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.

Recommendations for the nutrition management of phenylalanine hydroxylase deficiency.

The effectiveness of a phenylalanine-restricted diet to improve the outcome of individuals with phenylalanine hydroxylase deficiency (OMIM no. 261600) has been recognized since the first patients were treated 60 years ago. However, the treatment regime is complex, costly, and often difficult to maintain for the long term. Improvements and refinements in the diet for phenylalanine hydroxylase deficiency have been made over the years, and adjunctive therapies have proven to be successful for certain patients. Yet evidence-based guidelines for managing phenylalanine hydroxylase deficiency, optimizing outcomes, and addressing all available therapies are lacking. Thus, recommendations for nutrition management were developed using evidence from peer-reviewed publications, gray literature, and consensus surveys. The areas investigated included choice of appropriate medical foods, integration of adjunctive therapies, treatment during pregnancy, monitoring of nutritional and clinical markers, prevention of nutrient deficiencies, providing of access to care, and compliance strategies. This process has not only provided assessment and refinement of current nutrition management and monitoring recommendations but also charted a direction for future studies. This document serves as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylalanine hydroxylase deficiency.

Nutritional therapy improves growth and protein status of children with a urea cycle enzyme defect.

BACKGROUND: Poor growth has been described in patients with urea cycle enzyme defects treated with protein-restricted diets, while protein status is seldom reported. OBJECTIVE: To assess the effects of nutritional therapy with a medical food on growth and protein status of patients with a urea cycle enzyme defect. METHODS: A 6-mo multicenter outpatient study was conducted with infants and toddlers managed by nutrition therapy with Cyclinex-1 Amino Acid-Modified Medical Food with Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome variables were anthropometrics and plasma amino acids (selected), albumin, and transthyretin concentrations. RESULTS: Seventeen patients completed the study. Mean (+/-SE) baseline age was 11.30+/-3.20 months (median 4.40 months; range 0.22-38.84 months). Length and weight z-scores increased significantly during the 6-month study. Head circumference increased, but not significantly. Three patients were stunted and two were wasted (-2.0 z-score) at baseline while at study end, only one patient was both stunted and wasted. The majority of patients increased in length, head circumference, and weight z-scores during study. Mean (+/-SE) plasma albumin concentration increased from 34+/-2g/L at baseline to 38+/-1g/L at study end. Plasma transthyretin increased from a mean (+/-SE) of 177+/-13 mg/L at baseline to 231+/-15 mg/L at study end. No correlation was found between plasma NH(3) concentrations and medical food intake. Plasma NH(3) concentration was positively correlated with the percentage of Food and Agriculture Organization/World Health Organization/United Nations recommended protein ingested. CONCLUSIONS: Intakes of adequate protein and energy for age result in anabolism and linear growth without increasing plasma NH(3) concentrations. Medical food intakes did not correlate with plasma NH(3) concentrations.

Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors.

PURPOSE: The purpose of the study was to determine the incidence of iron deficiency in children undergoing therapy for phenylketonuria using serum transferrin receptor and ferritin concentrations. METHODS: A 1-year study was conducted in 37 children 2 <13 years old with phenylketonuria (8 fed Periflex [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14 fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor, and ferritin concentrations were assessed at baseline and 12 months and intakes of protein, iron, and vitamin C were evaluated at baseline and at 3-month intervals. Transferrin receptor and ferritin concentrations were analyzed for group differences by analysis of variance. RESULTS: Mean protein, iron, and vitamin C intakes of all 3 groups of children were greater than Recommended Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children failed to contain 100% of Recommended Dietary Intakes for iron during study. The following number of children had iron status indices outside reference ranges at study end: 7 children, transferrin receptor/ferritin ratios; 4 children, transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation was found between iron intake and any index of iron status. CONCLUSIONS: The transferrin receptor/ferritin ratio appeared to be the most sensitive index of iron deficiency in this study. Reasons for iron deficiency with greater than recommended iron intakes by children with phenylketonuria may be multiple. Early assessment and therapy of iron deficiency may improve cognitive and behavioral outcomes of children with PKU.

Role of nutrition in pregnancy with phenylketonuria and birth defects.

OBJECTIVE: The maternal phenylketonuria (PKU) syndrome is caused by high blood phenylalanine (Phe) levels during pregnancy, leading to a host of birth defects, especially microcephaly and congenital heart disease (CHD). For finding whether the maternal PKU syndrome could be prevented, an international collaborative study was organized to evaluate treatment with a Phe-restricted diet. Blood Phe levels, maternal weight gain, and nutrient intakes during pregnancy were evaluated as to their effect on the rate of microcephaly and CHD in the offspring. METHODS: The study was a prospective, longitudinal effort aimed at lowering blood Phe during pregnancy. Women were enrolled at time of referral for pregnancy. Nutrient intake analysis, which serves as the basis for this report, was available from 251 pregnancies. Subjects were stratified by blood Phe control of < or =600 micromol/L by 8 weeks gestation or >600 micromol/L by 8 weeks gestation. Outcome of these pregnancies was correlated to blood Phe levels, weight gain, and nutrient intake. RESULTS: The study goal was to attain blood Phe levels of 120 to 360 micromol/L 3 months preconception; however, this goal was achieved by only a limited number of patients. Therefore, the data presented were based on blood Phe control < or =600 micromol/L or >600 micromol/L by 8 weeks of gestation. Blood Phe control of < or =600 micromol/L by 8 weeks of gestation was attained by 86 (34.3%) of the 251 women in this study, whereas the other 165 women had blood Phe control >600 micromol/L by 8 weeks of gestation. Of the 251 offspring, 166 were born with normal head circumference and 85 were born with microcephaly (<2 standard deviations below normal). Women with blood Phe >600 micromol/L at 8 weeks of gestation included 78 (92%) of the 85 infants with microcephaly compared with 8% in the group of women who had blood Phe levels < or =600 micromol/L. Weight gain during pregnancy was related to the rate of microcephaly. The highest occurrence of microcephaly (58%) was found in the pregnant women who gained <70% of recommended weight gain. Stepwise logistic regression analysis was used to determine factors associated with microcephaly. Significant factors included higher blood Phe levels when off diet, higher average Phe exposure during the pregnancy, low prepregnancy weight, poor weight gain during the pregnancy, and lower intake of protein and higher iron intake during the pregnancy. Infants with CHD were found only in the group of women who had blood Phe levels >600 micromol/L by 8 weeks of gestation. There was a higher rate of CHD in the offspring who were born to women who consumed <50% of the recommended intake of protein in the first trimester. The main source of protein for women with PKU is the medical food; therefore, when protein intake was low, vitamin and mineral intakes were also inadequate. CONCLUSIONS: The data indicate that blood Phe control and how soon it is attained during pregnancy with PKU is important. Normal pregnancy weight gain should be encouraged to reduce microcephaly. Adequate protein and vitamin intakes early in pregnancy may have a protective effect for the prevention of CHD, even if blood Phe is elevated. The rate of microcephaly and CHD may be reduced if nutrient intake is optimal while attempting to control blood Phe levels.

Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food.

BACKGROUND: Failure-to-thrive (FTT) has been described in patients with organic acidemias treated with low protein diets. OBJECTIVE: To determine if patients with methylmalonic (MMA) or propionic acidemia (PA) can achieve normal growth and nutrition status. METHODS: A 6-month multicenter outpatient study was conducted with infants and toddlers treated with Propimex-1 Amino Acid-Modified Medical Food With Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome measures were anthropometrics, protein status indices, plasma retinol, and alpha-tocopherol. RESULTS: Sixteen patients completed the study. Mean baseline age was 0.54 +/- 0.02 years (range 0.03-3.00 years). By study end, mean National Center for Health Statistics (NCHS) weight centile increased from 26 to 49%; mean crown-heel length centile from 25 to 33%; and mean head circumference centile from 43 to 54%. Mean (+/- SE) protein and energy intakes by <6-month-old, 6<12-month-old, and 1<4-year-old patients were 15.3 +/- 0.9 g and 645 +/- 10 kcal; 18.3 +/- 1.1 g and 741 +/- 92 kcal; and 25.1 +/- 2.46 g and 1062 +/- 100 kcal, respectively. Plasma glycine concentrations were significantly and negatively correlated with energy intake (r=-0.77, p<0.0005). No correlation was found between dietary protein intakes and plasma ammonia concentrations. Protein status indices, retinol and alpha-tocopherol concentrations were within reference ranges at study end. CONCLUSIONS: Propimex-1 improved growth and nutrition status in patients with MMA or PA in just 6 months when fed in sufficient amounts. Providing energy and protein for patients with FTT at intakes recommended for catch-up growth may have resulted in even better growth.

Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy.

OBJECTIVE: To evaluate nutrient intakes, plasma phenylalanine (PHE) and tyrosine (TYR) concentrations, and physical growth of children with phenylketonuria undergoing nutrition management. DESIGN: Children were fed three different medical foods during a one-year study. Subjects/setting Children were evaluated at baseline and every three months in metabolic clinics. Children's diets were managed at home. Statistical analyses Intakes of medical foods and nutrients, number of diaries with nutrients <67% and <100% of Recommended Dietary Intakes (RDI), and mean plasma PHE and TYR concentrations were compared among groups using two-way ANOVA. chi-squared test compared the percentage of plasma PHE and TYR concentrations in each group in specific categories. Height and body mass index were plotted against National Center for Health Statistics reference data; means were compared among groups. Tukey's test compared groups with significant treatment effects. RESULTS: Mean intakes of nutrients, except energy by all groups and vitamin B-12 by the Periflex-fed group, met or exceeded RDIs. The oldest children tended to have the highest PHE intakes and plasma PHE concentrations. Mean length or height z score indicated normal linear growth. Mean body mass index z scores at study end suggested many children were overweight. APPLICATIONS: Dietitians should prescribe adequate medical food and encourage children with phenylketonuria to ingest all prescribed daily. Linear growth of children, where mean protein equivalent intakes ranged from 113% to 129% of RDI, was normal, demonstrating the need for a protein intake greater than RDIs when an elemental diet is the primary protein source. Dietitians should prescribe and carefully monitor energy intake, physical activity, and weight.

Challenges of managing patients with inherited metabolic disorders in a developing country.

The main problems encountered in managing patients with inherited metabolic disorders (IMDs) are inadequate numbers of clinicians and scientists with experience in IMDs, ill-equipped laboratory facilities, lack of funding, and lack of a well-organized plan. Other challenges that must be faced in developing countries include basic health care, birthing centers, and funding. The community environment including a clean water supply and appropriate waste disposal may also be problems. A stable communication system is necessary, as well as the means of paying for these systems. Analyses of local foods, at least for protein and energy, are required to utilize local materials in the diet. The home environment must also be considered. Adequate housing, clothing, and fuel are essential to help prevent frequent infections that may lead to serious illness or death of patients with IMDs. Adequate parental education is necessary along with adequate finances to purchase equipment to measure a prescribed diet and any necessary foods. Specialized medical, public health, community and home environments all contribute challenges of managing patients with IMDs in developing countries.