MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders

Background: Mutations in the MECP2 gene (methyl-CpG-binding protein-2) are responsible for 60-95% of cases of Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder affecting mostly girls. Classic RTT is characterized by normal early development followed by psychomotor regression and onset of microcephaly, although variant forms are also observed. MECP2 has also been implicated in variable mental retardation (MR) phenotypes, including X-linked Mental Retardation (XLMR), Fragile-X-like Syndrome (FXS) and Angelman-like (AS) phenotypes.

Aim: The aim of the study was: (a) to evaluate the incidence and spectrum of MECP2 mutations in children with RTT and variant MR; (b) to evaluate phenotype-genotype correlations.

Methods: Exons 3-4 were analyzed for mutations in 281 MR patients (aged 13 months-27 years old, 144 males-137 females) consisting of 88 patients referred for RTT and 193 patients referred for AS-like and FXS-like types of MR. Statistical analysis included correlation between classic MECP2-positive and MECP2-negative and variant RTT patients, and frequency of MECP2 mutations in the various categories.

Results: Mutations were detected in ≈ 70% of classic and ≈ 21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. MECP2-positive females had more problems in ambulation, muscle tone, tremor and ataxia, respiratory disturbances, head growth, hand use and stereotypies. Classic RTT-positive versus negative had significant respiratory and sitting problems and versus variant RTT-positive females ambulatory, hand and stereotypies problems.

Conclusion: The analysis of the MECP2 gene could provide a diagnostic tool for RTT and non-specific MR research.