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.

Patients with Phenylketonuria (PKU) reportedly have decreased bone mineral density (BMD). The primary aim of this study was to perform a systematic review and meta-analysis to determine the extent and significance of low BMD in early treated patients with PKU. Secondary aims were to assess other bone status indicators including bone turnover markers (BTM) and to define areas for future research. Two research teams (Amsterdam, Netherlands and Atlanta, USA) performed literature searches for articles reporting data on BMD, osteopenia and osteoporosis, BTM or other bone indicators in patients with PKU. Included articles were compared between research teams and assessed for quality and risk of bias. A total of 13 unique articles were included; 11/13 articles reported BMD including a total of 360 patients. Ten out of 11 articles found BMD was significantly lower in patients with PKU. Meta-analyses for total BMD (TBMD; 3 studies; n = 133), lumbar spine BMD (LBMD; 7 studies; n = 247), and femoral neck BMD (FBMD; 2 studies; n = 78) Z-scores were performed. Overall effect sizes were: TBMD −0.45 (95% CI −0.61, −0.28); LBMD −0.70 (95% CI −0.82, −0.57); FBMD −0.96 (95% CI −1.42, −0.49). Definitions of osteopenia and osteoporosis were highly heterogeneous between studies and did not align with World Health Organization standards and the International Society for Clinical Densitometry positions on BMD measurement. Despite individual study findings of low BMD indicating higher risk of osteoporosis, pooled available data suggest reduction in BMD is not clinically important when using standard definitions of low BMD. Results from studies evaluating BTM are inconclusive. Phenylalanine concentration, vitamin D, PTH, and nutrient intake do not correlate with BMD or BTM. We recommend forthcoming studies use standard definitions of low BMD to determine clinical implications of BMD Z-scores below 0, explore cause of low BMD in the subset of patients with low BMD for chronological age (Z-score < −2) and assess fracture risk in patients with PKU.

Background: Sapropterin dihydrochloride effectively lowers plasma phenylalanine (Phe) for at least a third of phenylketonuria (PKU) patients, with potential for increased dietary Phe tolerance and decreased medical food requirement. Objective: To investigate long-term quality of life (QOL) in patients with phenylketonuria (PKU) who took sapropterin (BH4, Kuvan®) for up to one year. Methods: 37 PKU patients, ages 10–49 years, were asked to complete a PKU-specific self-report QOL questionnaire (QOLQ) at baseline, 1, 4, 8, and 12 months. Questions were scored on a 5-point Likert scale under 5 sub-sections measuring Impact, Worries, Satisfaction, Support, and General wellbeing in relation to PKU. Responders with a plasma Phe decrease ≥ 15% after 1 month on sapropterin remained on the drug; Nonresponders ceased sapropterin after the trial month. Responders able to relax medical diet and maintain plasma Phe control were classified as Definitive; Responders unable to relax medical diet were classified as Provisional. All patients were routinely monitored by a registered dietitian. Data was analyzed in SPSS 19.0 using regression techniques. Results: Of 17 Responders, 11 could maintain adequate Phe control on a less restrictive diet. One year mean Impact sub-score trends improved significantly for all sapropterin response groups, with greatest improvement among Definitive Responders (p < 0.0001). Satisfaction sub-scores also improved for Definitive Responders (p = 0.001). Trends for Total QOL score improved significantly over time for both Definitive (p = 0.001) and Provisional Responders (p = 0.028). Improvements in Definitive Responder scores were associated with increased Phe tolerance (Impact: p < 0.0001, Satisfaction: p = 0.022, Total QOL: p = 0.005) and MF adjustment (Satisfaction: p = 0.014, Total QOL: p = 0.026). Other sub-section scores remained steady, unaffected by sapropterin response or diet modification. Conclusion: Increased Phe tolerance and reduced MF requirement in sapropterin Definitive Responders improves QOL perception across one year, specifically for life impact and satisfaction.

Primary care physicians (PCPs) are considered the gatekeepers of genetic services, but they often underutilize or inappropriately utilize such services, leading to lack of early treatment, incorrect diagnoses, and unnecessary procedures. This study aims to delineate PCP referral patterns, including the frequency of, motivators for, and barriers to genetic referrals and testing in the present landscape of genomics. A 34-item online survey was distributed to PCPs in the United States (US). PCP demographics, practice characteristics, and referral patterns, motivators, and barriers were analyzed. Six hypothetical clinical scenarios included in the survey also were presented to a cohort of clinical geneticists. We calculated PCPs’ rates of ordering genetic tests and of referral to genetics services in the past year. Rates and responses to clinical scenarios were compared based on respondents’ personal and practice characteristics. A total of 95 PCPs and 25 clinical geneticists participated. Among the PCPs, 79% reported referring and 50% reported ordering genetic testing in the last year. PCPs with genetic counselors (GCs) in their clinic referred at significantly higher rates than those without (P = .008). White PCPs referred at significantly higher rates compared to Black or African American PCPs (P = .009). The most commonly reported motivators for referring patients to genetic services were preference for specialist coordination, lack of knowledge, and family’s desire for risk information. The most commonly reported barriers were patient refusal, provider concerns about costs to patients, and uncertainty of when a genetic referral is appropriate. In response to clinical scenarios, clinical geneticists were in agreement about the need for genetic testing or referral for 2 of the scenarios. For these 2 scenarios, only 48% and 71% of PCPs indicated that they would offer genetic testing or referral, respectively. Responses to clinical scenarios suggest that it is not clear to PCPs when referrals or testing are needed. Collaboration with GCs is one approach to reducing barriers to and improving PCPs’ utilization of genetic services. Clear guidelines from clinical geneticists may help facilitate appropriate use of genetics services by PCPs. Additional research is needed to further describe barriers that PCPs face in genetic testing/referrals.