Walking Capacity in Children With Ataxia Telangiectasia From the Global Ataxia Telangiectasia Family Data Platform.

Orphan (or rare) disorders, defined as conditions that affect less than one‐half of 1% of individuals in the United States, collectively afflict more than 30 million individuals and their families. Previously, rare disorders received limited attention for the development of new treatments due to an incomplete understanding of the biology of these disorders, limited financial incentives for drug developers and industry, and, importantly, a lack of detailed understanding of the clinical features and natural longitudinal progression within the individual rare disorders. Prior to 1983, only 38 drugs were developed for rare disorders (Rare Disease Act of 2002). However, passage of the Orphan Drug Act by Congress in 1983 () helped spur development of rare disease treatment by providing incentives for tax credits, waiver of expensive Food and Drug Administration (FDA) fees, and exclusive marketing. Additionally, this act established the Orphan Product Grants Program within the FDA and together with the National Organization for Rare Disorders (NORD) encouraged and enabled individuals with rare disorders and their families in the drug development process. Success of the act is evident by the approval of over 220 new drugs by 2002 coincident with the Rare Disease Act of 2002 and a wave of new therapies on the horizon. Despite this progress, the number of rare disorders with specific FDA‐approved drugs is small relative to the estimated total of 10 000 specific entities. Although the Orphan Drug Act of 1983 enabled FDA focus on rare disorders, broader emphasis on the study of these rare disorders received little additional attention at the national level until the National Institutes of Health (NIH) Office of Rare Diseases was created in 1993. Unfortunately, that office still lacked any statutory authority or budget to promulgate further study. Even worse, funding for rare disease research did not increase in parallel with the large increases in research funding for behavioral and biomedical research in general through the 1990s. This changed in 2002 with the passage of the Rare Diseases Act, which established the Office of Rare Diseases (ORD) within the Office of the NIH Director and provided necessary funding to increase research for the diagnosis and treatment of these rare disorders (Public Law 107‐280‐Nov. 6, 2002: Rare Diseases Act of 2002). One of the first initiatives of ORD was to request applications for Orphan Disease Natural History Studies in 2003. Under this mechanism, a proposal was funded principally through the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the NIH (HD061222) in cooperation with ORD to conduct natural history studies for three related neurodevelopmental disorders of childhood: Angelman syndrome (Beaudet, Baylor College of Medicine), Prader‐Willi syndrome (Driscoll, University of Florida), and Rett (RTT) syndrome (Percy, University of Alabama at Birmingham). As outlined below, the study evolved over time and in the third round of funding focused on RTT and RTT‐related disorders exclusively, no longer including Angelman or Prader‐Willi syndromes. This article focuses on the 16‐year experience of the RTT and RTT‐related disorders Natural History Study (NHS) component of this grant funding and describes the long and successful program to improve our understanding of the clinical features and longitudinal progression of RTT and RTT‐related disorders as well as the development of clinical trial readiness for these disorders.