Investigating Rett Syndrome Through Genetic Mouse Models: Presymptomatic, Clearly Symptomatic Phases, and Innovative Therapeutic Approaches

Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) have been found to be responsible for about 90% of classical RTT cases. After the discovery of a monogenic origin for RTT, several lines of mice carrying endogenous MeCP2 mutations have been generated. They have been reported to recapitulate several RTT symptoms. An overview on the behavioral domains so far investigated in RTT mouse models, including the very few mouse data concerning RTT developmental course are described. Evidence supporting the presence of early subtle deficits from both clinical and animal studies are reported. They suggest that probing the presymptomatic phase, for both the precocious identification of biomarkers and the early assessment of potential therapies, is extremely important. Innovative pharmacological (primarily targeting respiratory dysfunction) and nonpharmacological interventions (nutritional perinatal choline and environmental enrichment) so far carried out in RTT mouse models are also illustrated. Genetic interventions are reported that demonstrate the rescuing of the damage caused by the absence of MeCP2 even at a mature stage. The discovery of a monogenic origin for RTT has provided to research the necessary tools for understanding, and hopefully treating, this devastating syndrome. Future research efforts can therefore be anticipated to make significant progress towards providing a better quality of life for RTT patients.