charcot marie tooth disease

Summary

Summary: A hereditary motor and sensory neuropathy transmitted most often as an autosomal dominant trait and characterized by progressive distal wasting and loss of reflexes in the muscles of the legs (and occasionally involving the arms). Onset is usually in the second to fourth decade of life. This condition has been divided into two subtypes, hereditary motor and sensory neuropathy (HMSN) types I and II. HMSN I is associated with abnormal nerve conduction velocities and nerve hypertrophy, features not seen in HMSN II. (Adams et al., Principles of Neurology, 6th ed, p1343)

Top Publications

  1. Reilly M, De Jonghe P, Pareyson D. 136th ENMC International Workshop: Charcot-Marie-Tooth disease type 1A (CMT1A)8-10 April 2005, Naarden, The Netherlands. Neuromuscul Disord. 2006;16:396-402 pubmed
  2. Verhoeven K, Claeys K, Zuchner S, Schröder J, Weis J, Ceuterick C, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093-102 pubmed
    ..In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population...
  3. Banchs I, Casasnovas C, Montero J, Martinez Matos J, Volpini V. Two Spanish families with Charcot-Marie-Tooth type 2A: clinical, electrophysiological and molecular findings. Neuromuscul Disord. 2008;18:974-8 pubmed publisher
    ..Population studies of mutations in MFN2 should be undertaken to discover the real frequencies in the Mediterranean area...
  4. Spinosa M, Progida C, De Luca A, Colucci A, Alifano P, Bucci C. Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. J Neurosci. 2008;28:1640-8 pubmed publisher
    ..Altogether, these data demonstrate that all tested CMT2B-associated Rab7 mutations are mechanistically similar, suggesting that activated forms of the Rab7 are responsible for CMT2B disease...
  5. Guillet V, Gueguen N, Verny C, Ferre M, Homedan C, Loiseau D, et al. Adenine nucleotide translocase is involved in a mitochondrial coupling defect in MFN2-related Charcot-Marie-Tooth type 2A disease. Neurogenetics. 2010;11:127-33 pubmed publisher
    ..Furthermore, a twofold increase in the expression of ANT led to the reduced efficiency of oxidative phosphorylation in CMT2A cells, suggesting that MFN2 plays a role in controlling ATP/ADP exchanges...
  6. Chung K, Kim S, Park K, Choi K, Lee J, Eun H, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain. 2006;129:2103-18 pubmed
    ..Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype...
  7. Dziewas R, Waldmann N, Böntert M, Hor H, Muller T, Okegwo A, et al. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: a case control study. J Neurol Neurosurg Psychiatry. 2008;79:829-31 pubmed publisher
    ..Pathophysiologically, one may assume that CMT1 related pharyngeal neuropathy increases the collapsibility of the upper airway which in turn leads to recurring obstructive respiratory events...
  8. Chojnowski A, Ravisé N, Bachelin C, Depienne C, Ruberg M, Brugg B, et al. Silencing of the Charcot-Marie-Tooth associated MTMR2 gene decreases proliferation and enhances cell death in primary cultures of Schwann cells. Neurobiol Dis. 2007;26:323-31 pubmed
    ..These results support the hypothesis that loss of MTMR2 in patients, by decreasing Schwann cells proliferation and survival, may impair the first stages of myelination of the peripheral nervous system...
  9. Neusch C, Senderek J, Eggermann T, Elolff E, Bahr M, Schneider Gold C. Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A). Eur J Neurol. 2007;14:575-7 pubmed
    ..The disease course was rapidly progressive in the first years and slowed afterwards. We also suggest that single patients with early-onset axonal polyneuropathies should be screened for MFN2 mutations...

