symptoms of peripheral nerve dysfunction.

Historically, the primary hereditary neuropathies were designated by eponyms that had the connotation of specific clinical features (eg, Charcot-Marie-Tooth disease [CMT] or Dejerine-Sottas disease). However, phenotypic variability resulted in substantial diagnostic confusion.

The Dyck classification developed in the 1970s helped to define specific types based upon clinical and electrophysiologic features [1]. Many of the primary hereditary neuropathies were divided into hereditary motor sensory neuropathy (HMSN) and hereditary sensory autonomic neuropathy (HSAN). However, the eponym Charcot-Marie-Tooth disease has had a resurgence in popularity, and today the term "CMT" is regarded as being synonymous with HMSN.

CMT/HMSN is the focus of the current review and for the sake of simplicity will be referred to as CMT for the remainder of this review. This topic will review the genetics, clinical features, and evaluation of CMT. Management and prognosis are reviewed separately. (See "Charcot-Marie-Tooth disease: Management and prognosis".)

The primary hereditary sensory autonomic neuropathies (HSAN), the neuropathies not included in this classification, and the disorders affecting both the central and peripheral nervous systems are discussed elsewhere. (See "Overview of hereditary neuropathies" and "Hereditary sensory and autonomic neuropathies" and "Neuropathies associated with hereditary disorders".)

                                
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Oct 30, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Peripheral Neuropathy, Dyck PJ, Thomas PK, Lambert EH, et al (Eds), WB Saunders, Philadelphia 1984. Vol 2.
  2. Lupski JR. Charcot-Marie-Tooth polyneuropathy: duplication, gene dosage, and genetic heterogeneity. Pediatr Res 1999; 45:159.
  3. Kamholz J, Menichella D, Jani A, et al. Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy. Brain 2000; 123 ( Pt 2):222.
  4. Klein CJ, Duan X, Shy ME. Inherited neuropathies: clinical overview and update. Muscle Nerve 2013; 48:604.
  5. Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol 2017; 30:471.
  6. Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69:22.
  7. Rossor AM, Polke JM, Houlden H, Reilly MM. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol 2013; 9:562.
  8. Barreto LC, Oliveira FS, Nunes PS, et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology 2016; 46:157.
  9. Mersiyanova IV, Ismailov SM, Polyakov AV, et al. Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Hum Mutat 2000; 15:340.
  10. Fridman V, Bundy B, Reilly MM, 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; 86:873.
  11. Roy EP 3rd, Gutmann L, Riggs JE. Longitudinal conduction studies in hereditary motor and sensory neuropathy type 1. Muscle Nerve 1989; 12:52.
  12. Rudnik-Schöneborn S, Röhrig D, Nicholson G, Zerres K. Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology 1993; 43:2011.
  13. Hagberg B, Lyon G. Pooled European series of hereditary peripheral neuropathies in infancy and childhood. A "correspondence work shop" report of the European Federation of Child Neurology Societies (EFCNS). Neuropediatrics 1981; 12:9.
  14. Krajewski KM, Lewis RA, Fuerst DR, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000; 123 ( Pt 7):1516.
  15. Videler AJ, van Dijk JP, Beelen A, et al. Motor axon loss is associated with hand dysfunction in Charcot-Marie-Tooth disease 1a. Neurology 2008; 71:1254.
  16. Gabreëls-Festen AA, Gabreëls FJ, Jennekens FG, et al. Autosomal recessive form of hereditary motor and sensory neuropathy type I. Neurology 1992; 42:1755.
  17. Hahn AF, Brown WF, Koopman WJ, Feasby TE. X-linked dominant hereditary motor and sensory neuropathy. Brain 1990; 113 ( Pt 5):1511.
  18. Bergoffen J, Trofatter J, Pericak-Vance MA, et al. Linkage localization of X-linked Charcot-Marie-Tooth disease. Am J Hum Genet 1993; 52:312.
  19. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 1993; 262:2039.
  20. Shaffer LG, Kennedy GM, Spikes AS, Lupski JR. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet 1997; 69:325.
  21. Hanemann CO, D'Urso D, Gabreëls-Festen AA, Müller HW. Mutation-dependent alteration in cellular distribution of peripheral myelin protein 22 in nerve biopsies from Charcot-Marie-Tooth type 1A. Brain 2000; 123 ( Pt 5):1001.
