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Semin Neurol 2008; 28(2): 185-194
DOI: 10.1055/s-2008-1062264
© Thieme Medical Publishers

Charcot-Marie-Tooth Neuropathies: Diagnosis and Management

Agnes Jani-Acsadi1 , Karen Krajewski1 , Michael E. Shy1
  • 1Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan
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Publication History

Publication Date:
19 March 2008 (online)

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ABSTRACT

Charcot-Marie-Tooth (CMT) disease is caused by mutations in several genes expressed in myelinating Schwann cells and the axons they ensheathe. Typical patients present with distally accentuated motor weakness, muscle wasting, and sensory loss leading to significant and progressive clinical morbidity and impaired quality of life. The wealth of recent information regarding genotype-phenotype correlations, recognition of disease heterogeneity, and newly characterized animal models provide exciting insights into the molecular disease-related pathogenetic and pathophysiologic mechanisms. These advances at the same time also represent a challenge for the diagnosis and management of these patients, with no presently available specific curative or disease modifying treatments. A better understanding of the pathogenesis of peripheral neuropathies is an invaluable tool in developing future supportive and curative therapies for patients with CMT disease that will improve their quality of life. In this review, we provide practical insights on current diagnostic and therapeutic modalities and suggest future diagnostic and therapeutic directions.

