Fran Rohr

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.Genet Med 16 2, 121–131.

Barriers to successful dietary control among pregnant women with phenylketonuria

Purpose: The teratogenic effects of maternal PKU are preventable, yet affected babies continue to be born. This studys purpose was to identify barriers to successful dietary control among pregnant women with PKU.Methods: An interview-based study was conducted of women with PKU who were known to metabolic disease clinics in three states and pregnant during 1998 to 2000. Medical records were used to document timing of metabolic control.Results: Of 24 women in the study, only 8 (33%) initiated the diet before pregnancy. Of 22 medical records received, only 12 (55%) indicated control of blood phenylalanine levels before 10 weeks gestation. Risk factors for late dietary control included young age and belief that treatment costs complicated the diet. Although all of the women expressed confidence in the metabolic clinic staff, few perceived their obstetricians were knowledgeable about the maternal PKU diet. Of 13 women enrolled in state-based assistance programs, 9 (69%) reported proof of pregnancy was required for eligibility. Many women using private insurance reported their insurers were unwilling to pay for medical foods. When the data were stratified according to state of residence, differences were observed in the rate of live-born infants, prepregnancy medical food use, average travel time to the metabolic clinic, and gestational week when metabolic control was achieved.Conclusion: Our studys findings may be used to target educational messages to women with PKU and to direct future research directions. For example, obstetric knowledge of maternal PKU needs further evaluation. Discrepancies should be resolved between maternal PKU medical recommendations and the policies of third party-payers. The disparities in financial assistance and services available to pregnant women with PKU residing in different states should be examined further.

Intake and blood levels of fatty acids in treated patients with phenylketonuria.

Background Investigators in Italy and Spain have suggested that therapy for patients with phenylketonuria (PKU) may result in essential fatty acid (EFA) deficiency. Objectives of this study were to determine if the diets of patients with PKU in the United States provided adequate EFA intakes and whether patients could form long-chain polyunsaturated fatty acids. Methods Patients (1–13 years of age) with classic PKU undergoing therapy and their non-PKU sibling closest in age were compared. Nutrient intakes were calculated from 3-day diet diaries. Fatty acids in plasma and erythrocytes were identified and quantified. Paired t tests compared results for the patients and their non-PKU siblings. Results Twenty-eight patients and 26 siblings were studied. Mean fat intake was greatest by siblings (34.8 ± 1.3% of energy) and lowest by Phenyl-Free–fed patients (19.5 ± 1.2% of energy;P < 0.05). Fat intake (30.4 ± 1.8% of energy) by Phenex-fed patients did not differ from that of siblings. Percentage of energy ingested as C18:2n-6 and C18:3n-3 did not differ significantly between patients and siblings. No clinically significant, consistent differences were found in fatty acid levels (wt%) in plasma or erythrocytes between patients with PKU and siblings. Conclusions No patient in this study exhibited a Holman index of EFA deficiency. Siblings ingested animal protein containing C20:5n-3 and C22:6n-3 fatty acids, and this may account for their greater wt% of these plasma and erythrocyte fatty acids. Because patients with PKU do not ingest fatty acids >C18 but C20:4n-6, C20:5n-3, and C22:6n-3 were found in their plasma and erythrocytes, in vivo synthesis from C18:2n-6 and C18:3n-3 appears to occur. Lack of EFA deficiency in patients in this study may be the result of the use of canola and soy oils containing C18:2n-6 and C18:3n-3 rather than olive oil in the diets.

Recommendations for Personalized Dietary Adjustments Based on Patient Response to Tetrahydrobiopterin (BH4) in Phenylketonuria

Phenylketonuria (PKU) is an inherited metabolic disorder that results from reduced phenylalanine hydroxylase (PAH) activity. Historically, PKU treatment has involved a phenylalanine-restricted diet substituting high-protein foods with medical food. Despite the treatments success, diet adherence remains problematic. Sapropterin dihydrochloride* is a formulation of tetrahydrobiopterin (BH4), a cofactor required for PAH activity. Clinical trials demonstrate that, in a subset of PKU patients, sapropterin dihydrochloride enhances PAH activity, leading to better tolerance of dietary phenylalanine, hence natural protein. The present recommendations, based on experience during clinical trials, are intended to guide nutrition specialists overseeing the dietary adjustments associated with sapropterin dihydrochloride therapy.

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

BACKGROUNDnDeficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF).nnnMETHODSnSubjects with PKU consumed a low-Phe diet combined with AA-MF or GMP-MF for 3weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-h urine samples.nnnRESULTSnIntake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA-MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF.nnnCONCLUSIONSnThe Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU. This trial is registered at www.clinicaltrials.gov as NCT01428258.

