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...

Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment.

Inborn errors of metabolism (IEM) are genetic disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. In the U.S., many IEM are detected through state newborn screening (NBS) programs. To inform research on IEM and provide necessary resources for researchers, we are providing: tabulation of ten-year state NBS data for selected IEM detected through NBS; costs of medical foods used in the management of IEM; and an assessment of corporate policies regarding provision of nutritional interventions at no or reduced cost to individuals with IEM. The calculated IEM incidences are based on analyses of ten-year data (2001–2011) from the National Newborn Screening Information System (NNSIS). Costs to feed an average person with an IEM were approximated by determining costs to feed an individual with an IEM, minus the annual expenditure for food for an individual without an IEM. Both the incidence and costs of nutritional intervention data will be useful in future research concerning the impact of IEM disorders on families, individuals and society.