Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients

Only recently have mutations in MECP2 been found to be a cause of Rett Synd rome (RTT), a neurodevelopmental disorder characterized by mental retardati on, loss of expressive speech, deceleration of head growth and loss of acqu ired skills that almost exclusively affects females. We analysed the MECP2 gene in 31 patients diagnosed with RTT. Sequencing of the coding region and the splice sites revealed mutations in 24 females (77.40%). However, no ab normalities were detected in any of the parents that were available for inv estigation. Eleven mutations have not been described previously. Confirming two earlier studies, we found that most mutations are truncating and only a few of them are missense mutations. Several females carrying the same mut ation display different phenotypes indicating that factors other than the t ype or position of mutations influence the severity of RTT. Four females wi th RTT variants were included in the study. Three of these presented with p reserved speech while the fourth patient with congenital RTT lacked the ini tial period of normal development. Detection of mutations in these cases re veals that they are indeed variants of RTT. They represent the mild and the severe extremes of RTT. Conclusions: mutations in MECP2 seem to be the mai n cause for RTT and can be expected to be found in similar to 77% of patien ts that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R2 55X) were confirmed and a further one (R270X) newly identified. We recommen d screening for these mutations before analysing the coding region.