More Information

Publications62

  1. Verhamme C, van Schaik I, Koelman J, de Haan R, de Visser M. The natural history of Charcot-Marie-Tooth type 1A in adults: a 5-year follow-up study. Brain. 2009;132:3252-62 pubmed publisher
    ..The slow increase in physical disability in adulthood may well be explained by decreased reserves and compensatory mechanisms together with progression of skeletal deformations due to muscle weakness...
  2. Aboussouan L, Lewis R, Shy M. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. Lung. 2007;185:1-7 pubmed
    ..The risk of progression to bilateral vocal cord dysfunction in CMT and the risk of aspiration with laryngeal neuropathy may limit the therapeutic options available for vocal cord paralysis...
  3. Tersar K, Boentert M, Berger P, Bonneick S, Wessig C, Toyka K, et al. Mtmr13/Sbf2-deficient mice: an animal model for CMT4B2. Hum Mol Genet. 2007;16:2991-3001 pubmed
  4. Zhang X, Chow C, Sahenk Z, Shy M, Meisler M, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 2008;131:1990-2001 pubmed publisher
    ..This study represents the first documentation of the natural history of CMT4J. Physical obstruction of organelle trafficking by vacuoles is a potential novel cellular mechanism of neurodegeneration. ..
  5. Houlden H, Laura M, Wavrant De Vrieze F, Blake J, Wood N, Reilly M. Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. Neurology. 2008;71:1660-8 pubmed publisher
  6. Burns J, Ouvrier R, Yiu E, Joseph P, Kornberg A, Fahey M, et al. Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial. Lancet Neurol. 2009;8:537-44 pubmed publisher
    ..We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A...
  7. Chow C, Zhang Y, Dowling J, Jin N, Adamska M, Shiga K, et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448:68-72 pubmed
    ..This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J...
  8. Zuchner S, Vance J. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol. 2006;2:45-53 pubmed
    ..The known CMT2-related genes represent key players in these pathways, however, and are likely to provide powerful tools for identifying targets for future therapeutic intervention...
  9. Berger P, Niemann A, Suter U. Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease). Glia. 2006;54:243-57 pubmed
    ..These networks include the control of myelin formation and stability, membrane trafficking, intracellular protein sorting and quality control, and may extend to mitochondrial dynamics and basic protein biosynthesis...
  10. Engelfried K, Vorgerd M, Hagedorn M, Haas G, Gilles J, Epplen J, et al. Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet. 2006;7:53 pubmed
    ..Charcot-Marie-Tooth neuropathies are a group of genetically heterogeneous diseases of the peripheral nervous system. Mutations in the MFN2 gene have been reported as the primary cause of Charcot-Marie-Tooth disease type 2A...
  11. Zuchner S, Vance J. Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:63-74 pubmed
    ..The known CMT2 genes present key players in these pathways and will likely prove as powerful tools in identifying eventual future targets for therapeutic intervention...
  12. Solari A, Laura M, Salsano E, Radice D, Pareyson D. Reliability of clinical outcome measures in Charcot-Marie-Tooth disease. Neuromuscul Disord. 2008;18:19-26 pubmed
    ..All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength...
  13. Casasnovas C, Banchs I, Corral J, Martinez Matos J, Volpini V. Clinical and molecular analysis of X-linked Charcot-Marie-Tooth disease type 1 in Spanish population. Clin Genet. 2006;70:516-23 pubmed
    ..1 +/- 16.6%) were the most frequently affected codon and domain of the connexin 32. Six novel mutations, Leu39fs, Glu47Gly, His153fs, Cys179Tyr, Cys201Phe and Ser211fs, were found in our study...
  14. Meggouh F, Bienfait H, Weterman M, de Visser M, Baas F. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology. 2006;67:1476-8 pubmed
    ..471G>C, p.Lys157Asn missense mutation. This observation strongly supports the hypothesis that RAB7 mutations are responsible for CMT2B...
  15. Dubourg O, Azzedine H, Verny C, Durosier G, Birouk N, Gouider R, et al. Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:75-86 pubmed
    ..In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis...
  16. Padua L, Shy M, Aprile I, Cavallaro T, Pareyson D, Quattrone A, et al. Correlation between clinical/neurophysiological findings and quality of life in Charcot-Marie-Tooth type 1A. J Peripher Nerv Syst. 2008;13:64-70 pubmed publisher
    ..Both the PCS and MCS were abnormal also in this cohort, compared with the Italian population at large. In particular, the ability to ambulate independently as well as toe and heel walk correlated well with QoL measures in our patients...