  22. Dematteis M, Pépin JL, Jeanmart M, et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 2001; 357:267.
  23. Dziewas R, Waldmann N, Böntert M, et al. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: a case control study. J Neurol Neurosurg Psychiatry 2008; 79:829.
  24. Gabreëls-Festen AA, Gabreëls FJ, Joosten EM, et al. Hereditary neuropathy with liability to pressure palsies in childhood. Neuropediatrics 1992; 23:138.
  25. Mouton P, Tardieu S, Gouider R, et al. Spectrum of clinical and electrophysiologic features in HNPP patients with the 17p11.2 deletion. Neurology 1999; 52:1440.
  26. Potulska-Chromik A, Sinkiewicz-Darol E, Ryniewicz B, et al. Clinical, electrophysiological, and molecular findings in early onset hereditary neuropathy with liability to pressure palsy. Muscle Nerve 2014; 50:914.
  27. Korn-Lubetzki I, Argov Z, Raas-Rothschild A, et al. Family with inflammatory demyelinating polyneuropathy and the HNPP 17p12 deletion. Am J Med Genet 2002; 113:275.
  28. Luigetti M, Del Grande A, Conte A, et al. Clinical, neurophysiological and pathological findings of HNPP patients with 17p12 deletion: a single-centre experience. J Neurol Sci 2014; 341:46.
  29. Yilmaz U, Bird TT, Carter GT, et al. Pain in hereditary neuropathy with liability to pressure palsy: an association with fibromyalgia syndrome? Muscle Nerve 2015; 51:385.
  30. Choi YH, Dunn B. Low back pain with radicular symptoms as a presentation of hereditary neuropathy with liability to pressure palsies: the diagnostic challenge of an atypical presentation. Muscle Nerve 2016; 53:655.
  31. Sanahuja J, Franco E, Rojas-García R, et al. Central nervous system involvement in hereditary neuropathy with liability to pressure palsies: description of a large family with this association. Arch Neurol 2005; 62:1911.
  32. Tackenberg B, Möller JC, Rindock H, et al. CNS involvement in hereditary neuropathy with pressure palsies (HNPP). Neurology 2006; 67:2250.
  33. Meier C, Moll C. Hereditary neuropathy with liability to pressure palsies. Report of two families and review of the literature. J Neurol 1982; 228:73.
  34. Stögbauer F, Young P, Kuhlenbäumer G, et al. Hereditary recurrent focal neuropathies: clinical and molecular features. Neurology 2000; 54:546.
  35. Mariman EC, Gabreëls-Festen AA, van Beersum SE, et al. Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies. Ann Neurol 1994; 36:650.
  36. Bird TD. Hereditary neuropathy with liability to pressure palsies. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1392/ (Accessed on December 07, 2011).
  37. Li J, Ghandour K, Radovanovic D, et al. Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies. Arch Neurol 2007; 64:974.
  38. Infante J, García A, Combarros O, et al. Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve 2001; 24:1149.
  39. Guo J, Wang L, Zhang Y, et al. Abnormal junctions and permeability of myelin in PMP22-deficient nerves. Ann Neurol 2014; 75:255.
  40. Bird TD. Historical perspective of defining Charcot-Marie-Tooth type 1B. Ann N Y Acad Sci 1999; 883:6.
  41. Hayasaka K, Himoro M, Sato W, et al. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet 1993; 5:31.
  42. Hattori N, Yamamoto M, Yoshihara T, 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; 126:134.
  43. Saporta MA. Charcot-Marie-Tooth disease and other inherited neuropathies. Continuum (Minneap Minn) 2014; 20:1208.
  44. Shy ME, Jáni A, Krajewski K, et al. Phenotypic clustering in MPZ mutations. Brain 2004; 127:371.
  45. Mastaglia FL, Nowak KJ, Stell R, et al. Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1999; 67:174.
  46. Banchs I, Casasnovas C, Montero J, et al. Charcot-Marie-Tooth disease with intermediate conduction velocities caused by a novel mutation in the MPZ gene. Muscle Nerve 2010; 42:184.
