ABSTRACT
Rett syndrome (RTT), an X-linked neurodevelopment disorder, occurs in approximately one out of 10,000 females. Individuals afflicted by RTT display a constellation of signs and symptoms, affecting nearly every organ system. Most striking are the neurological manifestations, including regression of language and motor skills, increased seizure activity, autonomic dysfunction, and aberrant regulation of breathing patterns. The majority of girls with RTT have mutations in the gene encoding for methyl-CpG binding protein 2 (MeCP2). Since the discovery of this genetic cause of RTT in 1999, there has been an accelerated pace of research seeking to understand the role of MeCP2 in the brain in the hope of developing a disease-modifying therapy for RTT. In this study, we review the clinical features of RTT and then explore the latest mechanistic studies in order to explain how a mutation in MeCP2 leads to these unique features. We cover in detail studies examining the role of MeCP2 in neuronal physiology, as well as recent evidence that implicates a key role for glia in the pathogenesis of RTT. In the past 20 years, these basic and clinical studies have yielded an extraordinary understanding of RTT; as such, we end this narrative review considering the translation of these studies into clinical trials for the treatment of RTT.