  17. Shy M, Chen L, Swan E, Taube R, Krajewski K, Herrmann D, et al. Neuropathy progression in Charcot-Marie-Tooth disease type 1A. Neurology. 2008;70:378-83 pubmed publisher
    ..To determine the rate of disease progression in Charcot-Marie-Tooth disease type 1A (CMT1A)...
  18. Toth C. Poor tolerability of high dose ascorbic acid in a population of genetically confirmed adult Charcot-Marie-Tooth 1A patients. Acta Neurol Scand. 2009;120:134-8 pubmed publisher
    ..Preclinical studies have suggested that ascorbic acid (AA) treatment in a mouse model of Charcot-Marie-Tooth type 1A (CMT1A) improves motor function and prolongs lifespan...
  19. Sołtysińska E, Kabzinska D, Kochanski A. [Mutations in the mitofusin 2 gene are the most common cause of Charcot-Marie-Tooth type 2 disease]. Neurol Neurochir Pol. 2007;41:350-4 pubmed
    ..As MFN2 gene mutations are the most common cause of autosomal dominant CMT2 disease (33% of cases), MFN2 gene testing may be considered a diagnostic test for CMT2...
  20. Barisic N, Claeys K, Sirotkovic Skerlev M, Lofgren A, Nelis E, De Jonghe P, et al. Charcot-Marie-Tooth disease: a clinico-genetic confrontation. Ann Hum Genet. 2008;72:416-41 pubmed publisher
    ..The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients...
  21. Robinson F, Niesman I, Beiswenger K, Dixon J. Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A. 2008;105:4916-21 pubmed publisher
    ..Mtmr13-deficient mice will be an essential tool for studying how the loss of MTMR13 leads to CMT4B2...
  22. Amiott E, Lott P, Soto J, Kang P, McCaffery J, DiMauro S, et al. Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp Neurol. 2008;211:115-27 pubmed publisher
    ..We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease. ..
  23. Szigeti K, Lupski J. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009;17:703-10 pubmed publisher
    ..Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing...
  24. Loiseau D, Chevrollier A, Verny C, Guillet V, Gueguen N, Pou de Crescenzo M, et al. Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease. Ann Neurol. 2007;61:315-23 pubmed
    ..Mutations of the mitofusin 2 gene (MFN2) may account for at least a third of the cases of Charcot-Marie-Tooth disease type 2 (CMT2). This study investigates mitochondrial cellular bioenergetics in MFN2-related CMT2A...
  25. Baloh R, Schmidt R, Pestronk A, Milbrandt J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007;27:422-30 pubmed
  26. Kurihara S, Adachi Y, Wada K, Awaki E, Harada H, Nakashima K. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology. 2002;21:246-50 pubmed
    ..To identify the occurrence of mildly affected CMT, the exhaustive region-matched and family study was necessary...
  27. Zuchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, De Jonghe P, et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet. 2005;37:289-94 pubmed
    ..Additionally, in the Australian and Belgian pedigrees, which carry two different mutations affecting the same amino acid, Lys558, CMT cosegregated with neutropenia, which has not previously been associated with CMT neuropathies...
  28. Berger P, Schaffitzel C, Berger I, Ban N, Suter U. Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module. Proc Natl Acad Sci U S A. 2003;100:12177-82 pubmed
    ..Our data indicate that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for the correct regulation of MTMR2...
  29. Boerkoel C, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, et al. CMT4A: identification of a Hispanic GDAP1 founder mutation. Ann Neurol. 2003;53:400-5 pubmed
    ..Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina...
  30. Katoh H, Watanabe Y, Ebukuro M, Muguruma K, Takabayashi S, Shiroishi T. Chromosomal mapping of the peroneal muscular atrophy (pma) gene in the mouse. Exp Anim. 2003;52:433-6 pubmed
    ..The gene order was determined as follows: centromere-D5Mit263-[2.65 cM]-D5Mit141-[2.56 cM]-pma-[5.13 cM]-D5Mit97-telomere...
  31. Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, 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;73:1106-19 pubmed
    ..Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes...
  32. Marco A, Cuesta A, Pedrola L, Palau F, Marín I. Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes. Mol Biol Evol. 2004;21:176-87 pubmed
    ..Mutations affecting any of those characteristic domains are known to cause Charcot-Marie-Tooth disease. These features define the GDAP1 class of GST-like proteins...
  33. Sereda M, Meyer zu Horste G, Suter U, Uzma N, Nave K. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med. 2003;9:1533-7 pubmed
    ..Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A...
  34. Stojkovic T, Latour P, Viet G, De Seze J, Hurtevent J, Vandenberghe A, et al. Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene. Neuromuscul Disord. 2004;14:261-4 pubmed
