Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease

Nature Medicine volume 10, pages 396–401 (2004)Cite this article

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Rotarod results for ascorbic acid (AA)-treated and placebo-treated C22 male and female mice.
Figure 2: Locomotor test results from trial 3.
Figure 3: C22 males were systematically treated with either ascorbic acid (AA) or placebo until their natural death.
Figure 4: Histological analysis of peripheral nerves of male C22 mice.
Figure 5: β-gal reporter gene expression in MSC80 mouse Schwann cells.

Similar content being viewed by others

References

  1. Dyck, P.J., Oviatt, K.F. & Lambert, E.H. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann. Neurol. 10, 222–226 (1981).

    Article  CAS  PubMed  Google Scholar 

  2. Ouvrier, R.A. & Nicholson, G.A. Advances in the genetics of hereditary hypertrophic neuropathies in childhood. Brain Dev. 17, 31–38 (1995).

    Article  PubMed  Google Scholar 

  3. Skre, H. Genetic and clinical aspects of Charcot-Marie-Tooth disease. Clin. Genet. 6, 98–118 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Boerkoel, C.F. et al. CMT disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann. Neurol. 51, 190–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Nelis, E. et al. (The European CMT Consortium). Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and HNNP: a European collaborative study. Eur. J. Hum. Genet. 4, 25–33 (1997).

    Article  Google Scholar 

  6. Lupski, J.R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Raeymaekers, P. et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). Neuromuscul. Disord. 1, 93–97 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Matsunami, N. et al. Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth disease type 1A. Nat. Genet. 1, 176–179 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Patel, P.I. et al. The gene for peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nat. Genet. 1, 159–165 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Timmerman, V. et al. The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nat. Genet. 1, 171–175 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Valentijn, L.J. et al. The peripheral myelin protein gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nat. Genet. 1, 166–170 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Roa, B.B. et al. Charcot-Marie-Tooth disease type 1A: association with a spontaneous point mutation in the PMP 22 gene. N. Engl. J. Med. 329, 96–101 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Valentijn, L.J. et al. Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A. Nat. Genet. 2, 288–291 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Fenton C.F., Schlefman, B.S. & McGlamry, E.D. Surgical considerations in the presence of Charcot-Marie-Tooth disease. J. Am. Podiatr. Assoc. 74, 490–498 (1984).

    Article  Google Scholar 

  15. Gould, N. Surgery in advanced Charcot-Marie-Tooth disease. Foot Ankle 4, 267–273 (1984).

    Article  CAS  PubMed  Google Scholar 

  16. Njegovan, M.E., Leonard, E.I. & Joseph, F.B. Rehabilitation medicine approach to Charcot-Marie-Tooth disease. Clin. Podiatr. Med. Surg. 14, 99–116 (1997).

    CAS  PubMed  Google Scholar 

  17. Huxley, C. et al. Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. Hum. Mol. Genet. 5, 563–569 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Huxley, C. et al. Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice. Hum. Mol. Genet. 7, 449–458 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Carey, D.J. & Todd, M.S. Schwann cell myelination in a chemically defined medium: demonstration of a requirement for additives that promote Schwann cell extracellular matrix formation. Brain Res. 429, 95–102 (1987).

    Article  CAS  PubMed  Google Scholar 

  20. Eldridge, C.F. et al. Differentiation of axon-related Schwann cells in vitro. I. Ascorbic acid regulates basal lamina assembly and myelin formation. J. Cell. Biol. 105, 1023–1034 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Plant, G.W. et al. Purified adult ensheathing glia fail to myelinate axons under culture conditions that enable Schwann cells to form myelin. J. Neurosci. 22, 6083–6091 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hood, J. Femoral neuropathy in scurvy. N. Engl. J. Med. 281, 1292–1293 (1969).