  47. Wrabetz L, Feltri ML, Quattrini A, et al. P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol 2000; 148:1021.
  48. Tyson J, Ellis D, Fairbrother U, et al. Hereditary demyelinating neuropathy of infancy. A genetically complex syndrome. Brain 1997; 120 ( Pt 1):47.
  49. Maeda MH, Mitsui J, Soong BW, et al. Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease. Ann Neurol 2012; 71:84.
  50. Sabet A, Li J, Ghandour K, et al. Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B. Neurology 2006; 67:1141.
  51. Spiryda LB. Myelin protein zero and membrane adhesion. J Neurosci Res 1998; 54:137.
  52. Matsuyama W, Nakagawa M, Takashima H, Osame M. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol 2002; 103:501.
  53. Lee YC, Yu CT, Lin KP, et al. MPZ mutation G123S characterization: evidence for a complex pathogenesis in CMT disease. Neurology 2008; 70:273.
  54. Street VA, Goldy JD, Golden AS, et al. Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am J Hum Genet 2002; 70:244.
  55. Street VA, Bennett CL, Goldy JD, et al. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 2003; 60:22.
  56. 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.
  57. Kousseff BG, Hadro TA, Treiber DL, et al. Charcot-Marie-Tooth disease with sensorineural hearing loss--an autosomal dominant trait. Birth Defects Orig Artic Ser 1982; 18:223.
  58. Kovach MJ, Lin JP, Boyadjiev S, et al. A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet 1999; 64:1580.
  59. Jordanova A, De Jonghe P, Boerkoel CF, et al. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 2003; 126:590.
  60. Planté-Bordeneuve V, Guiochon-Mantel A, Lacroix C, et al. The Roussy-Lévy family: from the original description to the gene. Ann Neurol 1999; 46:770.
  61. Auer-Grumbach M, Strasser-Fuchs S, Wagner K, et al. Roussy-Lévy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA associated with a duplication on chromosome 17p11.2. J Neurol Sci 1998; 154:72.
  62. Keller MP, Chance PF. Inherited peripheral neuropathy. Semin Neurol 1999; 19:353.
  63. Reilly MM. Axonal Charcot-Marie-Tooth disease: the fog is slowly lifting! Neurology 2005; 65:186.
  64. Bennett CL, Lawson VH, Brickell KL, et al. Late-onset hereditary axonal neuropathies. Neurology 2008; 71:14.
  65. 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.
  66. Bouhouche A, Birouk N, Azzedine H, et al. Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain 2007; 130:1062.
  67. Ouvrier R, Geevasingha N, Ryan MM. Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. Muscle Nerve 2007; 36:131.
  68. Murphy SM, Laura M, Fawcett K, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012; 83:706.
  69. Ouvrier R, Grew S. Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults. Dev Med Child Neurol 2010; 52:328.
  70. Züchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004; 36:449.
  71. Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005; 65:197.
  72. Feely SM, Laura M, Siskind CE, et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 2011; 76:1690.
  73. Polke JM, Laurá M, Pareyson D, et al. Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 2011; 77:168.
  74. Carr AS, Polke JM, Wilson J, et al. MFN2 deletion of exons 7 and 8: founder mutation in the UK population. J Peripher Nerv Syst 2015; 20:67.
  75. Zhao C, Takita J, Tanaka Y, et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 2001; 105:587.
  76. Bissar-Tadmouri N, Nelis E, Züchner S, et al. Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene. Neurology 2004; 62:1522.
  77. Elliott JL, Kwon JM, Goodfellow PJ, Yee WC. Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics. Neurology 1997; 48:23.
  78. Verhoeven K, De Jonghe P, Coen K, et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 2003; 72:722.
  79. Klein CJ, Cunningham JM, Atkinson EJ, et al. The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 2003; 60:1151.
  80. McEntagart ME, Reid SL, Irrthum A, et al. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol 2005; 57:293.
  81. Auer-Grumbach M, Olschewski A, Papić L, et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 2010; 42:160.
  82. Chen DH, Sul Y, Weiss M, et al. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 2010; 75:1968.
  83. Ionasescu V, Searby C, Sheffield VC, et al. Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet 1996; 5:1373.
  84. 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. Am J Hum Genet 2003; 72:1293.
