X-linked Charcot-Marie-Tooth disease

Abstract

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive muscle atrophy and weakness, areflexia, and variable sensory abnormalities; central nervous system manifestations occur, too. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and distal axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. More than 400 different mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32), cause CMT1X. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. An effective therapy remains to be developed.

Figure 1

CMT1X mutants. This schematic shows the basic structure of Cx32, which has four transmembrane domains, one intracellular and two extracellular loops, as well as an amino- and a carboxy-terminal cytoplasmic tail. The GJB1 mutations of the coding region are indicated, more than 400 altogether (http://www.molgen.ua.ac.be/CMTMutations/Mutations/MutByGene.cfm).