Management Of Phenylketonuria Research Articles

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.

Dietary management practices in phenylketonuria across European centres

Dietary phenylalanine restriction is the cornerstone of phenylketonuria (PKU) management. However, there are no European consensus guidelines for its optimal dietary care. Detailed information on the routine dietary management of PKU was obtained from 10 European centres using structured questionnaires. Each centre was represented by one dietitian/nutritionist or physician (European Nutritionist Expert Panel). All centres screened for PKU within the first 10 days of life. PKU prevalence was highest in Turkey. The training, roles and responsibilities of dietitians and nutritionists varied widely; in some centres dietitians were responsible for managing the diet, while in others this was performed by a physician. There were marked differences in target blood phenylalanine concentrations, the dosages of protein substitutes, systems for allocating daily phenylalanine allowance, and the definition of foods that could be eaten without restriction ('free foods'). Eighty percent (n=8/10) of centres encouraged breastfeeding together with protein substitute in infants with PKU. Important differences exist among centres across Europe in the dietary management of PKU, and in support systems designed to assist patients in managing their diets. Further studies are needed to compare different dietary treatments with the aim of identifying best practice to optimise phenylalanine control and dietary adherence.

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 PKU with glycomacropeptide from cheese whey

Individuals with phenylketonuria (PKU) must follow a lifelong low-phenylalanine (Phe) diet to prevent neurological impairment. Compliance with the low-Phe diet is often poor owing to restriction in natural foods and the requirement for consumption of a Phe-free amino acid formula or medical food. Glycomacropeptide (GMP), a natural protein produced during cheese-making, is uniquely suited to a low-Phe diet because when isolated from cheese whey it contains minimal Phe (2.5-5 mg Phe/g protein). This paper reviews progress in evaluating the safety, acceptability and efficacy of GMP in the nutritional management of PKU. A variety of foods and beverages can be made with GMP to improve the taste, variety and convenience of the PKU diet. Sensory studies in individuals with PKU demonstrate that GMP foods are acceptable alternatives to amino acid medical foods. Studies in the PKU mouse model demonstrate that GMP supplemented with limiting indispensable amino acids provides a nutritionally adequate source of protein and improves the metabolic phenotype by reducing concentrations of Phe in plasma and brain. A case report in an adult with classical PKU who followed the GMP diet for 10 weeks at home indicates safety, acceptability of GMP food products, a 13-14% reduction in blood Phe levels (p<0.05) and improved distribution of dietary protein throughout the day compared with the amino acid diet. In summary, food products made with GMP that is supplemented with limiting indispensable amino acids provide a palatable alternative source of protein that may improve dietary compliance and metabolic control of PKU.

Dietary Glycomacropeptide Supports Growth and Reduces the Concentrations of Phenylalanine in Plasma and Brain in a Murine Model of Phenylketonuria ,

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of phenylalanine hydroxylase (PAH) that requires life-long adherence to a low-phenylalanine (Phe) diet. Glycomacropeptide (GMP) is uniquely suited to the nutritional management of PKU, because pure GMP contains no Phe. Our aim was to assess how ingestion of diets containing GMP support growth and affect the concentrations of amino acids in plasma and brains of mice with a deficiency of PAH, the Pahenu2 mouse (PKU mouse). Experiments were conducted in 4- to 6-wk-old wild-type (WT) (C57Bl/6) and PKU mice fed diets containing 20% protein from casein, amino acids, or GMP supplemented with limiting indispensable amino acids (IAA). PKU mice fed the GMP diet showed gains in body weight, feed efficiency, and a protein efficiency ratio that did not differ from the amino acid diet. The concentrations of isoleucine and threonine in plasma showed a significant 2- to 3-fold increase for WT and PKU mice fed GMP compared with casein or amino acid diets, respectively. PKU mice fed the GMP diet had decreased concentrations of Phe in plasma (11% decrease) and in 5 regions of the brain (20% decrease) compared with the amino acid diet. The concentration of Phe in the brain was inversely correlated with the concentrations of isoleucine, threonine, and valine in plasma (R2 = 0.74; P < 0.0001), suggesting competitive inhibition of Phe transport into the brain. In summary, PKU mice fed GMP showed comparable growth and reduced concentrations of Phe in plasma and the brain compared with an amino acid diet. These data support the use of GMP supplemented with IAA as an alternative source of dietary protein for individuals with PKU.

