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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.
Summary
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.
doi:10.1097/MCO.0000000000000002
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.
doi:10.1016/j.jand.2012.05.004
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.
doi:10.1111/j.1750-3841.2009.01134.x
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.
doi:10.1016/j.ymgme.2009.07.016
PMCID: PMC2783926  PMID: 19747868
PKU; amino acid requirements; genotype-phenotype relationship; low-phenylalanine diet
5.  Nutritional management of PKU with glycomacropeptide from cheese whey 
Summary
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.
doi:10.1007/s10545-008-0952-4
PMCID: PMC3633220  PMID: 18956251
6.  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.
doi:10.1016/j.ymgme.2010.04.003
PMCID: PMC2906609  PMID: 20466571
satiety; hunger; insulin; PKU; GMP
7.  Low Bone Strength Is a Manifestation of Phenylketonuria in Mice and Is Attenuated by a Glycomacropeptide Diet 
PLoS ONE  2012;7(9):e45165.
Purpose
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.
Procedures
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.
Findings
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.
Conclusions
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.
doi:10.1371/journal.pone.0045165
PMCID: PMC3445501  PMID: 23028819
8.  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.
doi:10.1186/1743-7075-9-7
PMCID: PMC3395819  PMID: 22305125
PKU; treatment advances; new strategies; LCPUFA supplementation; LNAA; sapropterin
9.  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.
doi:10.1016/j.ymgme.2010.03.022
PMCID: PMC3135651  PMID: 20418136
phenylketonuria; sapropterin dihydrochloride; tetrahydrobiopterin
10.  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.
doi:10.1007/8904_2012_176
PMCID: PMC3565664  PMID: 23430545
11.  "MY PKU": increasing self-management in patients with phenylketonuria. A randomized controlled trial 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1750-1172-6-48
PMCID: PMC3133536  PMID: 21708003
12.  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.
doi:10.1007/8904_2011_31
PMCID: PMC3509851  PMID: 23430885
13.  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.
doi:10.1007/s10545-010-9253-9
PMCID: PMC3026661  PMID: 21153445
14.  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.
doi:10.1007/s10545-011-9277-9
PMCID: PMC4227302  PMID: 21305356
15.  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.
doi:10.1007/8904_2012_168
PMCID: PMC3565680  PMID: 23430527
16.  Nutritional Consequences of Adhering to a Low Phenylalanine Diet for Late-Treated Adults with PKU 
JIMD Reports  2012;7:109-116.
Background: The main treatment for phenylketonuria (PKU) is a low phenylalanine (Phe) diet, phenylalanine-free protein substitute and low-protein special foods. This study describes dietary composition and nutritional status in late-diagnosed adult patients adhering to a PKU diet.
Methods: Nineteen patients, followed at Oslo University Hospital in Norway, participated; median age was 48 years (range 26–66). Subjects were mild to severely mentally retarded. Food intake, clinical data and blood analyses relevant for nutritional status were assessed.
Results: Median energy intake was 2,091 kcal/day (range 1,537–3,277 kcal/day). Carbohydrates constituted 59% (range 53–70%) of the total energy, including 15% from added sugar; 26% was from fat. The total protein intake was 1.02 g/kg/day (range 0.32–1.36 g/kg/day), including 0.74 g/kg/day (range 0.13–1.07 g/kg/day) from protein substitutes. Median dietary Phe intake was 746 mg/day (range 370–1,370 mg/day). Median serum Phe was 542 μmol/L (range 146–1,310 mg/day). Fortified protein substitutes supplied the main source of micronutrients. Iron intake was 39.5 mg/day (range 24.6–57 mg/day), exceeding the upper safe intake level. Intake of folate and folic acid, calculated as dietary folate equivalents, was 1,370 μg/day (range 347–1744 μg/day), and resulted in high blood folate concentrations. Median intake of vitamin B12 was 7.0 μg/day (range 0.9–15.1 μg/day).
Conclusions: The diet supplied adequate protein and energy. Fortification of the protein substitutes resulted in excess intake of micronutrients. The protein substitutes may require adjustment to meet nutritional recommendations for adults with PKU.
doi:10.1007/8904_2012_157
PMCID: PMC3575047  PMID: 23430504
17.  A long-term study of bone mineral density in patients with phenylketonuria under diet therapy 
Introduction
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.