  35. Verhamme C, van Schaik I, Koelman J, de Haan R, Vermeulen M, de Visser M. Clinical disease severity and axonal dysfunction in hereditary motor and sensory neuropathy Ia. J Neurol. 2004;251:1491-7 pubmed
    ..Hereditary motor and sensory neuropathy type Ia (HMSN Ia) is known as a primarily demyelinating peripheral nerve disease. Evidence is accumulating that axonal involvement determines the course of the disease process...
  36. Nelis E, Erdem S, Van den Bergh P, Belpaire Dethiou M, Ceuterick C, Van Gerwen V, et al. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology. 2002;59:1865-72 pubmed
  37. Robaglia Schlupp A, Pizant J, Norreel J, Passage E, Sabéran Djoneidi D, Ansaldi J, et al. PMP22 overexpression causes dysmyelination in mice. Brain. 2002;125:2213-21 pubmed
    ..Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease...
  38. Berger P, Young P, Suter U. Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics. 2002;4:1-15 pubmed
  39. Azzedine H, Ruberg M, Ente D, Gilardeau C, Perie S, Wechsler B, et al. Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord. 2003;13:341-6 pubmed
    ..The phenotype included hoarse voice and paralysis of the diaphragm. This study shows the variability of the phenotype associated with mutations in GDAP1 gene in terms of associated signs and severity...
  40. Houlden H, King R, Muddle J, Warner T, Reilly M, Orrell R, et al. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol. 2004;56:586-90 pubmed
    ..The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7...
  41. Bonneick S, Boentert M, Berger P, Atanasoski S, Mantei N, Wessig C, et al. An animal model for Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet. 2005;14:3685-95 pubmed
  42. Thiel C, Kraus C, Rauch A, Ekici A, Rautenstrauss B, Reis A. A new quantitative PCR multiplex assay for rapid analysis of chromosome 17p11.2-12 duplications and deletions leading to HMSN/HNPP. Eur J Hum Genet. 2003;11:170-8 pubmed
    ..Thus, this method shows superior sensitivity to microsatellite analysis and has the additional advantage of being a fast and uniform assay for quantitative analysis of both CMT1A and HNPP...
  43. Kim S, Lee K, Jin H, Lee T, Koo S, Lee Y, et al. Rapid detection of duplication/deletion of the PMP22 gene in patients with Charcot-Marie-Tooth disease Type 1A and hereditary neuropathy with liability to pressure palsy by real-time quantitative PCR using SYBR Green I dye. J Korean Med Sci. 2003;18:727-32 pubmed
    ..This method is fast, highly sensitive, specific, and reproducible in detecting PMP22 duplication and deletion in CMT1A and HNPP patients, respectively...
  44. Baxter R, Ben Othmane K, Rochelle J, Stajich J, Hulette C, Dew Knight S, et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002;30:21-2 pubmed
    ..We found three different mutations in four different Tunisian families-two nonsense and one missense mutation. How mutations in GDAP1 lead to CMT4A remains to be understood...
  45. Taylor R, Simon E, Marks H, Scherer S. The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem. Neurology. 2003;61:1475-8 pubmed
  46. Nelis E, Erdem S, Tan E, Lofgren A, Ceuterick C, De Jonghe P, et al. A novel homozygous missense mutation in the myotubularin-related protein 2 gene associated with recessive Charcot-Marie-Tooth disease with irregularly folded myelin sheaths. Neuromuscul Disord. 2002;12:869-73 pubmed
    ..This is the second homozygous missense mutation associated with recessive Charcot-Marie-Tooth disease with focally folded myelin sheaths...
  47. Zhu D, Kennerson M, Walizada G, Zuchner S, Vance J, Nicholson G. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology. 2005;65:496-7 pubmed
  48. De Sandre Giovannoli A, Chaouch M, Kozlov S, Vallat J, Tazir M, Kassouri N, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002;70:726-36 pubmed
  49. Cuesta A, Pedrola L, Sevilla T, Garcia Planells J, Chumillas M, Mayordomo F, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet. 2002;30:22-5 pubmed
    ..1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes...
  50. Szigeti K, Garcia C, Lupski J. Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet Med. 2006;8:86-92 pubmed
    ..An evidence-based approach was used to determine the frequency distribution of genes contributing to the Charcot-Marie-Tooth (CMT) disease phenotype...
  51. Zuchner S, De Jonghe P, Jordanova A, Claeys K, Guergueltcheva V, Cherninkova S, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276-81 pubmed
    ..Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive...
  52. De Sandre Giovannoli A, Delague V, Hamadouche T, Chaouch M, Krahn M, Boccaccio I, 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;42:260-5 pubmed
  53. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet. 2005;116:23-7 pubmed
    ..Formation of a mitochondrial network would be required to maintain the functional peripheral nerve axon...