Response of Phenylketonuria to Tetrahydrobiopterin

A favorable response, indicated by decline of blood phenylalanine (Phe) in patients with phenylketonuria (PKU), to orally administered 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) has been reported in many countries following the first publication in 1999. In this review, we describe the experience in the United States with PKU patients and their response to BH4. A significant response to BH4 is arbitrarily considered as a decrease of 30% or greater of blood Phe concentration 24 h after administration of BH4. In our studies, 18 of 37 patients with PKU (49%) responded to oral BH4 by >30% decrease in blood Phe concentration. Four PKU patients responded with a decrease of blood Phe concentration between 17.3 and 26.3%. It is suggested that patients with sufficient response to BH4 are candidates who will benefit from BH4 as it becomes available for PKU management. In a separate trial, 20 patients with PKU were screened with ascending doses of BH4: 10, 20, and 40 mg/kg. A favorable response was found in 10 subjects (50%) after 10 mg/kg BH4 and 14 subjects (70%) after 20 mg/kg BH4. There was no additional advantage to 40mg/kg BH4. A 1-wk trial with 10 and 20 mg/kg BH4 in the same 20 patients showed blood Phe concentrations lowest after 7 d of BH4. The BH4-responsive patients were genotyped and most were compound heterozygotes with 1 mild mutation on 1 allele, responsible for the increase of the residual activity of Phe hydroxylase when BH4 was added. Individuals with the same genotype exhibit different responses upon administration of BH4, attributed to epigenetic factors, such as the metabolic makeup of the individual. Patients with PKU, regardless of their genotype or classification, need to be screened for response to BH4. The majority of patients are identified by 10 mg/kg BH4.

Optimal management of phenylketonuria: A centralized expert team is more successful than a decentralized model of care

ObjectiveTo compare phenylketonuria (PKU) management by a centralized, expert team in the Province of Nova Scotia (NS) with the decentralized approach in New Brunswick (NB). Study designRetrospective chart review documented frequency of outpatient visits, phenylalanine (Phe) concentration, and medical formula use. Structured telephone interviews with the 8 regional NB dietitians (NB-D) documented their knowledge and support in PKU management. Patients with PKU (n=108; age, birth to 42 years) reside in NB (n=69) and NS (n=39). More were lost to contact in NB than in NS (9/69 vs 1/39) and more were completely off diet in NB than in NS (24/60 vs 1/38, P=.05). All 15 children <2 years old followed by a PKU team in either NS or Saint John, NB had optimal Phe levels. Children 2 to 12 years of age in NS had better Phe control and more medical visits than in NB (P < .01). Older patients had more episodes of elevated Phe levels (P=.01). Formula was dispensed in appropriate yearly amounts to 52% in NB and >95% in NS. Mental handicap or borderline intelligence was common in both NB (44%) and NS (42%). All NB-D wished additional specialized medical, nursing, or social work assistance. ConclusionsPKU management appears to be more effective with an expert, coordinated team approach.

Protein substitutes for PKU: what's new?

Protein substitutes are an essential component in the management of phenylketonuria. A series of studies at Birmingham Children's Hospital have investigated their optimal dosage, timing and practical administration as well as the efficacy and tolerance of novel protein substitutes. The key findings are as follows. (1). Lower dosages of protein substitute (1.2 g/kg per day of protein equivalent) adversely affect blood phenylalanine control in children aged 1-10 years. (2). There is wide variability in 24 h blood phenylalanine concentrations. (3). Adjusting protein substitute timing during daytime does not reduce blood phenylalanine variability. (4). Repeated 4 h administration of protein substitute throughout 24 h markedly reduces phenylalanine variability and leads to lower phenylalanine concentrations. (5). The new, concentrated, low-volume protein substitutes and amino acid tablet preparations are efficacious and well tolerated by patients. (6). Administration of protein substitute as a gel or paste has reduced difficulties with administration of protein substitute in children. These findings are important in rationalizing treatment strategies, improving patient compliance and overall in improving blood phenylalanine control.

Benefits of mutation analysis and examination of brain phenylalanine levels in the management of phenylketonuria.

* Abbreviations: PKU = : phenylketonuria • PAH = : phenylalanine hydroxylase Phenylketonuria (PKU) was first described in 1934 by Folling in Norway1; however, the actual gene defect was not elucidated until 1983 by Woo and colleagues.2 During the past 17 years, progress in assessing the usefulness of DNA analyses in the management of PKU has been obscured by the numerous mutations of the phenylalanine hydroxylase (PAH) gene that have been described to date.3The fact that routine mutational analysis for PKU is unavailable in the United States at present is attributable to several factors, but speaks forcefully to the lack of appreciation of the usefulness of DNA technology by professionals as well as that of the general public. Although mutation analyses potentially represent new powerful techniques in a wide variety of medical disorders, such as cancer, societal attitudes have been influential in delaying implementation of the resources necessary for clinical application of these new methodologies. In the case of PKU, such delays are understandable because of the need to establish a scientific background of data, which demonstrates the value of mutational analysis of the PAH gene to the practicing clinician, thereby justifying the cost to parents, as well as funding agencies. The pioneering work of Scriver and colleagues in developing the Phenylalanine Hydroxylase Locus Database3and the …

Survey of national guidelines for the treatment of phenylketonuria.

