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.