CORRELATION BETWEEN THE HISTOPATHOLOGIC, GENOTYPIC, AND PHENOTYPIC FEATURES OF HEREDITARY PERIPHERAL NEUROPATHIES IN CHILDHOOD

In recent years, there have been remarkable advances in the understand ing of the molecular genetic basis of the hereditary polyneuropathies. Linkage of the genes for Charcot-Marie-Tooth disease to chromosomes 1 and then 17 was followed by the discovery that the commonest form of Charcot-Marie-Tooth disease (CMT1A) was due to a duplication of DNA at 17p11.2-12. This duplication was shown to contain the gene for periph eral myelin protein PMP22. The finding that mutations of the myelin pr otein PMP22 gene were present in some Charcot-Marie-Tooth disease case s lacking the duplication confirmed the myelin protein PMP22 gene as t he site of the defect in Charcot-Marie-Tooth disease. Similarly, defec ts of the myelin protein P-o gene on chromosome 1 have been demonstrat ed in a rarer form of Charcot-Marie-Tooth disease (CMTIB). A deletion of DNA at 17p11.2-12 results in the disorder hereditary neuropathy wit h Liability to pressure palsies. Other mutations of the myelin protein PMP22 and myelin protein P-o genes have been associated with the clin ical syndrome known as Dejerine-Sottas disease. An X-linked form of Ch arcot-Marie-Tooth disease (CMTX) has been characterized and shown to b e due to mutations of the gap junction protein, connexin 32. Transgeni c murine models with inactivated myelin protein PMP22 and myelin prote in P-o genes have shown pathologic changes strikingly similar to those seen in human patients with disturbances of those genes. In this pape r, the clinical and histopathologic characteristics of these condition s are discussed in relation to the genotypic basis. It will be argued that there is still an important place for the clinician and nerve pat hologist in a medical world immersed in the wonders of molecular genet ics.