CLINICAL STUDIES AND ANALYSIS OF THE RETT SYNDROME GENE (MECP2) IN CHILDREN WITH MENTAL RETARDATION IN THE GREEK POPULATION

Abstract

INTRODUCTION: Mutations in the methyl CpG-binding protein 2 (MECP2) gene are responsible for 70% to 95% of cases of Rett syndrome (RS), an X-linked dominant neurodevelopmental disorder that mostly affects girls. Classical RS is characterized by normal early development followed by psychomotor regression and gradual onset of microcephaly, although variable atypical forms have also been observed. MECP2 has also been implicated in a variety of other mental retardation (MR) phenotypes, including X-linked MR, fragile X syndrome–like and Angelman syndrome (AS)–like phenotypes. OBJECTIVE: Our goals were to evaluate the incidence and spectrum of MECP2 mutations in children with RS and atypical MR and to correlate the phenotype and genotype. METHODS: Exons 3 and 4 of the MECP2 gene were analyzed by using denaturing gradient gel electrophoresis, sequencing, and gap polymerase chain reaction for (1) 124 children with FXS-like symptoms (102 boys, 22 girls) and 41 children with AS-like symptoms (14 boys, 27 girls) who tested negative for gene variation at the FXS and AS loci, respectively, (2) 23 girls with classical RS and 25 girls with atypical RS, and (3) 11 boys who were referred with possible RS. Statistical analysis (t and nonparametrical tests) included correlation of RS clinical severity score (Kerr, 2001) with MECP2 mutations and frequency of MECP2 mutations in the various patient categories. RESULTS: Mutations were detected in 78.3% of classical and 20% of atypical RS cases, respectively. One boy carried the p.R106W mutation, and another boy showed a large rearrangement that required further characterization. Among AS- and FXS-like cases, 7.3% and 2.4% had MECP2 mutations, respectively, including an X-linked MR case. CONCLUSIONS: MECP2 gene analysis provides an appropriate diagnostic tool for RS and contributes additional information for research into MR.