Phenylketonuria treatment policies vary not only between different countries worldwide, but also within one country. Recommendations and guidelines for phenylketonuria should deal with the following subjects: 1. What is the target age to start dietary phenylalanine restriction under newborn-screening conditions? 2. At which plasma phenylalanine concentration should phenylalanine restriction be initiated? 3. Which are the recommended plasma phenylalanine concentrations at different ages? 4. What is the recommended frequency of monitoring phenylalanine in plasma? Statements from the following countries are presented: Czech Republic, Denmark, France, Germany, Great Britain, Hungary, Ireland, Poland, Slovakia and the United States. Due to the lack of internationally accepted guidelines, management of phenylketonuria still varies between different countries. Our efforts should focus on the formulation of internationally acceptable and accepted recommendations for the treatment of patients with phenylketonuria at different ages.

Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors.

The development of guidelines for phenylketonuria (PKU) management in the United Kingdom has resulted in much discussion in the community of parents and PKU clinics and parents have asked why the United States does not have such guidelines. The objective of this report is to discuss PKU management in the United States, the British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines in the United States. Members of the American Academy of Pediatrics (AAP) Committee on Genetics (COG) reviewed the literature and conducted surveys of parents of children with PKU, young adults with PKU, and directors of PKU clinics in the United States. A meeting was held at the National Institute of Child Health and Human Development to review the AAP/COG efforts at reviewing the status of PKU management and guideline development in the United States. The British guidelines are more stringent than the PKU management practices in many parts of the United States. Evidence exists that stricter management improves developmental outcome. The parents who responded to the surveys indicated willingness to comply with more stringent dietary management if that would improve outcome. They also identified problems that make such management difficult. The clinic directors supported the timeliness of the review. Some had begun a trend toward more stringent control of blood phenylalanine concentrations, at least in the first 4 years of life. The AAP Committee on Genetics will complete its subject review of the management of PKU. Guidelines for care of PKU in the United States probably would look quite similar to the existing guidelines in other countries. The parents surveyed supported more stringent PKU management, but information from a broader distribution of parents would provide a more representative view. The status of the US health care system creates problems for improved PKU management in the United States that do not exist in the countries already following stricter guidelines.

A survey of feeding practices in infants with phenylketonuria

Summary Background: Although the management of phenylketonuria (PKU) in infancy and early childhood is a critical part of the overall care of the disorder, there are few guidelines on infant feeding in this condition. This survey was undertaken to establish the practices of dietitians from major PKU centres in Australia and the UK. Methods: A postal questionnaire examining infant feeding practices was sent to dietitians at nine major PKU centres in the UK and four in Australia, with each dietitian describing the infant feeding process in their last five infants. A total of 63 infants were investigated. Results: A lower than expected incidence of infants with PKU were breast fed at the time of diagnosis: 28% of infants in the UK and 41% from Australia. Amino acid intake varied between 2.0 g kg−1 day−1 to 3.5 g kg−1 day−1 with 86% of dietitians calculating total amino acid intake derived from both protein substitute intake and normal infant formula. Amino acid intake was not calculated in breast‐fed infants. In breast‐fed infants, phenylalanine‐free protein substitute was always given before breast feeds. In bottle‐fed infants, normal infant formula was given before phenylalanine‐free protein substitute in 75% of infants. Solids were usually introduced between 3 and 6 months and phenylalanine‐free solids were given initially to the majority of infants. Most problems were seen when introducing a more concentrated phenylalanine‐free protein substitute to maintain the required amino acid intake in older infants. Age of introduction varied between 4 and 12 months and type of approach included concentrating infant protein substitutes, use of L‐amino acid protein substitutes only, or L‐amino acid protein substitutes with added carbohydrate, vitamins and minerals. Conclusions: There appeared to be no uniform policy of infant feeding in PKU and more work is needed correlating practices to develop national and even international protocols for management.

Maternal Phenylketonuria: A New Cause for Concern

The start of newborn screening for phenylketonuria (PKU) during the early 1970s has given rise to an increasing number of women who have been identified and successfully treated for the disease in childhood and are now preparing to have children of their own. Early detection and initiation of nutritional therapy before conception is key to a successful pregnancy outcome. Nurses who understand the pathophysiology, dietary limitations, and management of PKU in pregnancy can provide the care necessary for optimal maternal and neonatal health.