KEYWORDS

Charcot-Marie-Tooth disease - heterogeneity - diagnosis - treatment

REFERENCES

  • 1 Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease.  Clin Genet. 1974;  6 98-118
    PubMedSearch in Google Scholar
  • 2 Shy M, Lupski J R, Chance P F, Klein C J, Dyck P. The hereditary motor and sensory neuropathies: an overview of the clinical, genetic, electrophysiologic and pathologic features. In: Dyck PJ Peripheral Neuropathy. 4th ed. Philadelphia; WB Saunders 2005: 1623-1658
    Search in Google Scholar
  • 3 Song S J, Zhang Y Z, Chen B et al.. No mutation was detected in the LMNA gene among sporadic Charcot-Marie-Tooth patients.  Beijing Da Xue Xue Bao. 2006;  38 78-79
    PubMedSearch in Google Scholar
  • 4 Charcot J, Marie P. Sue une forme particulaire d'atrophie musculaire progressive souvent familial debutant par les pieds et les jamber et atteingnant plus tard les mains.  Re Med. 1886;  6 97-138
    PubMedSearch in Google Scholar
  • 5 Tooth H. The Peroneal Type of Progressive Muscular Atrophy. London; Lewis 1886
    Search in Google Scholar
  • 6 Dejerine H, Sottas J. Sur la nevritte interstitielle, hypertrophique et progressive de l'enfance.  CR Soc Biol Paris. 1893;  45 63-96
    PubMedSearch in Google Scholar
  • 7 Roussy G, Levy G. A sept cas d'une maladie familiale particulaire.  Rev Neurol. 1926;  33 427-450
    PubMedSearch in Google Scholar
  • 8 Dawidenkow S. Uber die neurotische Muskelatrophie Charcot-Marie: Klinisch-genetische Studien.  Z Ges Neurol Psychiat. 1927;  107 259
    PubMedSearch in Google Scholar
  • 9 Dawidenkow S. Uber dir neurotische Muskelatrophie Charcot-Marie: Klinisch-genetische Studien.  Z Neurol. 1927;  108 344
    PubMedSearch in Google Scholar
  • 10 Dyck P J, Lambert E H. 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
    PubMedSearch in Google Scholar
  • 11 Dyck P J, Lambert E H. 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
    CrossrefPubMedSearch in Google Scholar
  • 12 Harding A E, Thomas P K. The clinical features of hereditary motor and sensory neuropathy types I and II.  Brain. 1980;  103 259-280
    CrossrefPubMedSearch in Google Scholar
  • 13 Harding A E, Thomas P K. Genetic aspects of hereditary motor and sensory neuropathy (types I and II).  J Med Genet. 1980;  17 329-336
    CrossrefPubMedSearch in Google Scholar
  • 14 Aguayo A J, Attiwell M, Trecarten J, Perkins S, Bray G M. Abnormal myelination in transplanted Trembler mouse Schwann cells.  Nature. 1977;  265 73-75
    PubMedSearch in Google Scholar
  • 15 Aguayo A J, Kasarjian J, Skamene E, Kongshavn P, Bray G M. Myelination of mouse axons by Schwann cells transplanted from normal and abnormal human nerves.  Nature. 1977;  268 753-755
    CrossrefPubMedSearch in Google Scholar
  • 16 Lupski J R, de Oca-Luna R M, Slaugenhaupt S et al.. DNA duplication associated with Charcot-Marie-Tooth disease type 1A.  Cell. 1991;  66 219-232
    CrossrefPubMedSearch in Google Scholar
  • 17 Raeymaekers P, Timmerman V, Nelis E et al.. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). The HMSN Collaborative Research Group.  Neuromuscul Disord. 1991;  1 93-97
    CrossrefPubMedSearch in Google Scholar
  • 18 Shy M E, Jani A, Krajewski K M et al.. Phenotypic clustering in MPZ mutations.  Brain. 2004;  127 371-384
    CrossrefPubMedSearch in Google Scholar
  • 19 Bradley W G, Madrid R, Davis C J. The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological and nerve biopsy studies. Part 3: Clinical, electrophysiological and pathological correlations.  J Neurol Sci. 1977;  32 123-136
    CrossrefPubMedSearch in Google Scholar
  • 20 Lovelace R. Hereditary induced peripheral neuropathies.  Clin Podiatr Med Surg. 1990;  7 37-50
    PubMedSearch in Google Scholar
  • 21 Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families.  Neurology. 1993;  43 2558-2564
    CrossrefPubMedSearch in Google Scholar
  • 22 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
    PubMedSearch in Google Scholar
  • 23 Shy M E, Scavina M T, Clark A et al.. T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy.  Ann Neurol. 2006;  59 358-364
    CrossrefPubMedSearch in Google Scholar
  • 24 Dyck P J, Oviatt K F, Lambert E H. Intensive evaluation of unclassified neuropathies yields improved diagnosis.  Ann Neurol. 1981;  10 222-226
    CrossrefPubMedSearch in Google Scholar
  • 25 Ionasescu V V, Burns T L, Searby C, Ionasescu R. X-linked dominant Charcot-Marie-Tooth neuropathy with 15 cases in a family genetic linkage study.  Muscle Nerve. 1988;  11 1154-1156
    CrossrefPubMedSearch in Google Scholar
  • 26 Wise C A, Garcia C A, Davis S N et al.. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication.  Am J Hum Genet. 1993;  53 853-863
    PubMedSearch in Google Scholar
  • 27 Li J, Krajewski K, Lewis R A, Shy M E. Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies.  Muscle Nerve. 2004;  29 205-210
    CrossrefPubMedSearch in Google Scholar
  • 28 Nicholson G A. Mutation testing in Charcot-Marie-Tooth neuropathy.  Ann N Y Acad Sci. 1999;  883 383-388
