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1.  Advances in the nutritional and pharmacological management of phenylketonuria 
Structural Abstract
Purpose of review
The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU).
Recent findings
Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phe intact protein that represents a new dietary alternative to synthetic amino acids (AAs) for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an AA diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin (BH4), acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral AAs (LNAA) inhibit phe transport across the intestinal mucosa and blood brain barrier; LNAA are most effective for individuals unable to comply with the low-phe diet.
Although a low-phe synthetic AA diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to AA formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.
PMCID: PMC4004170  PMID: 24136088
phenylketonuria; glycomacropeptide; tetrahydrobiopterin; large neutral amino acids; bone biomechanical performance
2.  Food Products Made With Glycomacropeptide, a Low Phenylalanine Whey Protein, Provide a New Alternative to Amino Acid-Based Medical Foods for Nutrition Management of Phenylketonuria 
Phenylketonuria (PKU), an inborn error in phenylalanine (phe) metabolism, requires lifelong nutrition management with a low-phe diet, which includes a phe-free amino acid-based medical formula to provide the majority of an individual’s protein needs. Compliance with this diet is often difficult for older children, adolescents and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet since it is naturally low in phe. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein utilization and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phe dietary protein for those with PKU.
PMCID: PMC3402906  PMID: 22818728
Inborn Errors of Metabolism; Whey Proteins; Phenylalanine Metabolism; Glycomacropeptide
3.  Purification and Use of Glycomacropeptide for Nutritional Management of Phenylketonuria 
Journal of food science  2009;74(4):E199-E206.
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.
PMCID: PMC3632067  PMID: 19490325
foods; glycomacropeptide; phenylalanine; phenylketonuria; purification
4.  Reassessment of Phenylalanine Tolerance in Adults with Phenylketonuria is Needed as Body Mass Changes 
Molecular genetics and metabolism  2009;98(4):331-337.
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 8 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 5 subjects were overweight, body mass index (BMI) 25–28. With the guidance of a metabolic dietitian, 7 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 (R2=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.
PMCID: PMC2783926  PMID: 19747868
PKU; amino acid requirements; genotype-phenotype relationship; low-phenylalanine diet
5.  Nutritional status of patients with phenylketonuria in Japan 
Accumulating evidence suggests that hyperphenylalaninemia in phenylketonuria (PKU) can cause neuropsychological and psychosocial problems in diet-off adult patients, and that such symptoms improve after resumption of phenylalanine-restricted diet, indicating the need for lifetime low-phenylalanine diet. While limiting protein intake, dietary therapy should provide adequate daily intake of energy, carbohydrates, fat, vitamins, and microelements. We evaluated nutrient balance in 14 patients with classical PKU aged 4–38 years. Approximately 80–85% of the recommended dietary allowance (RDA) of protein in Japanese was supplied through phenylalanine-free (Phe-free) milk and Phe-free amino acid substitutes. Nutritional evaluation showed that the calorie and protein intakes were equivalent to the RDA. Phenylalanine intake was 9.8 ± 2.2 mg/kg of body weight/day, which maintained normal blood phenylalanine concentration by the 80% Phe-free protein rule. The protein, fat, and carbohydrate ratio was 9.5:23.9:66.6% with relative carbohydrate excess. Phe-free milk and amino acid substitutes provided 33.7% of carbohydrate, 82.1% of protein, and 66.7% of fat intake in all. Selenium and biotin intakes were 25.0% and 18.1% of the RDA and adequate intake (AI) for Japanese, respectively; both were not included in Phe-free milk. PKU patients showed low serum selenium, low urinary biotin, and high urinary 3-hydroxyisovaleric acid in this study. The intakes of magnesium, zinc, and iodine were low (71.5%, 79.5%, and 71.0% of the RDA, respectively) and that of phosphorus was 79.7% of the AI, although they were supplemented in Phe-free milk. PKU patients depend on Phe-free milk and substitutes for daily requirement of microelements and vitamins as well as protein and fat. Development of low-protein food makes it possible to achieve the aimed phenylalanine blood level, but this lowers the intake of microelements and vitamins from natural foods. The dietary habits vary continuously with age and environment in PKU patients. We recommend the addition of selenium and biotin to Phe-free milk in Japan and the need to review the composition of microelements and vitamins in A-1 and MP-11 preparations.
•80- 85% of the recommended amount of protein should be supplied from Phe-free amino acid substitutes for good control.•Nutritional evaluation in PKU patients is necessary for dietary control and for checking the contents of medical foods.•Selenium, and biotin in Phe-free milk in Japan is insufficient and should be supplied immediately.•Microelement from early children to adults is necessary more than in infants due to low protein diet.
PMCID: PMC4995528  PMID: 27595068
Phenylketonuria; Phenylalanine hydroxylase; Nutrition; Microelement; Vitamin; Selenium; Biotin; Magnesium; Zinc; Iodine; Phosphorus
6.  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.
PMCID: PMC3633220  PMID: 18956251
7.  Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries 
The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL.
A multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient’s health status by the investigator and treatment with tetrahydrobiopterin (BH4).
Data from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake.
Patients with PKU showed good HRQoL in the study, both with the generic and PKU-specific measures. Negative impacts of PKU on a patient’s life, including the emotional impact of PKU and its management, was delineated by the PKU-QOLs across all age groups.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0294-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4542123  PMID: 26084935
Rare disease; Phenylketonuria; Questionnaires; Health-related quality of life
8.  The personal burden for caregivers of children with phenylketonuria: A cross-sectional study investigating time burden and costs in the UK 
Management of phenylketonuria (PKU) is mainly achieved through strict dietary control that aims to limit the intake of phenylalanine (Phe). Adherence to this diet is burdensome due to the need for specially prepared low-Phe meals and regular monitoring of Phe concentrations. A UK cross-sectional study was conducted to identify the personal time and monetary burden associated with aspects of the PKU lifestyle for caregivers of children (aged < 18 years) living with PKU.
Caregivers of pediatric patients with PKU attending one of four specialist metabolic centers in the UK were invited to participate in a questionnaire-based survey that evaluated different aspects of PKU management that could potentially present out-of-pocket costs (OOPCs) or time burden. Medical clinicians/dieticians provided patient information on PKU severity and an assessment of blood Phe control.
The survey was completed by 114 caregivers of 106 children having mild or moderate (n = 45; 39%) or classical (n = 60; 53%) PKU (severity data missing for n = 1), among whom 8 (8%) and 87 (82%) reported poorly controlled and controlled blood Phe status, respectively; Phe control data were missing for 11 children. Dietary management of PKU incurred a median time burden of > 19 h per week. OOPCs were incurred via attendance at PKU events, PKU-related equipment, and extra holiday expenditure. 21% of caregivers reduced their working hours (median 18.5 h/week) to care for their child, with a further 24% leaving their paid jobs completely.
Discussion and conclusions
Dietary management of PKU is associated with a considerable time burden for caregivers of pediatric patients with PKU. A personal financial burden also arises from OOPCs and lost earnings.
PMCID: PMC5009233  PMID: 27622144
ACBS, Advisory Committee on Borderline Substances; DLA, Disability Living Allowance; NHS, National Health Service; NRES, NHS Research Ethics Committees; OOPC, out-of-pocket cost; PAH, phenylalanine hydroxylase; Phe, phenylalanine; PKU, phenylketonuria; Burden; Caregiver; Diet; Phenylalanine; Phenylketonuria; Pediatric
9.  Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids 
Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation.
A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks.
Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study.
In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment.
PMCID: PMC5222990  PMID: 27623981
10.  Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria 
Molecular genetics and metabolism  2010;100(4):303-308.
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 minutes after breakfast. Satiety was assessed using a visual analog scale before, immediately after and 180 minutes 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 180 minutes 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 of AAs from GMP. These results show sustained ghrelin suppression, and suggest greater satiety with ingestion of a meal containing GMP compared with AAs.