Results
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.
Conclusions
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.
doi:10.5114/aoms.2011.23417
PMCID: PMC3258737  PMID: 22295034
phenylketonuria; osteoporosis; bone mineral density; diet
18.  Born at 27 weeks of gestation with classical PKU: challenges of dietetic management in a very preterm infant 
Pediatric Reports  2011;3(4):e26.
Few cases of premature infants with classical phenylketonuria (PKU) have been reported. Treatment of these patients is challenging due to the lack of a phenylalanine (Phe)-free amino acid (AA) solution for parenteral nutrition. A boy born at 27 weeks of gestation with a weight of 1000 g was diagnosed with classical PKU on day 7 because of highly elevated Phe level at newborn screening (2800 µmol/L). Phe intake was suspended for 5 days and during this time intravenous glucose and lipids as well as small amounts of Phe-free formula through nasogastric tube were given. Because of insufficient weight gain attributable to deficiency of essential AA, a Phe-reduced, BCAA-enriched parenteral nutrition was added to satisfy AA requirements without overloading in Phe. Under this regimen, the boy started to gain weight, Phe plasma levels progressively reduced and normalized on day 19. At the age of 40 months, the patient shows normal growth parameters (height 25th percentile, weight 25–50th percentile, head circumference 50th percentile) with a normal result for formally tested psychomotor development (WPPSI-III). The good outcome of the patient in spite of over 2 weeks of extremely high Phe concentrations suggests that the premature brain may still have enough plasticity to recover. Lacking a Phe-free intravenous AA solution, successful management of premature infants with PKU depends on the child's tolerance of enteral nutrition. Although the coincidence of PKU and prematurity is rare, there is strong need for the development of an appropriate Phe-free amino acid solution for parenteral nutrition especially in case of gastro-intestinal complications of prematurity.
doi:10.4081/pr.2011.e26
PMCID: PMC3283194  PMID: 22355511
phenylketonuria; PAH deficiency; prematurity; dietetic management.
19.  Longitudinal quality of life analysis in a phenylketonuria cohort provided sapropterin dihydrochloride 
Background
Sapropterin dihydrochloride effectively lowers plasma phenylalanine (Phe) for at least a third of phenylketonuria (PKU) patients, with potential for increased dietary Phe tolerance and decreased medical food requirement.
Objective
To investigate long-term quality of life (QOL) in patients with phenylketonuria (PKU) who took sapropterin (BH4, Kuvan®) for up to one year.
Methods
37 PKU patients, ages 10–49 years, were asked to complete a PKU-specific self-report QOL questionnaire (QOLQ) at baseline, 1, 4, 8, and 12 months. Questions were scored on a 5-point Likert scale under 5 sub-sections measuring Impact, Worries, Satisfaction, Support, and General wellbeing in relation to PKU. Responders with a plasma Phe decrease ≥ 15% after 1 month on sapropterin remained on the drug; Nonresponders ceased sapropterin after the trial month. Responders able to relax medical diet and maintain plasma Phe control were classified as Definitive; Responders unable to relax medical diet were classified as Provisional. All patients were routinely monitored by a registered dietitian. Data was analyzed in SPSS 19.0 using regression techniques.
Results
Of 17 Responders, 11 could maintain adequate Phe control on a less restrictive diet. One year mean Impact sub-score trends improved significantly for all sapropterin response groups, with greatest improvement among Definitive Responders (p < 0.0001). Satisfaction sub-scores also improved for Definitive Responders (p = 0.001). Trends for Total QOL score improved significantly over time for both Definitive (p = 0.001) and Provisional Responders (p = 0.028). Improvements in Definitive Responder scores were associated with increased Phe tolerance (Impact: p < 0.0001, Satisfaction: p = 0.022, Total QOL: p = 0.005) and MF adjustment (Satisfaction: p = 0.014, Total QOL: p = 0.026). Other sub-section scores remained steady, unaffected by sapropterin response or diet modification.
