Nutrition management of PKU with pegvaliase therapy: update of the web-based PKU nutrition management guideline recommendations.

BACKGROUND: The web-based GMDI/SERN PKU Nutrition Management Guideline, published before approval of pegvaliase pharmacotherapy, offers guidance for nutrition management of individuals with phenylketonuria (PKU) treated with dietary therapy and/or sapropterin. An update of this guideline aims to provide recommendations that improve clinical outcomes and promote consistency and best practice in the nutrition management of individuals with PKU receiving pegvaliase therapy. Methodology includes: formulation of a research question; review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature; expert input through Delphi surveys and a Nominal Group process; and external review by metabolic experts. RESULTS: Recommendations, summary statements, and strength of evidence are included for each of the following topics: (1) initiating a pegvaliase response trial, (2) monitoring therapy response and nutritional status, (3) managing pegvaliase treatment after response to therapy, (4) education and support for optimal nutrition with pegvaliase therapy, and (5) pegvaliase therapy during pregnancy, lactation, and adolescence. Findings, supported by evidence and consensus, provide guidance for nutrition management of individuals receiving pegvaliase therapy for PKU. Recommendations focus on nutrition management by clinicians, as well as the challenges for individuals with PKU as a result of therapy changes. CONCLUSIONS: Successful pegvaliase therapy allows the possibility for individuals with PKU to consume an unrestricted diet while still maintaining the benefits of blood phenylalanine control. This necessitates a perspective change in education and support provided to individuals in order to achieve healthy nutrient intake that supports optimal nutritional status. The updated guideline, and companion Toolkit for practical implementation of recommendations, is web-based, allowing for utilization by health care providers, researchers, and collaborators who advocate and care for individuals with PKU. These guidelines are meant to be followed always taking into account the provider's clinical judgement and considering the individual's specific circumstances. Open access is available at the Genetic Metabolic Dietitians International ( https://GMDI.org ) and Southeast Regional Genetics Network ( https://managementguidelines.net ) websites.

Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach.

BACKGROUND: In 2014, recommendations for the nutrition management of phenylalanine hydroxylase deficiency were published as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylketonuria (PKU). These were developed primarily from a summary of findings from the PKU scientific review conference sponsored by the National Institutes of Health and Agency for Healthcare Research & Quality along with additional systematic literature review. Since that time, the Genetic Metabolic Dietitians International and the Southeast Regional Newborn Screening and Genetics Collaborative have partnered to create a web-based technology platform for the update and development of nutrition management guidelines for inherited metabolic disorders. OBJECTIVE: The purpose of this PKU guideline is to establish harmonization in treatment and monitoring, to guide the integration of nutrition therapy in the medical management of PKU, and to improve outcomes (nutritional, cognitive, and developmental) for individuals with PKU in all life stages while reducing associated medical, educational, and social costs. METHODS: Six research questions critical to PKU nutrition management were formulated to support guideline development: Review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature, along with expert Delphi survey feedback, nominal group process, and external review from metabolic physicians and dietitians were utilized for development of recommendations relevant to each question. Recommendations address nutrient intake, including updated protein requirements, optimal blood phenylalanine concentrations, nutrition interventions, monitoring parameters specific to life stages, adjunct therapies, and pregnancy and lactation. Recommendations were graded using a rigorous system derived from the Academy of Nutrition and Dietetics. RESULTS AND CONCLUSION: These guidelines, updated utilizing a thorough and systematic approach to literature analysis and national consensus process, are now easily accessible to the global community via the newly developed digital platform. For additional details on specific topics, readers are encouraged to review materials on the online portal: https://GMDI.org/.

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.

Diagnostic guidelines for newborns who screen positive in newborn screening.