  85. Mersiyanova IV, Perepelov AV, Polyakov AV, 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; 67:37.
  86. De Jonghe P, Mersivanova I, Nelis E, et al. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol 2001; 49:245.
  87. Yum SW, Zhang J, Mo K, et al. A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol 2009; 66:759.
  88. Fabrizi GM, Cavallaro T, Angiari C, et al. Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain 2007; 130:394.
  89. Ismailov SM, Fedotov VP, Dadali EL, et al. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet 2001; 9:646.
  90. 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. Nat Genet 2004; 36:602.
  91. Senderek J, Hermanns B, Lehmann U, 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; 10:235.
  92. Chapon F, Latour P, Diraison P, et al. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry 1999; 66:779.
  93. De Jonghe P, Timmerman V, Ceuterick C, 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; 122 ( Pt 2):281.
  94. Misu K, Yoshihara T, Shikama Y, 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; 69:806.
  95. Birouk N, Azzedine H, Dubourg O, 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; 60:598.
  96. Chung KW, Kim SM, Sunwoo IN, et al. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. J Hum Genet 2008; 53:360.
  97. Crimella C, Tonelli A, Airoldi G, 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; 47:712.
  98. Tang BS, Luo W, Xia K, et al. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet 2004; 114:527.
  99. Irobi J, Van Impe K, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004; 36:597.
  100. Fabrizi GM, Ferrarini M, Cavallaro T, et al. Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease. Neurology 2007; 69:291.
  101. Gallardo E, Claeys KG, Nelis 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; 255:986.
  102. Kennerson ML, Zhu D, Gardner RJ, et al. Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet 2001; 69:883.
  103. Züchner S, Noureddine M, Kennerson M, et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet 2005; 37:289.
  104. Nelis E, Berciano J, Verpoorten N, et al. Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3. J Med Genet 2004; 41:193.
  105. Peeters K, Palaima P, Pelayo-Negro AL, et al. Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1. Ann Neurol 2016; 80:823.
  106. Cottenie E, Kochanski A, Jordanova A, et al. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am J Hum Genet 2014; 95:590.
  107. Shi CH, Song B, Luo HY, et al. Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation. Neurology 2015; 85:383.
  108. Higuchi Y, Hashiguchi A, Yuan J, et al. Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. Ann Neurol 2016; 79:659.
  109. Pitceathly RD, Murphy SM, Cottenie E, et al. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology 2012; 79:1145.
  110. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009; 8:654.
  111. Boerkoel CF, Takashima H, Lupski JR. The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy. Curr Neurol Neurosci Rep 2002; 2:70.
  112. Huttner IG, Kennerson ML, Reddel SW, et al. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology 2006; 67:2016.
  113. Latour P, Lévy N, Paret M, et al. Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population. Neurogenetics 1997; 1:117.
  114. Shy ME, Siskind C, Swan ER, et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology 2007; 68:849.
  115. Yiu EM, Geevasinga N, Nicholson GA, et al. A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood. Neurology 2011; 76:461.
  116. Al-Mateen M, Craig AK, Chance PF. The central nervous system phenotype of X-linked Charcot-Marie-Tooth disease: a transient disorder of children and young adults. J Child Neurol 2014; 29:342.
  117. Basu A, Horvath R, Esisi B, et al. Recurrent stroke-like episodes in X-linked Charcot-Marie-Tooth disease. Neurology 2011; 77:1205.
  118. Paulson HL, Garbern JY, Hoban TF, et al. Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol 2002; 52:429.
  119. Taylor RA, Simon EM, Marks HG, Scherer SS. The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem. Neurology 2003; 61:1475.
  120. Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families. Neurology 1993; 43:2558.
  121. Ionasescu VV, Trofatter J, Haines JL, et al. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet 1991; 48:1075.
  122. Ionasescu VV, Trofatter J, Haines JL, et al. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 1992; 15:368.
  123. Wang Y, Yin F. A Review of X-linked Charcot-Marie-Tooth Disease. J Child Neurol 2016; 31:761.
  124. Brewer MH, Chaudhry R, Qi J, et al. Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3. PLoS Genet 2016; 12:e1006177.
  125. Cowchock FS, Duckett SW, Streletz LJ, et al. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet 1985; 20:307.
  126. Rinaldi C, Grunseich C, Sevrioukova IF, et al. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet 2012; 91:1095.
