5th Workshop of the European CMT Consortium, 69th ENMC International Workshop: Therapeutic approaches in CMT neuropathies and related disorders 23–25 April 1999, Soestduinen, The Netherlands

Abstract

Inherited demyelinating neuropathies are chronic disorders of the peripheral nervous system that cause muscle weakness, clumsiness in walking and sensory dysfunction. The disorders are mostly of dominant inheritance with a prevalence of 1/2.500. So far, four genes have been identified that are related to these disorders, including the peripheral myelin protein 22 (PMP22), the myelin protein zero (MPZ, P0), the gap junction protein connexin 32 (Cx32,GJB1), and the early growth response 2 transcription factor (EGR2). Dependent on the mutated gene and on the severity of the resulting disorder, different subforms can be distinguished. A duplication of or mutations in PMP22 causes the demyelinating Charcot–Marie–Tooth disorder type 1A (CMT1A), whereas some other mutations in this gene are associated with a particularly severe dysmyelinating neuropathy, the Dejerine–Sottas syndrome (DSS). Mutations in P0 can cause three different inherited neuropathies, CMT1B, DSS or congenital hypomyelination (CH). Cx32 is the culprit gene for CMTX, the X-chromosome linked, dominant form of the CMT disorders. Mutations in EGR2 have recently been identified to be associated with CMT1, DSS and CH. Although recent years have seen a profound increase in the knowledge about the culprit genes and their putative roles [1], the inherited neuropathies are still untreatable. Since most of the diseases are not only significantly disabling, but also lead to irreversible degenerative processes, such as muscle atrophy, treatment strategies are urgently needed. A common histopathological feature in nerve biopsies is the presence of abnormal myelin sheaths and reduced numbers of myelin profiles. Electrophysiologically, the disrupted myelin formation or myelin degeneration is reflected by lowered nerve conductions, increased muscle response latencies and dispersed compound action potentials. In addition, the disorders are often associated with reduced amplitudes of compound action potentials, a feature that is rather indicative of compromised axon properties than of myelin disruption. Axonal abnormalities or damage is of particular interest, since dysfunction of axons will have robust clinical consequences. Particularly in lower limbs, irreversible degenerative processes such as muscle atrophy are the typical consequence of axon damage and the increasing loss of muscle strength results in malformation of the skeleton. In severe cases, such changes manifest in wheel-chair dependency, scoliosis and reduced life span.