BACKGROUND: Recent expansion of the newborn screening panels has presented an interesting challenge to specialty care centers, especially the clinical genetics community. Some of the conditions in the core and secondary newborn screening panels have extremely variable clinical presentations; others are so rare that only a handful of newborns have been diagnosed with them to date (Region 4 Collaborative MS/MS project-http://region4genetics.org/msms_data_project/data_project_home.aspx). Definition of some disorders is problematic-does continued abnormality of the screening analyte constitute diagnosis or is further testing necessary? METHODS: A work group of the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (region 2), one of seven regional collaboratives funded by the Federal Health Resources and Services Administration and administered by the Maternal and Child Health Bureau (U22MC03956), has developed guidelines for the confirmation of diagnosis of the conditions in the newborn screening panels for use by the specialty care centers. DISCUSSION: The diagnostic guidelines are a work in progress and are being reviewed and revised regularly as our understanding of the newborn screened disorders improves. The aim is to make it a relevant guide for specialty care physicians and other healthcare professionals in the diagnostic workup of these patients.

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.

INTRODUCTION: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. METHOD: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. RESULTS: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. DISCUSSION: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.

Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up.

OBJECTIVES: A subset of patients with allergic eosinophilic gastroenteritis (AEG) has anemia and hypoalbuminemia caused by protein-losing enteropathy (PLE). Our goals were to describe the response to therapy and the long-term outcome of patients in this subgroup and to evaluate their gastric and intestinal biopsies for distinguishing features that might explain their protein and blood loss. METHODS: Patients with AEG + PLE were identified retrospectively and compared with controls and with patients with AEG only. Immunohistochemical staining for tryptase, a mast cell mediator, was performed on gastric and duodenal tissues. Eosinophils identified by hematoxylin/eosin stain and mast cells identified as tryptase-positive cells were counted in one high-power field area with maximal cell infiltration. RESULTS: Although all patients had excellent response to therapy with amino acid-based formula and tolerated gradual introduction of some foods with time, food-responsive disease persisted in all patients over 2.5 to 5.5 years of follow-up. Routine histological evaluation did not show any features differentiating AEG + PLE from AEG. When eosinophils and mast cells were counted in intestinal biopsies, however, significantly more mast cells were found in biopsies of the AEG + PLE group despite comparable numbers of eosinophils. In contrast, in gastric biopsies, eosinophils were more prominent in AEG + PLE, but mast cell numbers were similar in all groups. CONCLUSIONS: Patients with AEG + PLE responded well to therapy with amino acid-based formula. Food hypersensitivities did not completely resolve over up to 5.5 years. Intestinal mast cells were significantly increased in maximally infiltrated areas of the intestine, possibly causing increased intestinal permeability and protein loss.

Skin prick test to egg white provides additional diagnostic utility to serum egg white-specific IgE antibody concentration in children.

BACKGROUND: Levels of IgE antibody to egg white of greater than 7 kIU/L are highly predictive of clinical reactivity to egg, and lower levels often require evaluation with oral food challenge (OFC) to establish definitive diagnosis. OFCs have inherent risks, and diagnostic criteria indicating high likelihood of passing would be clinically useful. OBJECTIVE: We sought to determine whether the size of the skin prick test (SPT) to egg white adds diagnostic utility for children with low egg white-specific IgE antibody levels. METHODS: A retrospective analysis of clinical history, egg white-specific IgE antibody levels, SPT responses, and egg OFC outcomes was performed. RESULTS: Children who passed (n = 29) egg OFCs and those who failed (n = 45) did not differ significantly in age, clinical characteristics, or egg white-specific IgE levels. There were, however, significant differences between both egg white SPT wheal response size and egg/histamine SPT wheal index. Children who failed egg OFCs had a median wheal of 5.0 mm; those who passed had a median wheal of 3.0 mm (P = .003). Children who failed egg OFCs had a median egg/histamine index of 1.00; those who passed had a median index of 0.71 (P = .001). For egg white-specific IgE levels of less than 2.5 kIU/L, an SPT wheal of 3 mm or an egg/histamine index of 0.65 was associated with a 50% chance of passing. CONCLUSION: In children with low egg white-specific IgE levels, those with smaller SPT wheal responses to egg were more likely to pass an egg OFC than those with larger wheal responses. The size of the egg white SPT response might provide additional information to determine the timing of egg OFC. CLINICAL IMPLICATIONS: The size of the egg white SPT wheal response might provide the clinician with additional information to determine the timing of egg OFC in children with low egg white-specific IgE antibody levels.

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.

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.