    Article  CAS  PubMed  Google Scholar 

  23. Norreel, J.C. et al. Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model. Eur. J. Neurosci. 13, 1625–1634 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Chapillon, P. et al. Early development of synchronized walking on the rotarod in rats. Effects of training and handling. Behav. Brain Res. 93, 77–81 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Garcia, C.A. A clinical review of Charcot-Marie-Tooth disease. Ann. NY Acad. Sci. 883, 69–76 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Carter, R.J. et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J. Neurosci. 19, 3248–3257 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sancho, S. et al. Distal axonopathy in peripheral nerves of PMP22 mutant mice. Brain 122, 1563–1577 (1999).

    Article  PubMed  Google Scholar 

  28. Coschigano, K.T. et al. Deletions, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144, 3799–3804 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Sabéran-Djoneidi, D. et al. Molecular dissection of the Schwann cell specific promoter of the PMP22 gene. Gene 248, 223–231 (2000).

    Article  PubMed  Google Scholar 

  30. Agus, D.B. et al. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J. Clin. Invest. 100, 2842–2848 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nishikawa, Y. et al. Vitamin C metabolomic mapping in experimental diabetes with 6-DFA and high resolution 19F magnetic resonance spectroscopy. Metabolism 6, 760–770 (2003).

    Article  Google Scholar 

  32. Lopez-Lluch, G. et al. Redox regulation of cAMP levels by ascorbate in 1,25-dihydroxy-vitamin D3-induced differentiation of HL-60 cells. Biochem. J. 331, 21–27 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang, Z., Copolov, D.L. & Lim, A.T. Ascorbic acid augments the adenylate cyclase-cAMP system-mediated POMC mRNA expression and β-endorphin secretion from hypothalamic neurons in culture. Brain Res. 706, 243–248 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Arrigoni, O. & De Tullio, M.C. Ascorbic acid: much more than just an antioxidant. Biochim. Biophys. Acta 1569, 1–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Rodriguez-Melendez, R. Importance of water-soluble vitamins as regulatory factors of genetic expression. Rev. Invest. Clin. 54, 77–83 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

V.S. was a fellow of the Association Française contre les Myopathies (AFM), and P.N.-F. received support from the American Charcot-Marie-Tooth Association. This work was supported by an AFM grant. We thank CMT France for their constant support; L. Colleaux, N. Levy, M. Mitchell, F. Thomas and L. Villard for their critical reading of the manuscript; and UMAGT and A. Margotat for technical help with the real-time PCR experiments.

Author information

Author notes

  1. Edith Passage and Jean Chrétien Norreel: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale UMR491, IPHM, Faculté de Médecine de la Timone, 27 Bd. J. Moulin, Marseille, 13385 Cedex 5, France

    Edith Passage, Jean Chrétien Norreel, Pauline Noack-Fraissignes, Véronique Sanguedolce, Josette Pizant, Andrée Robaglia-Schlupp & Michel Fontés

  2. UPR Centre National de la Recherche Scientifique 9011, 31 Chemin J. Aiguier, Marseille, 13402 Cedex 20, France

    Jean Chrétien Norreel

  3. Laboratoire de Santé Publique, EA 3279, Faculté de Médecine de la Timone, 27 Bd. J. Moulin, Marseille, 13385 Cedex 5, France

    Xavier Thirion

  4. Service d'Anatomie Pathologique, CHU Timone Adulte, 264 Rue St. Pierre, Marseille, 13385 Cedex 5, France

    Jean François Pellissier

Authors
  1. Edith Passage
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean Chrétien Norreel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pauline Noack-Fraissignes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Véronique Sanguedolce
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josette Pizant
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xavier Thirion
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrée Robaglia-Schlupp
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean François Pellissier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michel Fontés
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Fontés.

Ethics declarations

Competing interests

A patent was deposited July 2002, approved in France (PCT in progress), by Université de la Méditerranée, INSERM and AFM. E.P., V.S., J.C.N. and M.F. are the discoverers.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Passage, E., Norreel, J., Noack-Fraissignes, P. et al. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10, 396–401 (2004). https://doi.org/10.1038/nm1023

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1023

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing