Abstract
BACKGROUND: To characterize frequency, timing, and trajectory of gain, loss, and regain of developmental skills in Classic Rett syndrome (RTT). METHODS: The frequency and timing of gain, loss, and regain of 51 developmental skills from 1228 females with Classic RTT and a pathogenic loss-of-function variant in MECP2 was assessed during in-person visits from participants enrolled in the US Natural History Study. The percentage of participants experiencing gain, loss, or regain events, mean and median age of event and time to event with confidence intervals, and the cumulative incidence curves were calculated and compared to normative data using SPSS v29.0.2.0. One-year incidence of either gain or regain of each skill from 0-20 years old and one-year incidence of either gain or regain of any of 51 developmental skills was calculated. RESULTS: The acquisition of skills was greatest for lower-level skills and conversely lowest for more advanced skills. Acquisition of skills peaked at 6 years. Skill loss occurred mainly within 2 years of acquisition. Loss of fine motor, communication, and social adaptive skills changed little after age 6 years. The regain of lost skills involved less than 30% of fine motor, communication, and social adaptation. Regain of skills generally ceased by age 6 years. CONCLUSION: These results provide critical endpoints essential for conducting clinical trials in RTT. The lack of acquisition of skills beyond age 6 years and absence of loss or regain of previously lost skills, aside from gross motor features, beyond 6 years suggest that functional gains in these realms would represent important indicators of efficacy.