Relevance of casual contact with peanut butter in children with peanut allergy.

BACKGROUND: Casual skin contact or inhalation of peanut butter fumes is reported and feared to cause allergic reactions in highly sensitive children with peanut allergy but has not been systematically studied. OBJECTIVE: We sought to determine the clinical relevance of exposure to peanut butter by means of inhalation and skin contact in children with peanut allergy. METHODS: Children with significant peanut allergy (recent peanut-specific IgE antibody concentration >50 kIU/L or evidence of peanut-specific IgE antibody and one of the following: clinical anaphylaxis, a reported inhalation-contact reaction, or positive double-blind, placebo-controlled oral challenge result to peanut) underwent double-blind, placebo-controlled, randomized exposures to peanut butter by means of contact with intact skin (0.2 mL pressed flat for 1 minute) and inhalation (surface area of 6.3 square inches 12 inches from the face for 10 minutes). Placebo challenges were performed by using soy butter mixed with histamine (contact), and scent was masked with soy butter, tuna, and mint (inhalation). RESULTS: Thirty children underwent the challenges (median age, 7.7 years; median peanut IgE level, >100 kIU/L; 13 with prior history of contact and 11 with inhalation reactions). None experienced a systemic or respiratory reaction. Erythema (3 subjects), pruritus without erythema (5 subjects), and wheal-and-flare reactions (2 subjects) developed only at the site of skin contact with peanut butter. From this number of participants, it can be stated with 96% confidence that at least 90% of highly sensitive children with peanut allergy would not experience a systemic-respiratory reaction from casual exposure to peanut butter. CONCLUSIONS: Casual exposure to peanut butter is unlikely to elicit significant allergic reactions. The results cannot be generalized to larger exposures or to contact with peanut in other forms (flour and roasted peanuts).

Nutritional management of pediatric food hypersensitivity.

The diagnosis and management of food allergy requires attention to several important dietary issues. Successful exclusion of identified dietary allergens requires extensive education regarding the interpretation of ingredient labels of commercial products and an appreciation for issues of cross-contact in settings such as restaurants and commercial manufacturing. Once a food or food group is eliminated, attention must be focused on potential dietary insufficiencies resulting from these exclusions. These dietary issues are also central to the successful use of diagnostic elimination diets and physician-supervised oral food challenges. This review provides a framework for the dietary management of food hypersensitivity in infants and children both for short-term diagnostic and long-term therapeutic purposes. In addition, approaches for maternal dietary restriction for breastfed infants with food allergy and the introduction of solid foods to atopic infants are reviewed.

Interpretation of commercial food ingredient labels by parents of food-allergic children.

BACKGROUND: To avoid allergic reactions, food-allergic consumers depend on the ingredient labels of commercial products. Complex ingredient terminology (eg, casein and whey for milk) and label ambiguities (eg, natural flavor and may contain peanut ) might compromise the ability of patients/parents to determine the safety of particular products. OBJECTIVE: The purpose of this investigation was to determine the accuracy of label reading among parents of food-allergic children. METHODS: Parents of children on restricted diets attending our referral center were asked to review a group of 23 food labels taken from widely available commercial products. For each label, each parent/parent pair was asked to indicate whether the product was safe for the allergic child and, if it was not, which foods restricted from the child's diet were in the product. RESULTS: There were 91 participants. Peanut was the most commonly restricted food (82 children), followed by milk, egg, soy, and wheat (60, 45, 27 and 16 children, respectively). Identification of milk and soy was the most problematic: only 4 (7%) of 60 parents correctly identified all 14 labels that indicated milk, and only 6 (22%) of 27 parents correctly identified soy protein in 7 products. Peanut was correctly identified in 5 products by 44 (54%) of the 82 parents restricting peanut. Wheat (10 labels) and egg (7 labels) were correctly identified by most parents (14/16 and 42/45, respectively). Correct label identification was associated with prior instruction by a dietitian. CONCLUSIONS: With current labeling practices, most parents are unable to identify common allergenic food ingredients. These results strongly support the need for improved labeling with plain-English terminology and allergen warnings as well as the need for diligent education of patients about reading labels.