3 GENES, 4 DEMYELINATING PERIPHERAL NEUROPATHIES - FIRST GENOTYPE PHENOTYPE CORRELATIONS/

In most vertebrates, axons are usually ensheathed by myelin, a multi-l amellar structure that ensures the fidelity of nerve transmission and increases considerable nerve conduction velocity along the fibers. In the peripheral nervous system (PNS), myelin is formed by the extension of the plasma membrane of Schwann cells that wrap in spiral as many a s 50 lavers of double membrane structures around the axon. The myelin sheaths consist mostly of compact myelin that expresses a distinct set of structural proteins, namely myelin protein zero (PO), which is the most abundant component, peripheral myelin protein 22 (PMP22) and mye lin basic protein. PNS compact myelin is interrupted by regions filled with cytoplasm, the incisures of Schmidt-Lanterman. These and the par anodal regions of Schwann cells express a distinct set of proteins tha t include myelin-associated glycoprotein and connexin 32 (Cx32). It ha s now been demonstrated that genetic abnormalities in the genes encodi ng PMP22, P0 and Cx32, are responsible for the vast majority of demyel inating peripheral neuropathies, known as Charcot-Marie-Tooth disease type 1, X-linked Charcot-Marie-Tooth, Dejerine-Sottas syndrome, heredi tary neuropathy with liability to pressure palsies and congenital hypo myelination, PMP22 is an integral membrane protein whose function is s till poorly understood. P0 is a cell adhesion protein that contributes a sort of adhesive tape that holds together the extracellular leaflet s of compact myelin. Cx32 is a channel-forming protein that is thought to provide the basis for a radial diffusional pathway of signaling mo lecules and metabolites the myelin layers. Recent studies on the molec ular structure and cell biology of these three pivotal proteins for my elin homeostasis have begun to shed light on some of the pathophysiolo gical mechanisms that are specific to each syndrome.