Phenylketonuria Scientific Review Conference: state of the science and future research needs.

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 Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Medical Foods for Inborn Errors of Metabolism: History, Current Status, and Critical Need.

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.

OPRISK: a structured checklist assessing security needs for mentally disordered offenders referred to high security psychiatric hospital.

BACKGROUND: More mentally disordered offenders (MDOs) are referred to secure psychiatric care settings than are accepted for admission. Psychiatrists working in different care settings may disagree on the appropriate level of security for MDOs, resulting in treatment delay. A pre-admission structured assessment of security needs for MDOs may facilitate agreement and access to care. AIMS: To assess the predictive validity and reliability of a structured assessment of security need (OPRISK) in a prospective cohort of referrals to high security hospital. METHOD: Operationalized criteria describing risk factors related to security need were used to develop OPRISK, an 18 item checklist. The predictive validity of OPRISK was assessed prospectively on the outcome of 140 referrals to Broadmoor high security hospital. RESULTS: Receiver operating characteristic curves of the predictive validity of OPRISK yielded an area under the curve of 0.765 (p < 0.001, 95% CI: 0.686-0.844). Internal consistency (>0.75) and inter-rater reliability (0.925) were high. CONCLUSION: OPRISK makes the evidence for an MDO's security needs explicit, aiding communication across service settings and improving access to care.

Phenylketonuria (PKU): A problem solved?

Phenylketonuria (PKU) is a rare metabolic disorder characterized by impaired conversion of phenylalanine (Phe) to tyrosine. If left untreated, the resultant accumulation of excess blood Phe can cause physiological, neurological, and intellectual disabilities. The National PKU Alliance (NPKUA) conducted a survey of its membership to assess current health status and interest in new treatments for PKU. Of the 625 survey respondents, less than half (46.7%) reported blood Phe within (120-360 µmol/L) - the range recommended by the American College of Medical Genetics and Genomics (ACMG). The survey results also showed that younger (≤ 18 years) individuals were about 3-times as successful in keeping their blood Phe concentrations within the recommended clinical range compared with adults. Blood Phe over 360 µmol/L was reported in one-quarter (25.5%) of ≤ 18 year old individuals and almost two-thirds (61.5%) of adults. A little more than half (51.7%) of respondents reported having difficulty in managing their PKU, including the maintenance of a Phe-restricted diet. Individuals with PKU desire new treatments that would allow them to increase their intake of natural protein, discontinue or reduce their intake of medical foods (medical formula and foods modified to be low in protein), improve their mental health (including a reduction in depression and anxiety), and a reduction of their blood Phe concentrations. Respondents preferred oral administration of any newly developed therapies and, in general, disliked therapeutic injections. Injections at home were preferred over injections at a clinic. Payers, government agencies, clinicians, and industry partners should consider patient input when developing and approving new therapies and treatments for PKU.