PMCID: PMC2906609  PMID: 20466571
satiety; hunger; insulin; PKU; GMP
11.  Phenylketonuria (PKU): A problem solved? 
Phenylketonuria (PKU) is a rare metabolic disorder characterized by impaired conversion of phenylalanine (Phe) to tyrosine. If left untreated, the resultant accumulation of excess blood Phe can cause physiological, neurological, and intellectual disabilities. The National PKU Alliance (NPKUA) conducted a survey of its membership to assess current health status and interest in new treatments for PKU. Of the 625 survey respondents, less than half (46.7%) reported blood Phe within (120–360 μmol/L) — the range recommended by the American College of Medical Genetics and Genomics (ACMG). The survey results also showed that younger (≤ 18 years) individuals were about 3-times as successful in keeping their blood Phe concentrations within the recommended clinical range compared with adults. Blood Phe over 360 μmol/L was reported in one-quarter (25.5%) of ≤ 18 year old individuals and almost two-thirds (61.5%) of adults. A little more than half (51.7%) of respondents reported having difficulty in managing their PKU, including the maintenance of a Phe-restricted diet. Individuals with PKU desire new treatments that would allow them to increase their intake of natural protein, discontinue or reduce their intake of medical foods (medical formula and foods modified to be low in protein), improve their mental health (including a reduction in depression and anxiety), and a reduction of their blood Phe concentrations. Respondents preferred oral administration of any newly developed therapies and, in general, disliked therapeutic injections. Injections at home were preferred over injections at a clinic. Payers, government agencies, clinicians, and industry partners should consider patient input when developing and approving new therapies and treatments for PKU.
PMCID: PMC4789336  PMID: 27014571
ACMG, American College of Medical Genetics and Genomics; NPKUA, National PKU Alliance; PAH, phenylalanine hydroxylase; Phe, phenylalanine; PKU, phenylketonuria; Phenylalanine; Phenylketonuria; Phenylalanine hydroxylase deficiency
12.  Low Bone Strength Is a Manifestation of Phenylketonuria in Mice and Is Attenuated by a Glycomacropeptide Diet 
PLoS ONE  2012;7(9):e45165.
Phenylketonuria (PKU), caused by phenylalanine (phe) hydroxylase loss of function mutations, requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP), a low-phe whey protein, provides a palatable alternative to AA formula. Skeletal fragility is a poorly understood chronic complication of PKU. We sought to characterize the impact of the PKU genotype and dietary protein source on bone biomechanics.
Wild type (WT; Pah+/+) and PKU (Pahenu2/enu2) mice on a C57BL/6J background were fed high-phe casein, low-phe AA, and low-phe GMP diets between 3 to 23 weeks of age. Following euthanasia, femur biomechanics were assessed by 3-point bending and femoral diaphyseal structure was determined. Femoral ex vivo bone mineral density (BMD) was assessed by dual-enengy x-ray absorptiometry. Whole bone parameters were used in prinicipal component analysis. Data were analyzed by 3-way ANCOVA with genotype, sex, and diet as the main factors.
Regardless of diet and sex, PKU femora were more brittle, as manifested by lower post-yield displacement, weaker, as manifested by lower energy and yield and maximal loads, and showed reduced BMD compared with WT femora. Four principal components accounted for 87% of the variance and all differed significantly by genotype. Regardless of genotype and sex, the AA diet reduced femoral cross-sectional area and consequent maximal load compared with the GMP diet.
Skeletal fragility, as reflected in brittle and weak femora, is an inherent feature of PKU. This PKU bone phenotype is attenuated by a GMP diet compared with an AA diet.
PMCID: PMC3445501  PMID: 23028819
13.  Phenylketonuria: nutritional advances and challenges 
Despite the appearance of new treatment, dietary approach remains the mainstay of PKU therapy. The nutritional management has become complex to optimize PKU patients' growth, development and diet compliance. This paper review critically new advances and challenges that have recently focused attention on potential relevant of LCPUFA supplementation, progress in protein substitutes and new protein sources, large neutral amino acids and sapropterin. Given the functional effects, DHA is conditionally essential substrates that should be supplied with PKU diet in infancy but even beyond. An European Commission Programme is going on to establish quantitative DHA requirements in this population. Improvements in the palatability, presentation, convenience and nutritional composition of protein substitutes have helped to improve long-term compliance with PKU diet, although it can be expected for further improvement in this area. Glycomacropeptide, a new protein source, may help to support dietary compliance of PKU subject but further studies are needed to evaluate this metabolic and nutritional issues. The PKU diet is difficult to maintain in adolescence and adult life. Treatment with large neutral amino acids or sapropterin in selected cases can be helpful. However, more studies are necessary to investigate the potential role, dose, and composition of large neutral amino acids in PKU treatment and to show long-term efficacy and tolerance. Ideally treatment with sapropterin would lead to acceptable blood Phe control without dietary treatment but this is uncommon and sapropterin will usually be given in combination with dietary treatment, but clinical protocol evaluating adjustment of PKU diet and sapropterin dosage are needed.
In conclusion PKU diet and the new existing treatments, that need to be optimized, may be a complete and combined strategy possibly positive impacting on the psychological, social, and neurocognitive life of PKU patients.
PMCID: PMC3395819  PMID: 22305125
PKU; treatment advances; new strategies; LCPUFA supplementation; LNAA; sapropterin
14.  Differential Effects of Low-Phenylalanine Protein Sources on Brain Neurotransmitters and Behavior in C57Bl/6-Pahenu2 Mice 
Molecular genetics and metabolism  2014;111(4):452-461.
Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase, which metabolizes phenylalanine (phe) to tyrosine. A low-phe diet plus amino acid (AA) formula is necessary to prevent cognitive impairment; glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to the AA formula. Our objective was to assess neurotransmitter concentrations in brain and the behavioral phenotype of PKU mice (Pahenu2 on the C57Bl/6 background) and how this is affected by low-phe protein sources. Wild type (WT) and PKU mice, both male and female, were fed high-phe casein, low-phe AA, or low-phe GMP diets between 3–18 weeks of age. Behavioral phenotype was assessed using the open field and marble burying tests, and brain neurotransmitter concentration measured using HPLC with electrochemical detection system. Data were analyzed by 3-way ANOVA with genotype, sex, and diet as the main treatment effects. Brain mass and the concentrations of catecholamines and serotonin were reduced in PKU mice compared to WT mice; the low-phe AA and GMP diets improved these parameters in PKU mice. Relative brain mass was increased in female PKU mice fed the GMP diet compared to the AA diet. PKU mice exhibited hyperactivity and impaired vertical exploration compared to their WT littermates during the open field test. Regardless of genotype or diet, female mice demonstrated increased vertical activity time and increased total ambulatory and horizontal activity counts compared with male mice. PKU mice fed the high-phe casein diet buried significantly fewer marbles than WT control mice fed casein; this was normalized in PKU mice fed the low-phe AA and GMP diets. In summary, C57Bl/6-Pahenu2 mice showed an impaired behavioral phenotype and reduced brain neurotransmitter concentrations that were improved by the low-phe AA or GMP diets. These data support lifelong adherence to a low-phe diet for PKU.
PMCID: PMC3995025  PMID: 24560888
Phenylketonuria; glycomacropeptide; marble burying; open field; catecholamines; serotonin
15.  Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria 
Molecular genetics and metabolism  2010;100(3):229-233.
Sapropterin dihydrochloride, a synthetic, stable form of the tetrahydrobiopterin cofactor of phenylalanine hydroxylase, has been shown to reduce plasma phenylalanine (Phe) levels in a significant portion of patients with phenylketonuria (PKU). When we undertook introducing this medication to our PKU clinic population, the challenges of recalling and reconnecting with a variably treated and variably compliant patient population became apparent. We offered a trial of sapropterin to all of our clinic patients with PKU. In order to determine responsiveness, we used a 2 tier dose escalation protocol. After diet records were taken, and baseline plasma Phe levels were established, a 7-day trial of sapropterin at 10 mg/kg/day was started. At day 8, plasma phenylalanine levels were measured. Patients were considered to be responders if they had a 30% reduction in plasma Phe. If they did not respond, the dose of sapropterin was increased to 20 mg/kg/day, and levels were rechecked again in 8 days. Patients who were not responders at this time continued sapropterin for a total of 30 days and had Phe levels checked one last time. Patients who were responders and who were on a Phe restricted diet underwent gradual liberalization of their diet to the maximum tolerated natural protein intake while still maintaining plasma levels in the acceptable treatment range of 120–360 µmol/L. In our population, 36/39 patients with hyperphenylalaninemia (HPA) who were offered a trial of sapropterin elected to start sapropterin. Five of 36 patients were non-adherent with diet records and/or medication doses and we were unable to determine if they were responders. We were unable to categorize 2 of 31 of the patients who completed the trial as responders due to dietary issues, though they were probably responders. Of the 29 patients who completed the sapropterin trial and we could categorize, 18/29 (62%) were determined to be responders. Patients were classified based on their off-diet diagnostic plasma phenylalanine levels as classical PKU (>1200 µmol/L) and variant PKU (>400and <1200 µmol/L). The group with variant PKU had a 100% response rate, and patients with classical PKU had a 27% response rate. For the patients in the responder group who were on Phe restricted diet, we were able to liberalize most diets, in two cases to unrestricted protein intake. We also had unexpected beneficial findings in our clinic experience, including positive behavioral improvements in an adult severely affected by untreated PKU. Even in patients who were not considered to be responders, the introduction of sapropterin provided a tool to reconnect with patients and re-introduce beneficial dietary measures.
PMCID: PMC3135651  PMID: 20418136
phenylketonuria; sapropterin dihydrochloride; tetrahydrobiopterin
16.  Nutritional Changes and Micronutrient Supply in Patients with Phenylketonuria Under Therapy with Tetrahydrobiopterin (BH4) 
JIMD Reports  2012;9:31-40.
Background: Since 2008 patients with BH4-sensitive phenylketonuria can be treated with sapropterin dihydrochloride (Kuvan®) in addition to the classic phenylalanine (Phe) restricted diet. The aim of this study was to evaluate the nutritional changes and micronutrient supply in patients with phenylketonuria (PKU) under therapy with tetrahydrobiopterin (BH4).
Subjects and Methods: 19 children with PKU (4–18 years) and potential BH4-sensitivity were included, 14 completed the study protocol. Dried blood Phe concentrations as well as detailed dietary records were obtained throughout the study at preassigned study days.
Results: Eight patients could increase their Phe tolerance from 629 ± 476 mg to 2131 ± 1084 mg (P = 0.006) under BH4 while maintaining good metabolic control (Phe concentration in dried blood 283 ± 145 μM vs. 304 ± 136 μM, P = 1.0), therefore proving to be BH4-sensitive. They decreased their consumption of special low protein products and fruit while increasing their consumption of high protein foods such as processed meat, milk and dairy products. Intake of vitamin D (P = 0.016), iron (P = 0.002), calcium (P = 0.017), iodine (P = 0.005) and zinc (P = 0.046) significantly declined during BH4 treatment while no differences in energy and macronutrient supply occurred.
Conclusion: BH4-sensitive patients showed good metabolic control under markedly increased Phe consumption. However, the insufficient supply of some micronutrients needs consideration. Long-term multicenter settings with higher sample sizes are necessary to investigate the changes of nutrient intake under BH4 therapy to further evaluate potential risks of malnutrition. Supplementation may become necessary.
PMCID: PMC3565664  PMID: 23430545
17.  Clinical relevance of the discrepancy in phenylalanine concentrations analyzed using tandem mass spectrometry compared with ion-exchange chromatography in phenylketonuria 
Metabolic control of phenylketonuria (PKU) and compliance with the low-phenylalanine (phe) diet are frequently assessed by measuring blood phe concentrations in dried blood spots (DBS) collected by patients instead of plasma phe concentrations.
