Animal models of Charcot-Marie-Tooth disease type 1A.

The most frequent genetic subtype of Charcot-Marie-Tooth disease is CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A is a gene dosage disease associated with a 1.5 Mb large genomic duplication. Transgenic models with extra copies of the Pmp22 gene have provided formal proof that overexpression of only this candidate gene is sufficent to cause peripheral demyelination, onion bulb formation, secondary axonal loss, and progressive muscle atrophy, the pathological hallmarks of CMT1A. The transgenic CMT rat with about 1.6-fold PMP22 overexpression exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimick findings in CMT1A patients. Also transgenic mice, carrying yeast artifical chromosomes as Pmp22 transgenes, demonstrate the variability of disease expression as a function of increased gene dosage. Recently, the first rational experimental therapies of CMT1A were tested, using transgenic animal models. In one proof-of-principle study with the CMT rat, a synthetic antagonist of the nuclear progesterone receptor was shown to reduce PMP22 overexpression and to ameliorate the clinical severity. In another study, administration of ascorbic acid, an essential factor of in vitro myelination, prolonged the survival and restored myelination of a dysmyelinated mouse model. Application of gene expression analysis to nerve biopsies that are readily available from such CMT1A animal models might identify additional pharmacological targets.