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People with Rett syndrome (RTT) have abnormal psychomotor skill development manifested by delay or failure to acquire skills, loss of skills, and potential regain of lost skills. This study aimed to provide detailed characterization of the frequency, timing, and trajectory of gain, loss, and regain of developmental skills in RTT. The occurrence and time of gain, loss, and regain of 51 developmental skills was collected during in-person visits in the RTT Natural History Study from 1228 females with Classic RTT and a pathogenic loss-of-function variant in MECP2. 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. One-year incidence of either gain or regain of each skill from 0 to 20 years old and one-year incidence of either gain or regain of any of 51 developmental skills was calculated. Across skill domains, acquisition occurred more frequently for lower-level skills than more advanced skills, with a median age of gain before 2 years old and rarely after 6 years old. Loss of previously gained skills occurred in all skill domains, with highest frequency in fine motor and expressive language domains. For most skills, loss occurred early in life and within 2 years of gain, except for loss of gross motor skills which occurred at older ages and further from age of gain. Regain of lost skills was infrequent for most skills, occurred mainly before 6 years old, and within 2 years of loss. After 6 years old, the incidence of either gaining or regaining skills was low. These results reveal that most skill gain, loss, and regain in RTT occurs early in life and stabilizes after 6 years old, except for the continued loss of gross motor skills beyond 6 years. The lack of gain or regain of skills beyond 6 years old suggest that any functional gains in these skills after a clinical intervention would represent an important indicator of efficacy as a clinical trial endpoint in RTT.