New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Confe...

Lysosomal storage diseases are characterized by deficiencies in lysosomal enzymes, allowing accumulation of target substrate in cells and eventually causing cell death. Enzyme replacement therapy is the principal treatment for most of these diseases. However, these therapies are often complicated by immune responses to the enzymes, blocking efficacy and causing severe adverse outcomes by neutralizing product activity. It is thus crucial to understand the relationships between genetic mutations, endogenous residual enzyme proteins (cross-reactive immunologic material), development of neutralizing antibodies and their impact on clinical outcomes of lysosomal storage diseases. For patients in whom neutralizing antibodies may cause severe adverse clinical outcomes, it is paramount to develop tolerance inducing protocols to preclude, where predictable, or treat such life-threatening responses.

We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics. This article reviews initiatives of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR) that are aimed at catalyzing rare diseases research. These initiatives fall into two groups: Promoting information sharing; and building multi-disciplinary multi-stakeholder collaborations. Among ORDR’s information sharing initiatives are GARD (The Genetics and Rare Diseases Information Center), RaDaR (The Rare Diseases Registries Program) and the NCATS Toolkit for Patient-Focused Therapy Development (Toolkit). Among the collaboration initiatives are the RDCRN (Rare Diseases Clinical Research Network), and the NCATS ORDR support for conferences and workshops. Despite the success of these programs, there remains substantial work to be done to build enhanced collaborations, clinical harmonization and interoperability, and stakeholder engagement so that the recent scientific advances can benefit all patients on the long list of rare diseases waiting for help.

A framework for the investigation of rare genetic disorders in neuropsychiatryThe MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. CitationSanders, Stephan J. et al. "A framework for the investigation of rare genetic disorders in neuropsychiatry." Nature Medicine 25, 10

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction, Molecular Genetics and Metabolism (2015), doi: 10.1016/j.ymgme.2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The opinions presented herein are those of the authors and do not reflect the positions of all participants nor the institutions they represent. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT