The CNS phenotype of X-linked Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is the second most common form of inherited demyelinating neuropathy, next to CMT type 1A, which is caused by duplication of the PMP22 gene.1 CMTX is caused by mutations in GJB1, the gene encoding connexin32 (Cx32), which belongs to a highly conserved family of proteins that form gap junctions in vertebrates. Myelinating Schwann cells express Cx32, which likely forms gap junctions between the layers of the myelin sheath, thereby providing a shorter pathway for the diffusion of small molecules and ions directly across the myelin sheath.2 Oligodendrocytes also express Cx32, which participates in the gap junction coupling of oligodendrocytes and astrocytes.3

More than 240 different GJB1 mutations have been described (http://molgen-www.uia.ac.be/CMTMutations/DataSource/MutByGene.cfm). Most patients with CMTX, including those with a deletion of the GJB1 gene, have a similar degree of neuropathy, indicating that most mutations probably cause a loss of function.1 In agreement, many Cx32 mutants do not form functional gap junctions,4 often related to their aberrant trafficking to the cell membrane.5 In addition to their peripheral neuropathy, many patients have asymptomatic evidence of brain involvement, such as abnormal brainstem auditory evoked responses (BAER).6,7⇓ Patients have also been found to have abnormal brain MRI results in association with transient CNS symptoms.8-11⇓⇓⇓ Here, we report a patient who had two episodes resembling acute demyelinating encephalomyelitis (ADEM), the first episode preceding the diagnosis of CMTX.