Bridging evidence and consensus methodology for inherited metabolic disorders: creating nutrition guidelines

RATIONALE, AIMS AND OBJECTIVESnThe management of many inherited metabolic disorders (IMDs) is dependent on nutrition intervention, but few clinical management guidelines for these uncommon disorders exist. Clinicians are forced to make nutrition treatment decisions using limited data. This results in clinical variations in both service and cost. We describe a method for establishing management guidelines to help clinicians treat patients with IMDs.nnnMETHODSnThe Southeast Newborn Screening and Genetics Collaborative (Region 3) convened a group of nine national experts in metabolic nutrition to determine the pertinent issues in the development of nutrition management guidelines for IMDs. These experts were trained in evidence analysis and examined established consensus techniques for guideline development.nnnRESULTSnThe workgroup developed a multi-step process for guideline development known as the Delphi-Nominal Group-Delphi-Field Testing methodology, which includes a review of scientific and grey (unpublished) literature, a Delphi survey of practice, a nominal group meeting to clarify discrepancies, a formulation of recommendations and a second Delphi round to assess the degree of consensus with the proposed recommendations. External review and field testing are also built into the process.nnnCONCLUSIONnThe evidence- and consensus-based method suggested for the development of nutrition management guidelines for IMDs will result in the production of consistent and accessible guidelines that can be created in a timely and cost-effective manner and offer a validated methodology to develop management guidelines for this field to optimize outcomes.

Dietary amino acid intakes associated with a low-phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects with phenylketonuria

This article provides original data on median dietary intake of 18 amino acids from amino acid medical foods, glycomacropeptide medical foods, and natural foods based on 3-day food records obtained from subjects with phenylketonuria who consumed low-phenylalanine diets in combination with amino acid medical foods and glycomacropeptide medical foods for 3 weeks each in a crossover design. The sample size of 30 subjects included 20 subjects with classical phenylketonuria and 10 with a milder or variant form of phenylketonuria. Results are presented for the Delis-Kaplan Executive Function System and the Cambridge Neuropsychological Test Automated Battery; the tests were administered at the end of each 3-week dietary treatment with amino acid medical foods and glycomacropeptide medical foods. The data are supplemental to our clinical trial, entitled “Glycomacropetide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial, 2016 (1) and “Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria, 2017 (2). This data has been made public and has utility to clinicians and researchers due to the following: 1) This provides the first comprehensive report of typical intakes of 18 amino acids from natural foods, as well as amino acid and glycomacropeptide medical foods in adolescents and adults with phenylketonuria; and 2) This is the first evidence of similar standardized neuropsychological testing data in adolescents and adults with early-treated phenylketonuria who consumed amino acid and glycomacropeptide medical foods.

Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria.

BackgroundnIndividuals with phenylketonuria (PKU) have a risk of cognitive impairment and inflammation. Many follow a low-phenylalanine (low-Phe) diet devoid of animal protein in combination with medical foods (MFs).nnnObjectivenTo assess lipid metabolism in participants with PKU consuming amino acid MFs (AA-MFs) or glycomacropeptide MFs (GMP-MFs), we conducted fatty acid and metabolomics analyses.nnnMethodsnWe used subsets of fasting plasma and urine samples from our randomized crossover trial in which participants with early-treated classical and variant (milder) PKU consumed a low-Phe diet combined with AA-MFs or GMP-MFs for 3 wk each. Fatty acid profiles of red blood cell (RBC) membranes were determined for 25 adults (aged 18-49 y) with PKU and 143 control participants. Metabolomics analyses of plasma and urine samples were conducted by Metabolon for 9-10 adolescent and adult participants with PKU and for 15 control participants.nnnResultsnRBC fatty acid profiles were not significantly different with AA-MFs or GMP-MFs. PKU participants showed higher total n-6:n-3 (ω-6:ω-3) fatty acids (mean ± SD percentages of total fatty acids: AA-MF = 5.45% ± 1.07%; controls = 4.33%; P < 0.001) and lower docosahexaenoic acid (DHA; AA-MF = 3.21% ± 0.98%; controls = 3.70% ± 1.01%; P = 0.02) and eicosapentaenoic acid (AA-MF = 0.33% ± 0.12%; controls = 0.60% ± 0.43%; P < 0.001) in RBCs than did control participants. Despite higher carnitine intake from AA-MFs than GMP-MFs (mean ± SE intake: AA-MFs = 58.6 ± 5.3 mg/d; GMP-MFs = 0.3 ± 0.01 mg/d; P < 0.001), plasma concentrations of carnitine were similar and not different from those in the control group (AA-MF compared with GMP-MF, P = 0.73). AA-MFs resulted in higher urinary excretion of trimethylamine N-oxide (TMAO), which is synthesized by bacteria from carnitine, compared with GMP-MFs (mean ± SE scaled intensity-TMAO: AA-MFs = 1.2 ± 0.1, GMP-MFs = 0.9 ± 0.1; P = 0.005). Plasma deoxycarnitine was lower in PKU participants than in control participants, suggesting reduced carnitine biosynthesis in PKU (AA-MF = 0.9 ± 0.1; GMP-MF = 1.0 ± 0.1; controls = 1.3 ± 0.1; AA-MF compared with controls, P = 0.01; GMP-MF compared with controls, P = 0.04).nnnConclusionsnSupplementation with DHA is needed in PKU. Carnitine supplementation of AA-MFs shows reduced bioavailability due, in part, to bacterial degradation to TMAO, whereas the bioavailability of carnitine is greater with prebiotic GMP-MFs. This trial was registered at www.clinicaltrials.gov as NCT01428258.

