Erin L. MacLeod

Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids.

BACKGROUND Phenylketonuria (PKU) requires a lifelong low-phenylalanine diet that provides the majority of protein from a phenylalanine-free amino acid (AA) formula. Glycomacropeptide (GMP), an intact protein formed during cheese production, contains minimal phenylalanine. OBJECTIVE The objective was to investigate the effects of substituting GMP food products for the AA formula on acceptability, safety, plasma AA concentrations, and measures of protein utilization in subjects with PKU. DESIGN Eleven subjects participated in an inpatient metabolic study with two 4-d treatments: a current AA diet (AA diet) followed by a diet that replaced the AA formula with GMP (GMP diet) supplemented with limiting AAs. Plasma concentrations of AAs, blood chemistries, and insulin were measured and compared in AA (day 4) and GMP diets (day 8). RESULTS The GMP diet was preferred to the AA diet in 10 of 11 subjects with PKU, and there were no adverse reactions to GMP. There was no significant difference in phenylalanine concentration in postprandial plasma with the GMP diet compared with the AA diet. When comparing fasting with postprandial plasma, plasma phenalyalanine concentration increased significantly with the AA but not with the GMP diet. Blood urea nitrogen was significantly lower, which suggests decreased ureagenesis, and plasma insulin was higher with the GMP diet than with the AA diet. CONCLUSIONS GMP, when supplemented with limiting AAs, is a safe and highly acceptable alternative to synthetic AAs as the primary protein source in the nutritional management of PKU. As an intact protein source, GMP improves protein retention and phenylalanine utilization compared with AAs.

Nutritional Management of Phenylketonuria

Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease. There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet.

Purification and use of glycomacropeptide for nutritional management of phenylketonuria.

Individuals with phenylketonuria (PKU) cannot metabolize phenylalanine (Phe) and must adhere to a low-Phe diet in which most dietary protein is provided by a Phe-free amino acid formula. Glycomacropeptide (GMP) is the only naturally occurring protein that does not contain Phe, and is of interest as a source of protein for dietary management of PKU. However, commercially available GMP contains too much Phe from residual whey proteins and does not contain adequate levels of all the indispensable amino acids to provide a nutritionally complete protein. The aim of this study was to increase purity of GMP and develop a mass balance calculation for indispensable amino acid supplementation of GMP foods. Cation exchange chromatography, ultrafiltration/diafiltration, and lyophilization were used at the pilot plant scale to decrease Phe. Enough purified GMP (5 kg) was manufactured to provide 15 PKU subjects with a 4-d diet in which the majority of protein was from GMP foods. A mass balance was used to supplement GMP foods so that all indispensable amino acids met or exceeded the daily recommended intake. GMP foods were tested in a human clinical trial as a replacement for the traditional amino acid formula. Nutritionally complete GMP foods created with high purity GMP provide individuals with PKU with more options to manage PKU, which may lead to improved compliance and quality of life.

Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria

Phenylketonuria (PKU) requires a lifelong low-phenylalanine (phe) diet where protein needs are met by consumption of a phe-free amino acid (AA) formula; complaints of persistent hunger are common. Foods made with glycomacropeptide (GMP), an intact protein that contains minimal phe and may promote satiety, provide an alternative to AA formula. The objective was to assess the ability of a GMP breakfast to promote satiety and affect plasma concentrations of AAs, insulin, and the appetite stimulating hormone ghrelin in those with PKU, when compared to an AA-based breakfast. Eleven PKU subjects (8 adults and 3 boys ages 11-14) served as their own controls in an inpatient metabolic study with two 4-day treatments: an AA-based diet followed by a diet replacing all AA formula with GMP foods. Plasma concentrations of AAs, insulin and ghrelin were obtained before and/or 180 min after breakfast. Satiety was assessed using a visual analog scale before, immediately after and 150 min after breakfast. Postprandial ghrelin concentration was significantly lower (p=0.03) with GMP compared to an AA-based breakfast, with no difference in fasting ghrelin. Lower postprandial ghrelin concentrations were associated with greater feelings of fullness after breakfast suggesting greater satiety with GMP compared to AAs. Postprandial concentrations of insulin and total plasma AAs were higher after a GMP breakfast compared to an AA-based breakfast consistent with slower absorption and less degradation of AAs from GMP. These results show sustained ghrelin suppression, and suggest greater satiety with ingestion of a meal containing GMP compared with AAs.

Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes

Lifelong treatment of phenylketonuria (PKU) includes a phenylalanine (phe) restricted diet that provides sufficient phe for growth and maintenance plus phe-free amino acid formula to meet requirements for protein, energy and micronutrients. Phe tolerance (mg phe/kg body weight/day) is the amount of phe those with PKU can consume and maintain acceptable blood phe levels; it requires individual assessment because of varying phenylalanine hydroxylase activity. The objective was to reassess phe tolerance in eight adults with PKU considering phe requirements, blood phe levels, genotype and phe tolerance at 5 years of age. Subjects had not received a personalized assessment of phe tolerance in several years, and five subjects were overweight, body mass index (BMI) 25-28. With the guidance of a metabolic dietitian, seven subjects increased phe tolerance (by 15-173%) without significantly increasing blood phe concentration. Increased phe tolerance was associated with both improved dietary compliance and inadequate phe intake at the onset of the protocol compared with current requirements. Improved dietary compliance reflected increased consumption of protein equivalents from amino acid formula and increased frequency of formula intake, from 2.2 to 3 times per day. Predictors of higher final phe tolerance following reassessment included being male and having a lower BMI (R(2)=0.588). This suggests that the rising trend of overweight and obesity may affect assessment of phe tolerance in adults. Therefore, interaction with the metabolic dietitian to reassess phe tolerance in relation to body mass is essential throughout adulthood to insure adequate intake of phe to support protein synthesis and prevent catabolism.

