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Clinical implications of genetic advances in Charcot–Marie–Tooth disease


Charcot–Marie–Tooth disease (CMT) refers to a group of inherited neuropathies with a broad range of phenotypes, inheritance patterns and causative genes. The number of disease genes identified in CMT has expanded rapidly over the past few decades, such that more than 60 CMT-associated genes have now been discovered. This rise in genetic discovery can be attributed to the development of next-generation sequencing (NGS) technology, which allows the entire exome or genome to be sequenced in a matter of days. In this Review, we discuss how NGS is being employed in the diagnostic evaluation of patients with CMT and how the genetic advances in CMT are influencing clinical practice. In particular, we explore how genetic advances have broadened the phenotype of CMT and related disorders and how NGS allows a large number of CMT genes to be screened simultaneously early in the evaluation of an unexplained neuropathy. Finally, we discuss the different methods of NGS that can be used in CMT and related disorders, and propose a simple diagnostic algorithm in which clinical assessment and neurophysiology are used to guide the application of phenotype specific 'panels'.

Key Points

  • Charcot–Marie–Tooth disease (CMT) should be considered as a differential diagnosis in an increasingly wide range of neuropathy phenotypes

  • In patients with autosomal dominant or sporadic demyelinating genetic neuropathy, screening for the chromosome 17p duplication should be performed first, before proceeding to a disease-specific panel

  • Disease-specific next-generation sequencing in which all known disease-causing genes are sequenced in parallel (disease-specific panels) is now the most efficient method of genetic testing in CMT

  • Incomplete coverage of whole-exome sequencing and whole-genome sequencing mean that their use is mainly restricted to research-led discovery of new genes

  • Genetic testing for appropriate CMT mutations should be considered in treatment-resistant inflammatory demyelinating neuropathies

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Figure 1: Genetic diagnoses in CMT and related disorders in patients attending a specialist CMT clinic in the UK.6,32
Figure 2: A timeline of discovery of genes involved in Charcot–Marie–Tooth disease and related disorders.
Figure 3: Known disease genes for CMT and related disorders, and their proposed pathomechanism.
Figure 4: An algorithm for genetic testing in CMT and related disorders using disease-specific panels.


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A. M. Rossor is funded by the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712), and an IPSEN clinical research fellowship. M. M. Reilly is funded by a Medical Research Council grant (G0601943), and by the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712). Work undertaken at University College London Hospitals/University College London was partly funded by the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

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A. M. Rossor and M. M. Reilly researched data for the article. All authors provided substantial contribution to discussion of content, to writing the article, and to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Mary M. Reilly.

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The authors declare no competing financial interests.

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Rossor, A., Polke, J., Houlden, H. et al. Clinical implications of genetic advances in Charcot–Marie–Tooth disease. Nat Rev Neurol 9, 562–571 (2013).

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