J Clin Neurol.  2006 Jun;2(2):92-106. 10.3988/jcn.2006.2.2.92.

Charcot-Marie-Tooth Disease: Seventeen Causative Genes

• Lee JH
• Choi BO

• KMID: 1700741
• DOI: http://doi.org/10.3988/jcn.2006.2.2.92

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common form of inherited motor and sensory neuropathy. Moreover, CMT is a genetically heterogeneous disorder of the peripheral nervous system, with many genes identified as CMT-causative. CMT has two usual classifications: type 1, the demyelinating form (CMT1); and type 2, the axonal form (CMT2). In addition, patients are classified as CMTX if they have an X-linked inheritance pattern and CMT4 if the inheritance pattern is autosomal recessive. A large amount of new information on the genetic causes of CMT has become available, and mutations causing it have been associated with more than 17 different genes and 25 chromosomal loci. Advances in our understanding of the molecular basis of CMT have revealed an enormous diversity in genetic mechanisms, despite a clinical entity that is relatively uniform in presentation. In addition, recent encouraging studies - shown in CMT1A animal models - concerning the therapeutic effects of certain chemicals have been published; these suggest potential therapies for the most common form of CMT, CMT1A. This review focuses on the inherited motor and sensory neuropathy subgroup for which there has been an explosion of new molecular genetic information over the past decade.

Keyword

Charcot-Marie-Tooth disease; Neuropathy; Axon; Gene; Mutation

MeSH Terms

Axons
Charcot-Marie-Tooth Disease*
Classification
Explosions
Genes, X-Linked
Humans
Inheritance Patterns
Models, Animal
Molecular Biology
Peripheral Nervous System

Figure

• 

  Figure 1 Contemporary portraits of Charcot (A), Marie (B), and Tooth (C). In 1886, Frenchmen Jean Martin Charcot (1825~1893) and Pierre Marie (1853~1940), and Briton Howard Henry Tooth (1856~1925), described hereditary motor and sensory neuropathies for the first time.

• 

  Figure 2 (A) CMT1A duplication and HNPP deletion are reciprocal products of a recombination event (unequal crossing-over) during meiosis, mediated by the flanking repeat elements (CMT1A-REPs). (B) Genomic map of the chromosome 17p11.2-p12. The genomic structure of the CMT1A/HNPP region (telomere-to-centromere orientation). Proximal and distal CMT1A-REPs are shown as vertical boxes.

• 

  Figure 3 Genomic structures of GJB1 (A) and EGR2 (B). The EGR2 gene encodes a zinc finger transcription factor that plays a major role in myelination of the peripheral nerves, and the EGR2 gene regulates the expressions of GJB1. Thus, mutations in EGR2 prevent Schwann cell development and lead to the development of demyelinating neuropathy (C).

• 

  Figure 4 Genomic structure and mutations of MFN2. Solid black boxes and solid white boxes indicate protein coding sequences and untranslated sequences, respectively. P, loop; GTP, binding-site motif; Cc, coiled-coil domain; TM, transmembrane domain; GTPase, GTPase functional domain; fzo mitofusin, fzo mitofusin functional domain.

• 

  Figure 5 Structure of the NEFL protein, which is one of the most abundant cytoskeletal components of the neuron. The NEFL gene encoding the neurofilament light chain plays an important role in axonal structure, including an extensive fibrous network in the cytoplasm of the neuron.

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