Prise en charge nutritionnelle de la phénylcétonurie

La phénylcétonurie (PCU) est due à un déficit de l’activité de la phénylalanine hydroxylase, nécessaire pour métaboliser un acide aminé (AA) essentiel, la phénylalanine (Phe), en tyrosine. Afin de prévenir les atteintes neurologiques, il est recommandé de suivre un régime pauvre en Phe à vie, c’est-à-dire de limiter la consommation d’aliments naturels et de consommer une préparation à base d’AA, sans Phe, pour couvrir les besoins protéiques. L’objectif de la prise en charge nutritionnelle des patients phénylcétonuriques est de maintenir une concentration plasmatique en Phe compatible avec une croissance, un développement, et une activité mentale optimaux tout en apportant un régime nutritionnellement complet. Cet article présente la mise en place d’une prescription alimentaire à vie pour les patients phénylcétonuriques, les résultats de cette prise en charge nutritionnelle, la compliance avec le régime pauvre en Phe durant les différentes étapes de la vie, et les nouvelles possibilités de prise en charge. La prescription alimentaire doit être individualisée pour répondre aux besoins nutritionnels de chaque patient, et l’adéquation des apports en Phe doit être régulée en fonction de la phénylalaninémie, contrôlée régulièrement. La maladie, des apports excessifs ou inadéquats en Phe, ou une consommation inadaptée de préparation à base d’AA peuvent induire une augmentation de la concentration sanguine en Phe. Même si l’observance du régime pauvre en Phe permet une croissance et un développement normaux, il est important de contrôler les statuts en vitamines, minéraux et acides gras essentiels, surtout chez les patients ne consommant pas suffisamment de mélange d’AA. Avec une population croissante d’adultes phénylcétonuriques, des recherches supplémentaires sont nécessaires pour comprendre les risques de développement d’ostéoporose ou de maladies cardiovasculaires. De nouvelles possibilités permettant d’assouplir le régime et d’améliorer le contrôle métabolique sont prometteuses, comme un traitement à base de tetrahydrobioptérine ou une complémentation avec des AA neutres de grande taille. De plus, les aliments fabriqués avec le glycomacropeptide, une protéine intacte contenant très peu de Phe, améliorent le régime en offrant une alternative plus appétissante que les mélanges d’AA. En résumé, la poursuite des efforts est nécessaire pour surmonter le plus grand défi pour un patient phénylcétonurique: l’observance à vie d’un régime pauvre en Phe.

Tratamiento nutricional de la fenilcetonuria

La fenilcetonuria (FCU) está causada por la actividad deficiente de la enzima fenilalanina hidroxilasa, necesaria para convertir el aminoácido (AA) esencial fenilalanina (phe) en tirosina. Con objeto de prevenir el daño neurológico es necesaria la adhesión permanente a una dieta pobre en phe, que restringe los alimentos naturales y requiere la ingestión de una fórmula de AA libre de phe para satisfacer las necesidades proteínicas. El objetivo del tratamiento nutricional de los pacientes con FCU reside en mantener concentraciones plasmáticas de phe capaces de sustentar un crecimiento, desarrollo y función mental óptimos al mismo tiempo que aporta una dieta nutricionalmente completa. En este trabajo se revisa el desarrollo de una prescripción alimentaria vitalicia para los pacientes con FCU, los resultados del tratamiento nutricional, el cumplimiento con la dieta pobre en phe durante todo el ciclo vital y nuevas opciones de terapéutica nutricional. Para satisfacer las necesidades de nutrientes se precisa una prescripción dietética individualizada, y se monitoriza la idoneidad de la ingestión de phe mediante la evaluación de sus niveles hemáticos. La elevación de las concentraciones de phe puede aparecer debido a enfermedad, ingestión excesiva o insuficiente de phe o ingestión insuficiente de la fórmula de AA. Aunque con la adhesión a la dieta pobre en phe, el crecimiento y el desarrollo son normales, es importante monitorizar el estado de las vitaminas, los minerales y los ácidos grasos esenciales, especialmente en aquellas personas que no consumen cantidades suficientes de fórmula de AA. Teniendo en cuenta la creciente población de adultos con FCU, se precisa una investigación ulterior para conocer los riesgos de aparición de osteoporosis y enfermedad cardiovascular. Existen nuevas opciones prometedoras para liberalizar la dieta y mejorar el control metabólico, como el tratamiento con tetrahidrobiopterina o el aporte complementario de AA neutros de gran tamaño. Por otra parte, los alimentos compuestos de glucomacropéptido, una proteína intacta que contiene una cantidad mínima de phe, mejoran la dieta de FCU, ofreciendo una alternativa sabrosa a la fórmula de AA. En suma, se precisan esfuerzos continuados para superar el enorme problema que conlleva la vida con FCU: la adhesión vitalicia a la dieta pobre en phe.