  127. Kim HJ, Hong SH, Ki CS, et al. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology 2005; 64:1964.
  128. Kim HJ, Sohn KM, Shy ME, 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; 81:552.
  129. Kennerson ML, Yiu EM, Chuang DT, 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; 22:1404.
  130. Ouvrier RA, McLeod JG, Conchin TE. The hypertrophic forms of hereditary motor and sensory neuropathy. A study of hypertrophic Charcot-Marie-Tooth disease (HMSN type I) and Dejerine-Sottas disease (HMSN type III) in childhood. Brain 1987; 110 ( Pt 1):121.
  131. Parman Y, Battaloglu E, Baris I, et al. Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain 2004; 127:2540.
  132. Parman Y, Planté-Bordeneuve V, Guiochon-Mantel A, et al. Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. Ann Neurol 1999; 45:518.
  133. Ikegami T, Ikeda H, Aoyama M, et al. Novel mutations of the peripheral myelin protein 22 gene in two pedigrees with Dejerine-Sottas disease. Hum Genet 1998; 102:294.
  134. Timmerman V, De Jonghe P, Ceuterick C, et al. Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. Neurology 1999; 52:1827.
  135. Boerkoel CF, Takashima H, Bacino CA, et al. EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics 2001; 3:153.
  136. Boerkoel CF, Takashima H, Stankiewicz P, et al. Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 2001; 68:325.
  137. Charnas L, Trapp B, Griffin J. Congenital absence of peripheral myelin: abnormal Schwann cell development causes lethal arthrogryposis multiplex congenita. Neurology 1988; 38:966.
  138. Ghamdi M, Armstrong DL, Miller G. Congenital hypomyelinating neuropathy: a reversible case. Pediatr Neurol 1997; 16:71.
  139. Levy BK, Fenton GA, Loaiza S, Hayat GR. Unexpected recovery in a newborn with severe hypomyelinating neuropathy. Pediatr Neurol 1997; 16:245.
  140. Phillips JP, Warner LE, Lupski JR, Garg BP. Congenital hypomyelinating neuropathy: two patients with long-term follow-up. Pediatr Neurol 1999; 20:226.
  141. Mandich P, Mancardi GL, Varese A, et al. Congenital hypomyelination due to myelin protein zero Q215X mutation. Ann Neurol 1999; 45:676.
  142. Kochanski A, Drac H, Kabzińska D, et al. A novel MPZ gene mutation in congenital neuropathy with hypomyelination. Neurology 2004; 62:2122.
  143. McMillan HJ, Santagata S, Shapiro F, et al. Novel MPZ mutations and congenital hypomyelinating neuropathy. Neuromuscul Disord 2010; 20:725.
  144. Bolino A, Lonie LJ, Zimmer M, 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; 3:107.
  145. Bird TD. Charcot-Marie-Tooth neuropathy type 4. Gene Reviews. https://www.ncbi.nlm.nih.gov/books/NBK1468/ (Accessed on July 13, 2017).
  146. Ben Othmane K, Hentati F, Lennon F, et al. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 1993; 2:1625.
  147. Baxter RV, Ben Othmane K, Rochelle JM, et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002; 30:21.
  148. Cuesta A, Pedrola L, Sevilla T, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002; 30:22.
  149. Pedrola L, Espert A, Wu X, et al. GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet 2005; 14:1087.
  150. Senderek J, Bergmann C, Ramaekers VT, et al. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 2003; 126:642.
  151. Chung KW, Hyun YS, Lee HJ, et al. Two recessive intermediate Charcot-Marie-Tooth patients with GDAP1 mutations. J Peripher Nerv Syst 2011; 16:143.
  152. Bolino A, Brancolini V, Bono F, 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; 5:1051.
  153. Bolino A, Levy ER, Muglia M, et al. Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22. Genomics 2000; 63:271.
  154. Quattrone A, Gambardella A, Bono F, et al. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology 1996; 46:1318.
  155. 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.
  156. Othmane KB, 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.
  157. Hirano R, Takashima H, Umehara F, et al. SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology 2004; 63:577.
  158. Senderek J, Bergmann C, Weber S, et al. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 2003; 12:349.
  159. Azzedine H, Bolino A, Taïeb T, 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; 72:1141.
  160. Kiwaki T, Umehara F, Takashima H, et al. Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma. Neurology 2000; 55:392.