Our objective was to investigate the difference in blood phe concentrations in DBS collected by subjects and analyzed using either a validated newborn screening tandem mass spectrometry (MS/MS) protocol or ion-exchange chromatography (IEC) compared to plasma phe concentrations obtained simultaneously and analyzed using IEC.
Three to four fasting blood samples were obtained from 29 subjects with PKU, ages 15–49 years. Capillary blood was spotted on filter paper by each subject and the DBS analyzed using both MS/MS and IEC. Plasma was isolated from venous blood and analyzed using IEC.
Blood phe concentrations in DBS analyzed using MS/MS are 28% ± 1% (n = 110, p < 0.0001) lower than plasma phe concentrations analyzed using IEC resulting in a blood phe concentration of 514 ± 23 μmol/L and a plasma phe concentration of 731 ± 32 μmol/L (mean ± SEM). This discrepancy is larger when plasma phe is > 600 μmol/L. Due to the large variability across subjects of 13.2%, a calibration factor to adjust blood phe concentrations is not recommended. Analysis of DBS using IEC reduced the discrepancy to 15 ± 2% lower phe concentrations compared to plasma analyzed using IEC (n = 38, p = 0.0001). This suggests that a major contributor to the discrepancy in phe concentrations is the analytical method.
Use of DBS analyzed using MS/MS to monitor blood phe concentrations in individuals with PKU yields significantly lower phe levels compared to plasma phe levels analyzed using IEC. Optimization of current testing methodologies for measuring phe in DBS, along with patient education regarding the appropriate technique for spotting blood on filter paper is needed to improve the accuracy of using DBS to measure phe concentrations in PKU management.
•Phe concentration in dried blood spots is significantly lower than plasma phe.•Blood phe concentration cannot be adjusted due to large variability across subjects.•Analysis of dried blood spots using IEC instead of MS/MS improves accuracy.•Plasma phe concentration using IEC is the most accurate for metabolic monitoring in PKU.
PMCID: PMC4789345  PMID: 27014575
PKU, phenylketonuria; pah, phenylalanine hydroxylase; phe, phenylalanine; AAA, amino acid analyzer; MS/MS, tandem mass spectrometry; IEC, ion-exchange chromatography; tyr, tyrosine; DBS, dried blood spot; Bland–Altman; Amino acid analyzer; Phenylalanine analytical methods; Newborn screening
18.  Phenylketonuria: a review of current and future treatments 
Translational Pediatrics  2015;4(4):304-317.
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed.
PMCID: PMC4728993  PMID: 26835392
Phenylketonuria (PKU); phenylalanine hydroxylase (PAH); dietary therapy; tetrahydrobiopterin; large neutral amino acids (LNAA); glycomacropeptides (GMP); phenylalanine ammonia lyase; probiotic
19.  The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply 
Background and aims
BH4-sensitive phenylketonuria (PKU) patients relax their phenylalanine (Phe) restricted diet due to increased Phe tolerance, while keeping dried blood Phe concentrations with in the therapeutic range. We aimed to investigate metabolic control, eating habits and nutrient supply under long-term BH4-therapy.
Patients and methods
Retrospective analysis of mean dried blood Phe concentrations and their variability, food and nutrient intake in BH4-sensitive patients (n = 8, 3f, age 6.0–16.6 y) under classical dietary treatment for one year and during the three years after initiation of BH4.
Phe concentrations of BH4-sensitve PKU patients remained within therapeutic range throughout the observation period, independent of therapeutic regime. Under BH4, Phe tolerance increased significantly (493.2 ± 161.8 mg/d under classical diet vs 2021.93 ± 897.4 mg/d two years under BH4; P = 0.004). Variability of Phe concentrations remained unchanged (mean SD; P = 1.000). Patients adjust their food choice and significantly increased their intake of cereals, potatoes, dairy products and meat (P = 0.019, P = 0.016, P = 0.016 and P = 0.016, respectively). Under diet changes after implementation of BH4 a drop in micronutrient intake (vitamin D, folic acid, iron, calcium, iodine) could be revealed (P = 0.005, P < 0.001, P = 0.004, P = 0.001, P = 0.003, respectively).
