X-linked Charcot Marie-tooth due to a c.475G> A mutation in the GJB1 gene in the Maltese population

Abstract

Introduction: X-linked Charcot Marie-Tooth (CMTX) is the second commonest type of hereditary motor and sensory neuropathy after CMTlA, occurring in approximately 10% of cases of Charcot Marie Tooth syndrome. CMTX1 - the commonest subtype of CMTX - is caused by mutations in the GJB1 gene. Methods: Patients with hereditary peripheral neuropathy attending the genetic clinic were asked to participate in the study. Clinical, electrophysiological, pedigree analysis and mutational data was collected on all. We identified 7 individuals from four families segregating the same mutation, a c.475G>A change in exon 2 of the GJB1 gene. The c.4 75G > A mutation has been reported previously in one patient and segregation studies were lacking. To determine whether the c.4 75G > A mutation is a polymorphism among the Maltese population, we analysed 400 random samples of cord blood from the Malta Biobank for the, presence of the mutation. Results: The c-475G>A mutation in the GJB1 gene was segregated in all affected members of the 4 families; both male and female family members carrying the mutation had symptoms and signs of polyneuropathy. The mutation was not identified in 400 random cord blood samples, confirming that it is not a polymorphism. The clinical and neurophysiological phenotype of the individuals with CMTX will be presented. Conclusion: CMTX seems to be a common cause of inherited peripheral neuropathy in Malta. The presence of the c-475G>A mutation in the GJB1 gene in all families might indicate a founder effect.