Molecular basis of inherited neuropathies.

Considerable advances in our knowledge of the most frequently encountered group of inherited neuropathies, Charcot-Marie-Tooth neurpathy (CMT) and related disorders, have recently been made by genetic studies demonstrating that these disorders are caused by duplication, deletion or point mutations of specific genes of the peripheral myelin. The present classification of CMT and related disorders is based on a combination of clinical, neurophysiological, and genetic findings, and new genes and distinct mutations responsible for different clinical phenotypes are continuously being added. The genes that encode peripheral myelin protein of 22 kDa, protein zero, connexin-32 and early growth response-2 are the genes known to be involved in the pathogenesis of inherited neuropathies. Overexpression or underexpression of peripheral myelin protein of 22 kDa are causative for the most frequent forms of CMT-CMT1A and hereditary neuropathy with liability to pressure palsies--but the mechanisms that lead to incorrect myelin formation and maintenance are still unknown. Point mutations in the myelin genes can determine a loss of function, but in some cases an aberrant protein can act through a dominant negative or a toxic gain of function mechanism, disrupting the regular and precise relationship between the different myelin genes. Animal and in-vitro models of inherited neuropathies have been developed and will probably give the information that is necessary to clarify the pathogenetic mechanisms of demyelination.