BH4-sensitive PKU patients can achieve good metabolic control under an adjuvant BH4- or a BH4 monotherapy. The liberalized diet under BH4 seems to jeopardize the quality of patients' nutrition, and these patients require close follow-up and special nutrition education to minimize the risk for imbalanced diet and nutrient deficiencies.
PMCID: PMC4750587  PMID: 26937412
AAM, amino acid mixture; BH4, tetrahydrobiopterin; Phe, phenylalanine; PKU, phenylketonuria
20.  "MY PKU": increasing self-management in patients with phenylketonuria. A randomized controlled trial 
Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism. The inability to convert phenylalanine (Phe) into tyrosine causes Phe to accumulate in the body. Adherence to a protein restricted diet, resulting in reduced Phe levels, is essential to prevent cognitive decline. Frequent evaluation of plasma Phe levels and, if necessary, adjustment of the diet are the mainstay of treatment. We aimed to assess whether increased self-management of PKU patients and/or their parents is feasible and safe, by providing direct online access to blood Phe values without immediate professional guidance.
Thirty-eight patients aged ≥ 1 year participated in a 10 month randomized controlled trial. Patients were randomized into a study group (1) or a control group (2). Group 2 continued the usual procedure: a phone call or e-mail by a dietician in case of a deviant Phe value. Group 1 was given a personal "My PKU" web page with a graph of their recent and previous Phe values, online general information about the dietary treatment and the Dutch PKU follow-up guidelines, and a message-box to contact their dietician if necessary. Phe values were provided on "My PKU" without advice. Outcome measures were: differences in mean Phe value, percentage of values above the recommended range and Phe sample frequency, between a 10-month pre-study period and the study period in each group, and between the groups in both periods. Furthermore we assessed satisfaction of patients and/or parents with the 'My PKU' procedure of online availability.
There were no significant differences in mean Phe value, percentage of values above recommended range or in frequency of blood spot sampling for Phe determination between the pre-study period and the study period in each group, nor between the 2 groups during the periods. All patients and/or parents expressed a high level of satisfaction with the new way of disease management.
Increased self-management in PKU by providing patients and/or parents their Phe values without advice is feasible and safe and is highly appreciated.
Trial registration
The trial was registered with The Netherlands National Trial Register (NTR #1171) before recruitment of patients.
PMCID: PMC3133536  PMID: 21708003
21.  Dietary Protein Counting as an Alternative Way of Maintaining Metabolic Control in Phenylketonuria 
JIMD Reports  2011;3:131-139.
Objective: To compare a gram protein exchange system (1g=50-mg Phenylalanine) with a unit exchange system (1unit=15-mg Phenylalanine) and its effect on the blood Phenylalanine (Phe) levels and acceptance in the dietary management for children and adolescents with Phenylketonuria.
Methods: In Phase One, participants were randomised to continue counting Phe unit exchanges (n=8) or changed to counting gram protein exchanges (n=10), using a new diet chart developed in-house. Foods containing less than 20mg Phe per serve were now considered “free.” Interim data analysis confirmed no significant deterioration in Phe levels of the study group and the control group was changed to protein counting.
In Phase Two, 18 participants were educated to use an updated version of the in-house diet chart – in this version foods containing less than 50mg Phe per serve were considered “free.”
In both phases, attitudes to PKU and its management were evaluated at baseline and 6months. Phenylalanine and tyrosine levels were measured from filter paper blood spots by tandem mass spectrometry.
Results: Phase One: Phe levels over 6months were comparable to pre-study levels (mean Phe pre 366μmol/L+/− 169, mean Phe post change=388μmol/L+/− 160).
Phase Two: Four participants had a significant improvement in blood Phe levels, nine showed no significant change and one participant’s levels were significantly higher. There was incomplete data on four participants. All participants preferred the freer diet chart.
