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ABSTRACT: The study of the morphological phenotypes in patients with different mutations of the PMP22 gene gives additional insights into the role of the protein in myelin function. The pathology in young patients is in some aspects different from the pathology in older patients, providing essential and additional information about the early disease processes in humans induced by different PMP22 mutational mechanisms.

Duplication of chromosome 17p11.2, causing an overexpression of the PMP22 gene, results in early hypermyelination. This suggests that PMP22 has a function in establishing the proper myelin thickness, probably in response to an axonal signal. Demyelination and remyelination with gradual formation of onion bulbs occur apparently as secondary processes, but these processes subside at the end of the first decade. PMP22 missense mutations usually result in a more severe phenotype showing an early hypomyelination and onion bulb formation, likely disturbing normal myelin formation and maintenance. The morphological differences with duplication cases underline the essential difference in pathogenesis between duplication and missense mutations despite the large overlap in clinical and electrophysiological phenotypes. The reciprocal deletion of chromosome 17p11.2, resulting in an underexpression of the PMP22 gene, is responsible for the clinical phenotype of HNPP. As the nerve abnormalities in HNPP show a marked resemblance to the changes in experimental and genuine human entrapment neuropathies, it is postulated that PMP22 has a function in adhesion of myelin lamellae, preventing mutual longitudinal sliding. Deletion of one PMP22 copy results in increased susceptibility for mechanical forces through which already minor nerve injuries might induce a longitudinal displacement of myelin lamellae. The frame shift mutation Gly94(insG) combines a loss of function like in the common deletion HNPP with a mild CMT1 phenotype, likely inducing a (mild) toxic gain of function by disturbing myelin formation and maintenance, comparable to the effect in missense mutations.