title: X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).
abstract: The sensorimotor neuropathy of the Charcot-Marie-Tooth type (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein connexin32. We examined four CMTX pedigrees two of which had potentially novel mutations in the only coding exon of connexin32. One previously unreported missense mutation, Ala39Val, was found in a family displaying a CMT phenotype with additional upper limb postural tremor reminiscent of a Roussy-Lévy syndrome. A novel single base insertion, 679insT, is among the first mutations found in the fourth transmembrane domain of connexin32. Frameshift and premature stop of translation are supposed to result in a non-functional carboxy-terminus. Two further families had the known missense mutations Arg15Trp and Arg22Gln. Several female carriers were found normal on clinical presentation, however, the genotype was paralleled by decreased nerve conduction velocities (NCV) and slowed central conduction of brain stem auditory evoked responses (BAER). Median motor NCVs showed mild (in women) to intermediate (in males) reduction, indicating a peripheral neuropathy with a predominating axonal component. Nerve biopsy findings were consistent with the electrophysiological data showing a marked loss of large myelinated fibres and clusters of regenerating axons. Electron microscopy revealed various alterations of the axoglial attachment zone. This suggests defective axon-Schwann cell interactions which may induce the axonopathy in CMTX.
authors.affiliation: Institut für Neuropathologie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule, Pauwelsstrasse 30, D-52074, Aachen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Senderek
authors.forename: B
authors.initials: B
authors.lastname: Hermanns
authors.forename: C
authors.initials: C
authors.lastname: Bergmann
authors.forename: B
authors.initials: B
authors.lastname: Boroojerdi
authors.forename: M
authors.initials: M
authors.lastname: Bajbouj
authors.forename: M
authors.initials: M
authors.lastname: Hungs
authors.forename: V T
authors.initials: VT
authors.lastname: Ramaekers
authors.forename: S
authors.initials: S
authors.lastname: Quasthoff
authors.forename: D
authors.initials: D
authors.lastname: Karch
authors.forename: J M
authors.initials: JM
authors.lastname: Schröder
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D020090:Chromosome Segregation; D017630:Connexins / Q000235:genetics*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology*; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014960:X Chromosome; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D000097002:Gap Junction beta-1 Protein