Charcot-Marie-Tooth disease and related inherited neuropathies.

Charcot-Marie-Tooth disease (CMT) was initially described more than 100 years ago by Charcot, Marie, and Tooth. It was only recently, however, that molecular genetic studies of CMT have uncovered the underlying causes of most forms of the diseases. Most cases of CMT1 are associated with a 1.5-Mb tandem duplication in 17p11.2-p12 that encompasses the PMP22 gene. Although many genes may exist in this large duplicated region, PMP22 appears to be the major dosage-sensitive gene. CMT1A is the first autosomal dominant disease associated with a gene dosage effect due to an inherited DNA rearrangement. There is no mutant gene, but instead the disease phenotype results from having 3 copies of a normal gene. Furthermore, these findings suggest that therapeutic intervention in CMT1A duplication patients may be possible by normalizing the amount of PMP22 mRNA levels. Alternatively, CMT1A can be caused by mutations in the PMP22 gene. Other forms of CMT are associated with mutations in the MPZ (CMT1B) and Cx32 (CMTX) genes. Thus, mutations in different genes can cause similar CMT phenotypes. The related but more severe neuropathy, Dejerine-Sottas syndrome (DSS), can also be caused by mutations in the PMP22 and MPZ genes. All 3 genes thus far identified by CMT researchers appear to play an important role in the myelin formation or maintenance of peripheral nerves. CMT1A, CMT1B, CMTX, hereditary neuropathy with liability to pressure palsies (HNPP), and DSS have been called myelin disorders or "myelino-pathies." Other demyelinating forms, CMT1C and CMT-AR, may be caused by mutations of not yet identified myelin genes expressed in Schwann cells. The clinically distinct disease HNPP is caused by a 1.5-Mb deletion in 17p11.2-p12, which spans the same region duplicated in most CMT1A patients. Underexpression of the PMP22 gene causes HNPP just as overexpression of PMP22 causes CMT1A. Thus, 2 different phenotypes can be caused by dosage variations of the same gene. It is apparent that the CMT1A duplication and HNPP deletion are the reciprocal products of a recombination event during meiosis mediated through the CMT1A-REPs. CMT1A and HNPP could be thought of as a "genomic disease" more than single gene disorders. Other genetic disorders may also prove to arise from recombination events mediated by specific chromosomal structural features of the human genome (102). Further studies on the recombination mechanism of CMT and HNPP might reveal the causes of site specific homologous recombination in the human genome. The discovery of the PMP22 gene in the 1.5-Mb CMT1A duplication/HNPP deletion critical region also suggests that the clinical phenotype of chromosome aneuploid syndromes may result from the effect of a small subset of dosage-sensitive genes mapping within the region of aneuploidy. The understanding of the molecular basis of CMT1 and related disorders has allowed accurate DNA diagnosis and genetic counseling of inherited peripheral neuropathies and will make it possible to develop rational strategies for therapy. As several loci for CMT2 have been identified, the genes responsible for CMT2 will most likely be disclosed using positional cloning and candidate gene approaches in the near future.