  161. Gambardella A, Bolino A, Muglia M, et al. Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Neurology 1998; 50:799.
  162. Conforti FL, Muglia M, Mazzei R, et al. A new SBF2 mutation in a family with recessive demyelinating Charcot-Marie-Tooth (CMT4B2). Neurology 2004; 63:1327.
  163. Nakhro K, Park JM, Hong YB, et al. SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology 2013; 81:165.
  164. LeGuern E, Guilbot A, Kessali M, et al. Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33. Hum Mol Genet 1996; 5:1685.
  165. Gabreëls-Festen A, van Beersum S, Eshuis L, et al. Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33. J Neurol Neurosurg Psychiatry 1999; 66:569.
  166. Guilbot A, Ravisé N, Bouhouche 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; 7:849.
  167. Varley TL, Bourque PR, Baker SK. Phenotypic variability of CMT4C in a French-Canadian kindred. Muscle Nerve 2015; 52:444.
  168. Laššuthová P, Mazanec R, Vondráček P, et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet 2011; 80:334.
  169. Colomer J, Gooding R, Angelicheva D, et al. Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2. Neuromuscul Disord 2006; 16:449.
  170. Senderek J, Bergmann C, Stendel C, et al. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet 2003; 73:1106.
  171. Azzedine H, Ravisé N, Verny C, et al. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 2006; 67:602.
  172. Kalaydjieva L, Hallmayer J, Chandler D, et al. Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet 1996; 14:214.
  173. 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.
  174. Guilbot A, Williams A, Ravisé N, et al. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet 2001; 10:415.
  175. 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.
  176. Sevilla T, Martínez-Rubio D, Márquez C, 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; 83:565.
  177. Hantke J, Chandler D, King R, et al. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR). Eur J Hum Genet 2009; 17:1606.
  178. De Sandre-Giovannoli A, Delague V, Hamadouche T, 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; 42:260.
  179. Stendel C, Roos A, Deconinck T, et al. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am J Hum Genet 2007; 81:158.
  180. Fabrizi GM, Taioli F, Cavallaro T, et al. Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H. Neurology 2009; 72:1160.
  181. Chow CY, Zhang Y, Dowling JJ, et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 2007; 448:68.
  182. Zhang X, Chow CY, Sahenk Z, et al. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 2008; 131:1990.
  183. Echaniz-Laguna A, Ghezzi D, Chassagne M, et al. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease. Neurology 2013; 81:1523.
  184. Ylikallio E, Woldegebriel R, Tumiati M, et al. MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability. Brain 2017; 140:2093.
  185. Berciano J, García A, Gallardo E, et al. Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review. J Neurol 2017; 264:1655.
  186. Liu L, Zhang R. Intermediate Charcot-Marie-Tooth disease. Neurosci Bull 2014; 30:999.
  187. Davis CJ, Bradley WG, Madrid R. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification. J Genet Hum 1978; 26:311.
  188. 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.
  189. Jordanova A, Thomas FP, Guergueltcheva V, et al. Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35. Am J Hum Genet 2003; 73:1423.
  190. Jordanova A, Irobi J, Thomas FP, et al. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet 2006; 38:197.
  191. McLaughlin HM, Sakaguchi R, Liu C, et al. Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am J Hum Genet 2010; 87:560.
  192. Kim HJ, Hong YB, Park JM, et al. Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease. Orphanet J Rare Dis 2013; 8:104.
  193. Azzedine H, Zavadakova P, Planté-Bordeneuve V, et al. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum Mol Genet 2013; 22:4224.
  194. Pareyson D. Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies. Neurol Sci 2004; 25:72.
  195. Karakis I, Gregas M, Darras BT, et al. Clinical correlates of Charcot-Marie-Tooth disease in patients with pes cavus deformities. Muscle Nerve 2013; 47:488.
  196. Bird TD. Charcot-Marie-Tooth hereditary neuropathy overview. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1358/ (Accessed on July 12, 2017).
  197. Amato AA, Reilly MM. The death panel for Charcot-Marie-Tooth panels. Ann Neurol 2011; 69:1.
  198. Andersson PB, Yuen E, Parko K, So YT. Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology 2000; 54:40.