Rett syndrome: Methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that manifests in females, typically after the first year of life. It is a leading cause of mental retardation and autistic behavior in girls and women; a hallmark of the disease is incessant hand movements in the form of wringing, twisting, or clapping. It was recently discovered that RTT is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. MECP2 assists in the transcriptional silencing process via DNA methylation; we hypothesize that disruption of this gene alters the normal developmental expression of various other genes, some of which must account for the peculiar neurologic phenotype of RTT. Molecular studies have identified MECP2 mutations in up to 80% of classic RTT patients; mutation type has some effect on the phenotypic manifestation of RTT, but the pattern of X inactivation seems to determine phenotypic severity. Favorable (skewed) X inactivation can so spare a patient from the effects of mutant MECP2 that they display only the mildest learning disability or no phenotype at all. The unmitigated impact of mutant MECP2 can be inferred from the few males who have been born into RTT kindreds with such severe neonatal encephalopathy that they did not survive their second year. MECP2 mutations thus manifest in a far broader array of phenotypes than classic RTT. This discovery should prove helpful in diagnosing cases of mild learning disability or severe neonatal encephalopathies of unknown cause and also should provide insight into the pathogenesis of RTT.