Molecular analysis of the litaf/simple and prx genes in patients with demyelinating charcot‐marie‐tooth (CMT) disease

Mutations in the GJB1/Cx32 gene (Xq13.1) cause the most common X‐linked form of CMT (CMTX1) and are the most frequent cause of CMT disease after the CMT1A duplication. The disorder is characterized by a moderate‐to‐severe neuropathy in affected males and mild‐to‐no symptoms in carrier females. We report here a CMT1A‐negative family in which 4 females and 2 males were affected, exhibiting different disease severity. Molecular analysis of the GJB1/Cx32 gene uncovered a nonsense mutation (Arg22stop) in exon 2. The mutation, which had been previously described by others and observed by us in numerous other families, occurred in heterozygous form in the 4 females. However, while one of the two male patients was severely affected and shown to be hemizygous, as expected, the other was mildly affected and found to carry the mutation in heterozygous form. Genotyping at the SRY (Yp11.3) and DMD (Xp21) loci suggested the occurrence of the XXY genotype associated with Klinefelter syndrome. Microsatellite analysis indicated that the nondysjunctional error was of paternal origin, as it is usually observed in about half the cases. The patient had no children. At clinical examination, he exhibited a very mild neurologic phenotype and showed signs of hypogonadism (mild gynecomastia and small testes) as well as moderate cognitive impairment. Electrophysiologic, cytogenetic and endocrinologic investigations are in progress in order to define the unusual phenotype in this patient.