Racing against time for the early diagnosis of Rett syndrome: evaluation of post-natal sensory-motor development in mouse models

Rett syndrome (RTT) is an incurable, rare female-prevalent neurological disorder affecting motor, cognitive and social skills. It is caused by de-novo mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), located on the X chromosome. RTT presents a peculiar clinical progression: after an apparently normal prenatal and perinatal period, a regression of acquired skills occurs. Given the late onset of overt symptoms, the diagnosis occurs around 2 years. Much evidence however points to the presence of an early time window in which subtle, but reliable, alterations can be found. The characterization of such early impairments would allow an anticipation of the age of diagnosis. While this is made difficult by the rare prevalence of the disease and the phenotypical variability caused by different RTT-causing MECP2 mutations, the availability of validated RTT murine models offers the opportunity to carry out a standardized characterization of the early phases of ontogenetic development. By exploiting different mouse models of RTT that recapitulate the most frequent RTT-causing MECP2 mutations, along with wild-type littermates, a test battery specifically tailored to evaluate the sensory-motor development was applied during the first two postnatal weeks. We demonstrate the presence of subtle and transient alterations in the sensory-motor development occurring before the onset of overt symptomatology. High variability was evidenced across the developmental profiles of the different RTT models, confirming that MeCP2 mutation type affects the phenotypic manifestation, even in early development. The alterations evidenced in the present study could inform on potential early clinical signs, opening the road to the anticipation of the diagnosis and the early treatment intervention in RTT. 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).