Beating the diagnostic clock: investigating sensory-motor alterations in mutant mice as early signs of Rett syndrome.

Rett syndrome (RTT) is a rare, still incurable, neurodevelopmental disorder, affecting mainly females, caused by de novo mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). It results in severe intellectual disability, motor dysfunction and peripheral comorbidities. RTT follows a peculiar progression. After a perinatal period of apparently normal development lasting until 6-18 months, patients experience a regression phase in motor, cognitive and autonomic skills. RTT is diagnosed around 2 years of age when clear symptoms lead to genetic screening. Increasing evidence has revealed subtle psychomotor alterations in newborns who later develop RTT, opening the possibility to exploit these signs for an earlier diagnosis. The phenotypic variability due to different RTT-causing MECP2 mutations and the rare prevalence of RTT however hampers systematic developmental studies on patients. Exploiting the experimental standardization offered by mouse models, this study aims to characterize somato-sensory and motor development of RTT during early postnatal phases. Mice from different transgenic lines, carrying the most common RTT-causing MECP2 mutations and mimicking the associated phenotypical manifestations, were tested during the first two postnatal weeks, alongside wild-type littermates as controls. We present the first systematic comparison of the early phenotype of different RTT mouse lines, showing mild and transient impairments in somato-sensory reflex acquisition as well as motor ability development, before obvious symptom onset. Significant variability in RTT model developmental profile was observed across Mecp2-mutated models, thus suggesting that phenotypic manifestations tightly depend on the type and localization of the Mecp2 mutation, also in early development. Our results could serve as a valuable starting point for translational studies aimed at exploiting early alterations as clinical tools for anticipating RTT diagnosis, ultimately leading to timely treatment intervention. Funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (code PNRR-MR1-2022-12376808).