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Mechanisms of Disease: a molecular genetic update on hereditary axonal neuropathies

Nature Clinical Practice Neurology volume 2, pages 45–53 (2006)Cite this article

Abstract

Hereditary axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under the name of Charcot–Marie–Tooth (CMT) disease type 2 (CMT2). Historically, two classes of CMT have been differentiated: demyelinating forms of CMT (CMT1), in which nerve conduction velocities are decreased, and the axonal CMT2 forms, in which nerve conduction velocities are preserved. Recently, a number of genes that are defective in patients with the main forms of CMT2 have been identified. The molecular dissection of cellular functions of the related gene products has only just begun, and detailed pathophysiological models are still lacking. 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.

Key Points

  • Traditionally, the Charcot–Marie–Tooth (CMT) neuropathies fall into two main groups: demyelinating forms (CMT1), in which nerve conduction velocities are reduced, and axonal forms (CMT2), in which nerve conduction velocities are preserved

  • Until recently, most of the known CMT-related genes were associated with the CMT1 phenotype, but several genes have now been identified that are defective in patients with CMT2

  • The CMT2-associated genes encode proteins that are involved in vital cellular processes, including mitochondrial function, endosomal trafficking and RNA processing

  • Despite considerable phenotypic overlap, symptoms that are associated with specific CMT2 neuropathies are beginning to emerge; for example, CMT2B is characterized by severe sensory loss, whereas motor symptoms are more prominent in CMT2A

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Figure 1: Schematic of a peripheral nerve axon, illustrating the molecular pathways involved in Charcot–Marie–Tooth disease type 2.

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Authors and Affiliations

  1. Department of Psychiatry,

    Stephan Züchner & Jeffery M Vance

  2. Center for Human Genetics, Duke University Medical Center, Durham, NC, USA

    Stephan Züchner & Jeffery M Vance

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  1. Stephan Züchner
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Correspondence to Stephan Züchner.

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The authors have licensed the testing of the MFN2 gene in CMT2 to Athena Neuroscience.

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Züchner, S., Vance, J. Mechanisms of Disease: a molecular genetic update on hereditary axonal neuropathies. Nat Rev Neurol 2, 45–53 (2006). https://doi.org/10.1038/ncpneuro0071

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