Nutritional management of phenylalanine hydroxylase (PAH) deficiency in pediatric patients in Canada: a survey of dietitians' current practices.

BACKGROUND: Phenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN's goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families. OBJECTIVES: We investigated Canadian metabolic dietitians' perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines. METHODS: We invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency. RESULTS: We received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ≥360 µmol/L (6 mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360 µmol/L (2-6 mg/dL) as the optimal treatment range for blood Phe in children 0-9 years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3 day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin. CONCLUSION: While Canadian dietitians' practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.

The Indicator Amino Acid Oxidation Method with the Use of l-[1-13C]Leucine Suggests a Higher than Currently Recommended Protein Requirement in Children with Phenylketonuria.

BACKGROUND: Phenylketonuria is characterized by mutations in the Phe hydroxylase gene that leads to the accumulation of Phe in plasma and the brain. The standard of care for phenylketonuria is nutritional management with dietary restriction of Phe and the provision of sufficient protein and energy for growth and health maintenance. The protein requirement in children with phenylketonuria is empirically determined based upon phenylketonuria nutritional guidelines that are adjusted individually in response to biochemical markers and growth. OBJECTIVE: We determined dietary protein requirements in children with phenylketonuria with the use of the indicator amino acid oxidation (IAAO) technique, with l-[1-13C]Leu as the indicator amino acid. METHODS: Four children (2 males; 2 females) aged 9-18 y with phenylketonuria [mild hyperphenylalanemia (mHPA); 6-10 mg/dL (360-600 µmol/L)] were recruited to participate in ≥7 separate test protein intakes (range: 0.2-3.2 g ⋅ kg-1 ⋅ d-1) with the IAAO protocol with the use of l-[1-13C]Leu followed by the collection of breath and urine samples over 8 h. The diets were isocaloric and provided energy at 1.7 times the resting energy expenditure. Protein was provided as a crystalline amino acid mixture based on an egg protein pattern, except Phe and Leu, which were maintained at a constant across intakes. Protein requirement was determined with the use of a 2-phase linear-regression crossover analysis of the rate of l-[1-13C]Leu tracer oxidation. RESULTS: The mean protein requirement was determined to be 1.85 g ⋅ kg-1 ⋅ d-1 (R2 = 0.66; 95% CI: 1.37, 2.33). This result is substantially higher than the 2014 phenylketonuria recommendations (1.14-1.33 g ⋅ kg-1 ⋅ d-1; based on 120-140% above the current RDA for age). CONCLUSIONS: To our knowledge, this is the first study to directly define a quantitative requirement for protein intake in children with mHPA and indicates that current protein recommendations in children with phenylketonuria may be insufficient. This trial was registered at clinicaltrials.gov as NCT01965691.

Metabolic Diet App Suite for inborn errors of amino acid metabolism.

BACKGROUND: An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. OBJECTIVES: To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. METHODS & RESULTS: The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicPro™, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. DISCUSSION: The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice.

Minimally invasive (13)C-breath test to examine phenylalanine metabolism in children with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of hepatic phenylalanine hydroxylase (PAH) leading to increased levels of phenylalanine in the plasma. Phenylalanine levels and phenylalanine hydroxylase (PAH) activity monitoring are currently limited to conventional blood dot testing. 1-(13)C-phenylalanine, a stable isotope can be used to examine phenylalanine metabolism, as the conversion of phenylalanine to tyrosine occurs in vivo via PAH and subsequently releases the carboxyl labeled (13)C as (13)CO2 in breath. OBJECTIVE: Our objective was to examine phenylalanine metabolism in children with PKU using a minimally-invasive 1-(13)C-phenylalanine breath test ((13)C-PBT). DESIGN: Nine children (7 M: 2 F, mean age 12.5 ± 2.87 y) with PKU participated in the study twice: once before and once after sapropterin supplementation. Children were provided 6 mg/kg oral dose of 1-(13)C-phenylalanine and breath samples were collected at 20 min intervals for a period of 2h. Rate of CO2 production was measured at 60 min post-oral dose using indirect calorimetry. The percentage of 1-(13)C-phenylalanine exhaled as (13)CO2 was measured over a 2h period. Prior to studying children with PKU, we tested the study protocol in healthy children (n = 6; 4M: 2F, mean age 10.2 ± 2.48 y) as proof of principle. RESULTS: Production of a peak enrichment (Cmax) of (13)CO2 (% of dose) in all healthy children occurred at 20 min ranging from 17-29% of dose, with a subsequent return to ~5% by the end of 2h. Production of (13)CO2 from 1-(13)C-phenylalanine in all children with PKU prior to sapropterin treatment remained low. Following sapropterin supplementation for a week, production of (13)CO2 significantly increased in five children with a subsequent decline in blood phenylalanine levels, suggesting improved PAH activity. Sapropterin treatment was not effective in three children whose (13)CO2 production remained unchanged, and did not show a reduction in blood phenylalanine levels and improvement in dietary phenylalanine tolerance. CONCLUSIONS: Our study shows that the (13)C-PBT can be a minimally invasive, safe and reliable measure to examine phenylalanine metabolism in children with phenylketonuria. The breath data are corroborated by blood phenylalanine levels in children who had increased responses in (13)CO2 production, as reviewed post-hoc from clinical charts.

Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations.

BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development. METHODS: In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients. Additionally, a proposal for a further observational study is suggested. RESULTS: (1) All patients with confirmed ATQ deficiency are eligible for adjunct treatment with lysine-restricted diet, unless treatment with pyridoxine alone has resulted in complete symptom resolution, including normal behavior and development. (2) Lysine restriction should be started as early as possible; the optimal duration remains undetermined. (3) The diet should be implemented and the patient be monitored according to these recommendations in order to assure best possible quality of care and safety. DISCUSSION: The implementation of this recommendation will provide a unique and a much needed opportunity to gather data with which to refine the recommendation as well as improve our understanding of outcomes of individuals affected by this rare disease. We therefore propose an international observational study that would utilize freely accessible, online data sharing technologies to generate more evidence.

Long-term outcomes of blood phenylalanine concentrations in children with classical phenylketonuria.

We are reporting a retrospective review of blood phenylalanine (Phe) concentrations in 33 patients with classical phenylketonuria (PKU) born between 1991 and 2009 and continuously followed up in our clinic in 2009. As an indicator of blood Phe control, we analysed the percentage of blood Phe concentrations within and outside of the treatment range for each individual for treatment periods between 1 month and 12 months, 1 to 6 years, and 6 to 12 years of age. Despite early diagnosis and medical management in a centralized care model, only approximately 40% of patients had 60% and more of their blood Phe concentrations within the treatment range during their lifetime treatment periods. There was no statistical difference for the percentage of blood Phe concentrations within the treatment range, the mean Phe concentrations or the SD between the various treatment periods. We found a correlation between Phe tolerance and percentage of blood Phe concentrations within the treatment range. Patients born between 1991 and 1999 had poorer control than those born later. A frequent quality assurance audit is recommended to assess treatment outcomes in clinics providing care to children with PKU.