Pre-clinical evaluation of the early sensory-motor development in Rett syndrome

Rett Syndrome (RTT) is a rare, incurable neurological disorder affecting primarily females carrying de novo mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), located on the X-chromosome. A wide spectrum of MECP2 mutations can cause RTT, resulting in miscellaneous phenotypical manifestations mainly affecting motor, cognitive and social skills. Patients exhibit a peculiar clinical progression: after an apparently normal prenatal and perinatal period, a regression of acquired skills occurs. Due to the late onset of overt symptoms, the diagnosis occurs late in infancy, preventing early interventions that could mitigate the onset and progression of the symptomatology and thus guarantee a better prognosis for RTT patients. Much evidence, however, points to the presence of subtle alterations early in development, although clear clinical evidence is limited due to the condition’s rarity and lack of heritability. Exploiting the availability of highly validated RTT murine models carrying the most frequent RTT-causing MECP2 mutations, the present study aimed to perform a standardized characterization of the early sensory motor development during the first two postnatal weeks. We provide evidence that early subtle and transient alterations preceding the onset of overt symptomatology can be detected in RTT mouse models well before the onset of overt symptoms. However, an high variability among RTT models was observed in the developmental profile, confirming that the type and localization of the MeCP2 mutation affect the phenotypic manifestation, even in early development. The alterations identified in this study could provide insight into potential early clinical signs, leading to an anticipation of the diagnosis and 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).