Conclusion
Increased Phe tolerance and reduced MF requirement in sapropterin Definitive Responders improves QOL perception across one year, specifically for life impact and satisfaction.
doi:10.1186/1477-7525-11-218
PMCID: PMC3880979  PMID: 24373161
Phenylketonuria; PKU; Quality of life; Sapropterin; Tetrahydrobiopterin; BH4; Medical diet
20.  A Pilot Study of Fluorodeoxyglucose Positron Emission Tomography Findings in Patients with Phenylketonuria before and during Sapropterin Supplementation 
Background and Purpose
PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy.
Methods
We enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects' Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake.
Results
None of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca's and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation.
Conclusions
Further studies with a larger sample size are needed to confirm the above changes in both sapropterin non-responsive and responsive PKU patients.
doi:10.3988/jcn.2013.9.3.151
PMCID: PMC3722466  PMID: 23894238
phenylketonuria; sapropterin; fluorodeoxyglucose positron emission tomography
21.  Insurance coverage of special foods needed in the treatment of phenylketonuria. 
Public Health Reports  1993;108(1):60-65.
Optimal medical management of phenylketonuria (PKU) requires the use of special low-phenylalanine foods for many years. For women with PKU, elevated maternal blood levels of phenylalanine even at conception can lead to fetal damage. Despite this need, private health insurance, Medicaid, and other public health programs often exclude the cost of these foods from their benefits. The New York State Department of Health conducted a survey of metabolic disorders treatment centers to elucidate the problems PKU patients have obtaining and paying for the special foods essential to their care. Payment for special foods was denied to nearly half of those with private health insurance policies and was covered for only 10 percent of Medicaid-eligibles. A public program for children with special health care needs covered these food costs in upstate New York but not in New York City. There is no program of assistance for adults who are not eligible for Medicaid and who do not have private insurance coverage of special foods. At present, many private health insurance policies and public programs do not cover the costs of low-phenylalanine foods other than infant formula. Payment for this essential part of the management of PKU should be mandated for all public programs for persons with chronic illnesses, public medical assistance (Medicaid) programs, and private health insurance. There is a need for a public program to assist adults with PKU who are not eligible for Medicaid and who do not have health insurance that covers these costs.
PMCID: PMC1403331  PMID: 8434099
22.  Whole body composition analysis by the BodPod air-displacement plethysmography method in children with phenylketonuria shows a higher body fat percentage 
Journal of Inherited Metabolic Disease  2010;33(Suppl 3):283-288.
Background
Phenylketonuria (PKU) causes irreversible central nervous system damage unless a phenylalanine (PHE) restricted diet with amino acid supplementation is maintained. To prevent growth retardation, a protein/amino acid intake beyond the recommended dietary protein allowance is mandatory. However, data regarding disease and/or diet related changes in body composition are inconclusive and retarded growth and/or adiposity is still reported. The BodPod whole body air-displacement plethysmography method is a fast, safe and accurate technique to measure body composition.
Aim
To gain more insight into the body composition of children with PKU.
Methods
Patients diagnosed with PKU born between 1991 and 2001 were included. Patients were identified by neonatal screening and treated in our centre. Body composition was measured using the BodPod system (Life Measurement Incorporation©). Blood PHE values determined every 1–3 months in the year preceding BodPod analysis were collected. Patients were matched for gender and age with data of healthy control subjects. Independent samples t tests, Mann–Whitney and linear regression were used for statistical analysis.
Results
The mean body fat percentage in patients with PKU (n = 20) was significantly higher compared to healthy controls (n = 20) (25.2% vs 18.4%; p = 0.002), especially in girls above 11 years of age (30.1% vs 21.5%; p = 0.027). Body fat percentage increased with rising body weight in patients with PKU only (R = 0.693, p = 0.001), but did not correlate with mean blood PHE level (R = 0.079, p = 0.740).
Conclusion
Our data show a higher body fat percentage in patients with PKU, especially in girls above 11 years of age.
doi:10.1007/s10545-010-9149-8
PMCID: PMC3757265  PMID: 20574715
23.  The effects of tetrahydrobiopterin (BH4) treatment on brain function in individuals with phenylketonuria☆ 
NeuroImage : Clinical  2013;3:539-547.
