Huda Zoghbi

The Kavli Symposia

"The Story of Rett Syndrome: Where Epigenetics Meets Neurobiology"

Rett syndrome is a postnatal developmental disorder characterized by stagnation of normal development and loss of acquired skills by 12-18 months of age. Although Rett syndrome is sporadic in over 99% of the cases, it is a genetic disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Loss of MeCP2 function in ~50% of neurons (due to random X chromosome inactivation [XCI]), causes classic Rett syndrome which is characterized by loss of language and social interaction skills, cognitive impairment, balance problems, seizures, tremors, stereotyped repetitive hand movements, and autonomic dysfunction. Girls with favorable XCI patterns manifest only partial features of the syndrome and may present with either classic autism or mild learning disability. Doubling of MeCP2 levels also causes a progressive neurological syndrome that shows overlapping features with Rett syndrome. The use of accurate genetic models of Rett and the duplication syndrome is providing insight into the pathogenic effects of MeCP2 dysfunction. Data demonstrating the role of MeCP2 in specific neurons, the transcriptional alterations resulting from MeCP2 dysfunction, and potential approaches to modulate the neuropsychiatric phenotypes will be presented.