Conclusion: Protein exchanges (foods containing less than 50mg Phe/serve uncounted) are an alternative method of measuring Phe intake in the dietary management of Phenylketonuria.
PMCID: PMC3509851  PMID: 23430885
22.  High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover trial 
The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need the strict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines to help them make well-informed choices. We have carried out the first randomised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two 4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one with placebo in randomly allocated order via a randomisation coding list in a double-blind cross-over design. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administered at the end of each study period. In addition, patients and for each patient a friend or relative, completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients’ mood. Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation (p = 0.029). Both patients and their friend or relative reported lower scores on the POMS questionnaires during Phe supplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted “diet for life” might be an advisable option for many.
PMCID: PMC3026661  PMID: 21153445
23.  A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria 
Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R=.32, P=.03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.
PMCID: PMC4227302  PMID: 21305356
24.  A Systematic Review of BH4 (Sapropterin) for the Adjuvant Treatment of Phenylketonuria 
JIMD Reports  2012;8:109-119.
Context: Dietary management is the mainstay of effective treatment in PKU, but dietary restriction is difficult and additional treatment options are needed.
Objective: To systematically review evidence regarding sapropterin (BH4) use as an adjunct to dietary restriction in individuals with PKU.
Data Sources: Five databases including MEDLINE up to August 2011.
Study Selection: Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria.
Data Extraction: Two reviewers independently extracted data regarding participant and intervention characteristics and outcomes and assigned overall quality and strength of evidence ratings based on predetermined criteria.
Results: BH4 research includes two randomized controlled trials (RCTs) and three uncontrolled open-label trials. Phenylalanine (Phe) levels were reduced by at least 30 % in up to half of treated participants (32–50 %). In one RCT comparing placebo on likelihood of a 30 % reduction in Phe, 9 % of those on placebo achieved this effect, compared with 44 % of the treated group after 6 weeks. Phe tolerance and variability were improved in treated participants in studies assessing those outcomes. No comparative studies assessed long-term outcomes including cognitive effects, nutritional status, or quality of life.
Conclusions: Adjuvant pharmacologic therapy has the potential to support individuals in achieving optimal Phe levels. BH4 has been shown to reduce Phe levels in some individuals, with significantly greater reductions seen in treated versus placebo groups. The strength of the evidence is moderate for short-term effects on reducing Phe in a subset of initially BH4-responsive individuals, moderate for a lack of significant harms, low for longer-term effects on cognition, and insufficient for all other outcomes.
PMCID: PMC3565680  PMID: 23430527
25.  A long-term study of bone mineral density in patients with phenylketonuria under diet therapy 
Dietary control of classic phenylketonuria (PKU) needs restriction of natural proteins; adequate protein intake is achieved by adding low phenylalanine (phe) formulae. The adequacy of this diet for normal bone mineralization had not been sufficiently evaluated. Our aim was to evaluate and follow up bone mineral density (BMD) in children and adolescents with PKU within a 2-year time interval to assess the adequacy of a phenylalanine restricted diet for bone mineralization and to search for a possible relationship between BMD, dietary control and blood phenylalanine (phe) concentrations.
Material and methods
Thirty-two patients with classic PKU (3-19 years) were evaluated for their bone mineral status using dual energy X-ray absorptiometry (DEXA) both at the beginning (baseline) and the end (follow-up) of the study.
Low BMD was detected in 31.25% at the start and in 6.25% of patients after 2 years follows-up. No relationship was found between BMD and the duration of diet compliance and phe level as well.
In this study the low BMD detected in our patients was both at baseline and follow-up independent of diet restriction. A yearly DEXA would be highly beneficial for early detection and treatment, thus preventing osteoporosis and decreasing the risk of fractures. We also suggest the importance of searching for new emerging therapies such as enzyme substitution or gene therapy as low protein diet compliance was not enough to maintain normal bone mineral density.
PMCID: PMC3258737  PMID: 22295034
phenylketonuria; osteoporosis; bone mineral density; diet

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