Role of medical food in MMA.

To the Editor: As senior metabolic dietitians who have provided nutritional management for individuals with methylmalonic acidemia (MMA), we wish to comment on the recent article by Manoli et al., “A Critical Reappraisal of Dietary Practices in Methylmalonic Acidemia Raises Concerns About the Safety of Medical Foods. Part 1: Isolated Methymalonic Acidemias”1, published online in this journal in August 2015. This title is misleading because it seems to imply that poor outcomes are due solely to the use of medical foods. We believe that their study does raise some concerns about some of the current management and monitoring practices2 in the context of a complex disease that, in many cases, cannot be optimized by diet alone. Medical food, a term created in 1988 by the Orphan Drug Amendments, is defined as “a food formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” (http://medpolicy.ibx.com/policies/mpi. nsf/f12d23cb982d59b485257bad00552d87/85256aa800623d 7a85257bf2004f103f!OpenDocument). Although the authors refer to these products as incomplete proteins, they are technically not proteins but, rather, amino acid mixtures that are formulated to minimize the intake of those amino acids that are not catabolized in a specific metabolic disorder, e.g., the propiogenic amino acids in medical foods designed for MMA or propionic acidemia. Medical foods are never intended to be the sole source of nutrient intake for the individual. Limited intake of dietary intact protein (also referred to as natural protein, food protein, or complete protein) is titrated to provide the required essential amino acids, as well as carbohydrates and fat, to provide a nonprotein energy source. The authors suggest that individuals with MMA may be able to meet their protein needs solely with dietary intact protein. However, this overlooks the fact that many individuals with MMA are poor eaters. This may be due in part to chronic acidosis causing anorexia, neurological sequelae that limit the ability to chew and swallow, or aversion to certain textures and tastes. The use of medical foods (in combination with other dietary components containing the propiogenic amino acids) can provide a consistent energy and nutrient source for these poor eaters or for others during intercurrent illness or metabolic crisis. The authors also failed to address the issue of the biological value/quality3 of intact or dietary proteins. Proteins derived from plant sources are less likely to be of high biological value and contain limiting amounts of certain essential amino acids. Moreover, these are the very foods—fruits, vegetables, and some grains—that are the major source of intact dietary protein for individuals with MMA. Reliance solely on these sources can compromise protein status. There are some individuals with milder forms of MMA who can tolerate an intake of intact protein that meets the Dietary Reference Intake for age, but even for these individuals, addition of medical food can provide a “buffer” to allow some leeway in intact protein sources as well as provide an important source of nonprotein energy and micronutrients to meet individual needs. It is important to emphasize that nutritional intervention is not a panacea for the management of individuals with various forms of MMA; these are complex disorders with probable mitochondria dysfunction, chronic renal disease, and risk for decompensation during intercurrent illness. Therefore, it is difficult to equate growth parameters with nutrient intake. The subjects enrolled in this study had diverse nutritional, medical, and supportive interventions and illness histories. Some were identified only after significant decompensation. All of these factors can impact their growth and development, even if they had all followed similar dietary interventions. The authors raise important concerns about practices of increasing total protein intake by giving very large quantities of medical food and the negative impact of elevated leucine intake on the concentration of other essential amino acids. Medical foods available for use by individuals with MMA vary widely in their leucine content, as shown in Supplementary Table S2 online. The composition of some of these products deserves careful reevaluation. Attempts to establish normal plasma amino acid ratios have been shown to improve growth parameters in other inborn errors of metabolism, such as phenylketonuria,4 and may be an important goal for individuals with MMA. Short-term use of intact dietary protein alone may help establish appropriate plasma amino acid ratios, but the data are not available to show the long-term nutritional, anthropometric, and developmental outcomes of omitting medical foods in the management of individuals with MMA. We believe their data suggest that the use of close and frequent monitoring should guide the balance between the amount of medical food amino acids and intact protein in providing the total protein required for adequate growth and maintenance. Even when using amino acids (medical foods) as part of the nitrogen source, total protein intake more than 1.2–1.5 times the Dietary Reference Intake is probably unnecessary. The authors demonstrated this by comparing anthropometric data with total protein intake. If additional energy is needed to promote anabolism, then this should probably come from nonprotein sources, rather than from additional amino acid–based medical food. If plasma levels of valine and isoleucine are low, then additional intact protein sources can be used and an equivalent decrease in amino acids from medical food can be considered. Genet Med

Nutrition Management of Urea Cycle Disorders

Urea cycle disorders (UCD) differ widely in their presentation and severity. n n nCorrecting hyperammonemia is the priority in treating UCD. n n nDietary protein is restricted in UCD. The amount of protein provided as whole protein versus medical food protein (essential amino acid) varies. n n nPreventing catabolism by providing sufficient energy is a critical part of nutrition management. n n nMedications that remove nitrogen by alternative pathways help to prevent hyperammonemia and increase protein tolerance. n n nOutcomes are guarded and depend on severity of the disease. n n nLiver transplantation is recommended for infants with severe forms of the disorder.