    CrossrefPubMedSearch in Google Scholar
  • 29 Ionasescu V V, Ionasescu R, Searby C. Screening of dominantly inherited Charcot-Marie-Tooth neuropathies.  Muscle Nerve. 1993;  16 1232-1238
    CrossrefPubMedSearch in Google Scholar
  • 30 Shy M E. Therapeutic strategies for the inherited neuropathies.  Neuromolecular Med. 2006;  8 255-278
    CrossrefPubMedSearch in Google Scholar
  • 31 Suter U, Scherer S S. Disease mechanisms in inherited neuropathies.  Nat Rev Neurosci. 2003;  4 714-726
    CrossrefPubMedSearch in Google Scholar
  • 32 Arroyo E J, Scherer S S. On the molecular architecture of myelinated fibers.  Histochem Cell Biol. 2000;  113 1-18
    CrossrefPubMedSearch in Google Scholar
  • 33 Massicotte C, Scherer S S. Neuropathies: translating causes into treatments. In: Waxman SG Neuroscience, Molecular Medicine, and the Therapeutic Transformation of Neurology. Philadelphia; Elsevier Science 2004: 405-418
    Search in Google Scholar
  • 34 Kamholz J, Menichella D, Jani A et al.. Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy.  Brain. 2000;  123 222-233
    CrossrefPubMedSearch in Google Scholar
  • 35 Wrabetz L, Feltri M L, Kleopa K. Inherited neuropathies: clinical, genetic, and biological features. In: Lazzarini RA Myelin Biology and Disorders. London; Elsevier 2004: 905-952
    Search in Google Scholar
  • 36 Michailov G V, Sereda M W, Brinkmann B G et al.. Axonal neuregulin-1 regulates myelin sheath thickness.  Science. 2004;  304 700-703
    CrossrefPubMedSearch in Google Scholar
  • 37 Taveggia C, Zanazzi G, Petrylak A et al.. Neuregulin-1 type III determines the ensheathment fate of axons.  Neuron. 2005;  47 681-694
    CrossrefPubMedSearch in Google Scholar
  • 38 Lewis R A, Sumner A J, Shy M E. Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis.  Muscle Nerve. 2000;  23 1472-1487
    CrossrefPubMedSearch in Google Scholar
  • 39 Brust J C, Lovelace R E, Devi S. Clinical and electrodiagnostic features of Charcot-Marie-Tooth syndrome.  Acta Neurol Scand Suppl. 1978;  68 1-142
    PubMedSearch in Google Scholar
  • 40 Davis C JF, Bradley W G, Madrid R. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy findings and classification.  J Genet Hum. 1978;  26 311-349
    PubMedSearch in Google Scholar
  • 41 Krajewski K M, Lewis R A, Fuerst D R et al.. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.  Brain. 2000;  123 1516-1527
    CrossrefPubMedSearch in Google Scholar
  • 42 Shy M E, Rose M R. Charcot-Marie-Tooth disease impairs quality of life: why? And how do we improve it?.  Neurology. 2005;  65 790-791
    CrossrefPubMedSearch in Google Scholar
  • 43 Arnold L D, Bachmann G A, Rosen R, Kelly S, Rhoads G G. Vulvodynia: characteristics and associations with comorbidities and quality of life.  Obstet Gynecol. 2006;  107 617-624
    PubMedSearch in Google Scholar
  • 44 Vinci P, Serrao M, Millul A et al.. Quality of life in patients with Charcot-Marie-Tooth disease.  Neurology. 2005;  65 922-924
    CrossrefPubMedSearch in Google Scholar
  • 45 Carter G T, Han J J, Abresch R T, Jensen M P. The importance of assessing quality of life in patients with neuromuscular disorders.  Am J Hosp Palliat Care. 2006;  23 493-497
    PubMedSearch in Google Scholar
  • 46 Krajewski K M, Shy M E. Genetic testing in neuromuscular disease.  Neurol Clin. 2004;  22 481-508
    CrossrefPubMedSearch in Google Scholar
  • 47 Bird T D. Risks and benefits of DNA testing for neurogenetic disorders.  Semin Neurol. 1999;  19 253-259
    PubMedSearch in Google Scholar
  • 48 Boerkoel C F, Takashima H, Garcia C A et al.. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.  Ann Neurol. 2002;  51 190-201
    CrossrefPubMedSearch in Google Scholar
  • 49 Sereda M, Griffiths I, Puhlhofer A et al.. A transgenic rat model of Charcot-Marie-Tooth disease.  Neuron. 1996;  16 1049-1060
    CrossrefPubMedSearch in Google Scholar
  • 50 Guenard V, Schweitzer B, Flechsig E et al.. Effective gene transfer of lacZ and P0 into Schwann cells of P0-deficient mice.  Glia. 1999;  25 165-178
    CrossrefPubMedSearch in Google Scholar
  • 51 Ianokova E, Lewis R, Acsadi G et al.. AAV-GDNF improves neuropathy in MPZ-/- mice.  Neurology. 2006;  66(suppl 2) A276
    PubMedSearch in Google Scholar
  • 52 Mäurer M, Kobsar I, Berghoff M, Schmid C D, Carenini S, Martini R. Role of immune cells in animal models for inherited neuropathies: facts and visions.  J Anat. 2002;  200 405-414
    CrossrefPubMedSearch in Google Scholar
  • 53 Passage E, Norreel J C, Noack-Fraissignes P et al.. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease.  Nat Med. 2004;  10 396-401
    CrossrefPubMedSearch in Google Scholar
  • 54 Sereda M W, Meyer Zu Horste G, Suter U, Uzma N, Nave K A. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A).  Nat Med. 2003;  9 1533-1537
    CrossrefPubMedSearch in Google Scholar

Agnes Jani-AcsadiM.D. 

Assistant Professor of Neurology, Department of Neurology, Wayne State University School of Medicine

8A UHC, 4201 St. Antoine, Detroit, MI 48201

Email: aacsadi@med.wayne.edu