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Genetic aspects of Charcot-Marie-Tooth disease
  1. Medical Genetics
  2. Department of Medicine and Therapeutics
  3. Department of Molecular and Cell Biology
  4. University of Aberdeen Medical School
  5. Foresterhill, Aberdeen AB25 2ZD

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    Historical perspective and nomenclature

    In 1886 Drs Charcot and Marie of France and Dr Tooth of England described patients with an inherited form of peroneal muscular atrophy, characterised by a progressive weakness and atrophy of distal muscles, usually originating in the feet and lower legs and progressing to the hands and forearms—a disorder now known as Charcot-Marie-Tooth (CMT) disease. Early literature attested to the existence of several distinct disorders in addition to CMT disease, including Dejerine-Sottas syndrome (DSS) and Roussy-Lévy syndrome, but histopathological evidence combined with the advent of electrodiagnostic testing and molecular investigation have demonstrated that these syndromes are clinical variants of CMT disease.

    Key messages

    • The duplication of a 1.5 Mb DNA fragment encompassing the PMP22 gene on chromosome 17p11.2 is associated with over 70% of CMT1 cases

    • Point mutations of the PMP22,P0, and Cx32 genes are also associated with the CMT1 phenotype

    • PMP22 and P0 encode myelin proteins which have important roles in the compaction of myelin. Cx32 encodes a gap junction protein which is considered to allow trafficking of metabolites and secondary messengers between the non-compact layers of myelin. Murine models have validated the hypothesised roles of these proteins

    • CMT disease is extremely heterogeneous, with at least eight additional loci identified. No genes have as yet been identified at these loci

    The term CMT disease is now applied to a range of hereditary peripheral neuropathies, with a population prevalence of approximately one in 2500, which are able to be differentiated at several levels. None the less, the nosology surrounding CMT disease remains confusing and is further confused by the term hereditary motor and sensory neuropathy (HMSN), introduced to describe a broad range of neurological disorders with both motor and sensory involvement.

    Classification of CMT disease


    A major differentiating factor between the different forms of CMT disease is identified by …

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