Phenylketonuria (PKU) is a rare genetic condition characterized by an absence or mutation of the PAH enzyme, which is necessary for the metabolism of the amino acid phenylalanine into tyrosine. Recently, sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), has been introduced as a supplemental treatment to dietary phe control for PKU. Very little is known regarding BH4 treatment and its effect on brain and cognition. The present study represents the first examination of potential changes in neural activation in patients with PKU during BH4 treatment. To this end, we utilized an n-back working memory task in conjunction with functional magnetic resonance imaging (fMRI) to evaluate functional brain integrity in a sample of individuals with PKU at three timepoints: Just prior to BH4 treatment, after 4 weeks of treatment, and after 6 months of treatment. Neural activation patterns observed for the PKU treatment group were compared with those of a demographically-matched sample of healthy non-PKU individuals who were assessed at identical time intervals. Consistent with past research, baseline evaluation revealed impaired working memory and atypical brain activation in the PKU group as compared to the non-PKU group. Most importantly, BH4 treatment was associated with improvements in both working memory and brain activation, with neural changes evident earlier (4-week timepoint) than changes in working memory performance (6-month timepoint).
Highlights
•We examine working memory and neural activation in patients with PKU at baseline.•We track behavioral and neural changes related to BH4 treatment in the patients.•BH4 treatment associated with improvement in neural activity at 4-week timepoint.•BH4 treatment associated with improvement in working memory at 6-month timepoint.
doi:10.1016/j.nicl.2013.08.012
PMCID: PMC3871382  PMID: 24371792
Prefrontal cortex; Phenylketonuria; Working memory; fMRI; Executive function; Sapropterin
24.  Quality of Life (QoL) assessment in a cohort of patients with Phenylketonuria 
BMC Public Health  2014;14(1):1243.
Background
Phenylketonuria (PKU) is a chronic inborn error of amino acid metabolism that requires lifelong follow-up and intervention, which may represent strains on Quality of Life (QoL). This observational study evaluated QoL in a cohort of PKU patients, using updated and detailed instruments.
Methods
22 patients with mild PKU respondent to BH4 and 21 patients with classical PKU treated with diet were recruited in this study. Adult patients completed WHOQOL questionnaire-100 (WHOQOL-100) and pediatric patients the Pediatric QoL inventory (PedsQLTM). Psychiatric and mood disorders were also evaluated using TAD or BDI and STAI-Y inventories. A multivariable linear regression model was fitted to investigate the predictors of QoL, including age, sex, treatment type, length of current treatment, educational level and employment status (only for adults) as covariates. Results were presented as regression coefficients with 95% confidence interval.
Results
Global QoL scores were within normal range both in patients with mild and classical disease but global QoL scores were significantly higher in patients with mild PKU under BH4 treatment as compared to those affected by classical disease who were under diet regimen. Furthermore, QoL significantly increased in long treated PKU patients. Among adult patients, QoL scores were significantly lower in males, in patients with lower education and in those employed or unemployed as compared to students (baseline).
Conclusions
Both diet and medical treatment based upon BH4 seem to be associated with higher QoL in the long run. However, patients with mild PKU can rely on BH4 to achieve a higher Phe tolerance and a better compliance to therapy due to diet relaxation/avoidance. Some specific categories of patients with a lower QoL should be investigated more in depth, engaging with those at risk of lower treatment compliance. The questionnaires employed in the present study seemed to be able to effectively detect criticalities in QoL assessment and represent an advance from previous inventories employed in the past.
doi:10.1186/1471-2458-14-1243
PMCID: PMC4265392  PMID: 25471331
Phenylketonuria; Tetrahydrobiopterin; Quality of life; Word Health Organization Quality Of Life questionnaire-100
25.  Phenylketonuria: An Inborn Error of Phenylalanine Metabolism 
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. A better understanding of the biochemistry, genetics and molecular basis of PKU, as well as the need for improved treatment options, has led to the development of new therapeutic strategies.
PMCID: PMC2423317  PMID: 18566668

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