Rett syndrome: The Natural History Study journey

Abstract Understanding clinical features and disease progression of Rett syndrome (RTT) and establishing clinical trial readiness was enhanced by the RTT Natural History Study (NHS). The NHS benefited from two key developments: one, the Orphan Drug Act passed by Congress in 1983 defining criteria for rare disorders in the United States and creating opportunities for pharmaceutical companies to develop products for individuals with rare disorders, and two, the Rare Diseases Act of 2002, which established the National Institutes of Health Office of Rare Diseases and provided research funding. Funding for the RTT and related disorders NHS was obtained in 2003, creating a broad network of experienced clinical investigators across the United States and producing critical results not only for RTT but also for related disorders: CDKL5 deficiency disorder, FOXG1 disorder, and MECP2 duplication syndrome. Longitudinal information from over 1800 participants (more than 1600 diagnosed with RTT) led to multiple reports describing their clinical features and natural progression and identified putative biomarkers and clinical outcome measures. Establishing clinical trial readiness assisted in evaluating the first FDA‐approved medication for RTT in 2023 and continues to provide opportunities to develop potentially life‐altering therapies. The experiences of the RTT NHS journey provide informative guidance for studying other rare neurological disorders. These lessons include positive features of developing productive collaborations focused on improving lives of people and families with RTT and related disorders, as well as lessons learned through retrospective analysis for improving overall conduct of natural history studies in rare disorders.