Trajectory of skill acquisition, loss, and regain in females with classic Rett syndrome.

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 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.