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Charcot–Marie–Tooth disease and related neuropathies

Nature Reviews Disease Primers volume 12, Article number: 3 (2026) Cite this article

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Abstract

Charcot–Marie–Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated.

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Fig. 1: Global estimated minimum prevalence of CMT by country.
Fig. 2: Genetic loci and their disease pathways in axonal and demyelinating CMT.
Fig. 3: Classic presentation of CMT and extra features by genotype.
Fig. 4: Recommended algorithm for diagnostic evaluation of CMT and related neuropathies.

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Acknowledgements

V.T. discloses support for the research for this work from the European Union via the EU4Health Programme (EUCMTSC, no. 101232916). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or HADEA. Neither the European Union nor the granting authority can be held responsible for them. J.B. discloses support for the research for this work from The Charcot-Marie-Tooth Association (Inherited Neuropathy Consortium, SR-202601) and Muscular Dystrophy Association (CERTIFYCMT, 1060929).

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Authors and Affiliations

  1. Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Joshua Burns

  2. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Vincent Timmerman

  3. Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    Vincent Timmerman & Jonathan De Winter

  4. µNEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium

    Vincent Timmerman

  5. Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK

    Matilde Laurá

  6. Department of Neurology, The Royal Children’s Hospital, Melbourne, Victoria, Australia

    Eppie M. Yiu

  7. Neuroscience Research Group, Murdoch Children’s Research Institute, Parkville, Victoria, Australia

    Eppie M. Yiu

  8. Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia

    Eppie M. Yiu

  9. Biology of Myelin Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy

    Maurizio D’Antonio

  10. Department of Neurology, John Hopkins University School of Medicine, Baltimore, MD, USA

    Bipasha Mukherjee-Clavin

  11. Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Jonathan De Winter

  12. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium

    Jonathan De Winter

  13. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

    Steven S. Scherer

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Contributions

Introduction (S.S.S. and J.B.); Epidemiology (B.M.-C., V.T. and S.S.S.); Mechanisms/pathophysiology (V.T., M.D’A., J.D.W. and S.S.S.); Diagnosis, screening and prevention (B.M.-C., J.D.W., M.L. and S.S.S.); Management (E.M.Y. and M.L.); Quality of life (E.M.Y. and M.L.); Outlook (J.B. and S.S.S.); overview of Primer (J.B.).

Corresponding author

Correspondence to Joshua Burns.

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Competing interests

J.B., V.T., M.L., E.M.Y., M.D’A., B.M.-C., J.D.W. and S.S.S. are principal and/or co-investigators for clinical studies of CMT and related neuropathies. J.B., B.M.-C. and S.S.S. have consulted for Applied Therapeutics. J.B. has consulted for Alesta Therapeutics and NMD Pharma. V.T. provides occasional service to the pharmaceutical industry and CROs to validate therapeutic compounds in iPSC-derived 2D and 3D cell model systems. M.D’A. has consulted for InFlectis Bioscience. S.S.S. has consulted for DTx Therapeutics, Novartis, Passage Bio, Pfizer and Toray Industries.

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Nature Reviews Disease Primers thanks A. Schenone, T. Sevilla, H. Takashima and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Burns, J., Timmerman, V., Laurá, M. et al. Charcot–Marie–Tooth disease and related neuropathies. Nat Rev Dis Primers 12, 3 (2026). https://doi.org/10.1038/s41572-025-00679-2

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