Low iron stores in infants and children with treated phenylketonuria: A population at risk for iron-deficiency anaemia and associated cognitive deficits

A retrospective study of 53 patients with phenylketonuria (PKU), whose disease was managed with a low-phenylalanine diet, revealed a high incidence of iron depletion (as reflected by subnormal serum ferritin concentrations). Serum ferritin concentrations under 10 micrograms/l were found in one out of six infants aged 5-12 months. Concentrations under 16 micrograms/l were found in 16 of 22 children aged 1-3 years and in 11 of 25 children aged 4-12 years. Dietary iron, estimated from prescribed intakes of medical foods, exceeded the Canadian recommended nutrient intake, suggesting that low stores of iron may be secondary to reduced bioavailability and absorption of iron. These findings suggest that the current dietary management of PKU is associated with an increased risk for low iron stores. Investigators have reported an association in young children between iron-deficiency anaemia and both cognitive and motor disturbances. Children with PKU, already at risk of neurological damage because of phenylalanine neurotoxicity, may be at increased risk as a result of iron depletion. Serum ferritin as well as haemoglobin concentration should be monitored, along with plasma phenylalanine and tyrosine, to ensure optimum treatment of affected children.

Implementation of a self-care approach in a pediatric interdisciplinary phenylketonuria (PKU) clinic.

Abstract A nursing practice framework, Orem's self-care deficit theory, was implemented within an interdisciplinary clinic to encourage greater client involvement in the management of phenylketonuria. Concepts from the literature related to planned change provided guidance in planning, implementing, and evaluating the change from a traditional approach to the self-care mode of client care. The reactions of the client and family and of the interdisciplinary team are discussed.

Direct amino acid analyses of mozzarella cheese

The amino acid content of mozzarella (low moisture, part skim milk) and asadero cheeses was determined by the column chromatographic method. Data from the direct analyses of the mozzarella cheeses were compared with the calculated amino acid composition reported in tables in Agriculture Handbook No. 8-1. Phenylalanine and tyrosine contents were found to be higher in the direct analyses than in the calculated data in Handbook No. 8-1 (1.390 gm and 1.127 gm for phenylalanine, and 1.493 gm and 1.249 gm for tyrosine per 100 gm edible portion, respectively). That is of particular concern in the dietary management of phenylketonuria, in which accuracy in computing levels of phenylalanine and tyrosine is essential.

Acidic metabolites of phenylalanine in plasma of phenylketonurics

Seven aromatic metabolites of phenylalanine were determined in plasma of 20 patients with classical phenylketonuria by means of capillary gas chromatography. The results obtained showed good correlation with plasma phenylalanine levels. Plasma aromatic acid levels may prove useful in the diagnosis and management of phenylketonuria, as well as in research of this disorder.

Phenylalanine Ammonia Lyase in the Management of Phenylketonuria: The Relationship Between Ingested Cinnamate and Urinary Hippurate in Humans

Phenylalanine Ammonia Lyase in the Management of Phenylketonuria: The Relationship Between Ingested Cinnamate and Urinary Hippurate in Humans

Effects of increasing Mg++ ion concentration on the PKU monitoring assay.

Inaccuracies in a commonly used bacterial inhibition assay for blood phenylalanine levels arise when the Mg++ ion concentration in the assay medium is increased. This has practical implications in the diagnosis and management of phenylketonuria.

Present Status of Different Mass Screening Procedures for Phenylketonuria: Medical Research Council Working Party on Phenylketonuria

The Phenistix screening test for phenylketonuria in newborn infants, when used routinely at the recommended age of 4 to 6 weeks, passes as normal a substantial proportion-perhaps between a quarter and a half-of children with the disease, who are then diagnosed only after brain damage has occurred. Screening procedures based on three other tests-namely, the paper chromatography test for o-hydroxyphenylacetic acid in urine, the Guthrie test for phenylalanine in blood, and a modification of the Guthrie test for phenylalanine in urine-have been compared with each other and with the Phenistix test in a special field inquiry. Each of the three tests is more efficient than the Phenistix test for the detection of phenylketonuria at an early age.A full appraisal indicates that the Guthrie test on blood would be the most satisfactory of the three tests to replace the Phenistix test as a screening procedure. Routine use of this would involve comprehensive arrangements for obtaining a single specimen of blood by heel-prick from every newborn infant at the age of 6 days or more, but preferably not later than 14 days, and for the rapid and economical processing of the specimens and skilled interpretation of the results at a few laboratory centres. These requirements have not proved difficult to meet in practice in the area where this procedure has been studied.A positive screening test result does not signify a firm diagnosis of phenylketonuria, but is an indication for fuller investigation, most suitably at one of a small number of centres specializing in the management of phenylketonuria and other inborn errors of metabolism.