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Background Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Main body In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. Conclusion This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Background Phenylketonuria (PKU) is an inherited metabolic disorder affecting the conversion of phenylalanine (Phe) to tyrosine. Medical nutrition therapy, consisting of a Phe‐restricted diet with medical formula, is the primary treatment for PKU. The Simplified Diet is an approach to PKU nutrition management that allows certain fruits, vegetables, and low‐protein foods to be eaten without measuring or tracking, referred to as free/uncounted foods. There is no consensus on how to implement this approach in metabolic centers in the United States (U.S.), and clinical practice varies. Aim This study describes the clinical experience of metabolic dietitians in U.S.‐based metabolic centers related to the use and implementation of the Simplified Diet. Methods A survey was developed and sent out to metabolic dietitians to query current clinical practices related to the Simplified Diet. Descriptive statistics were used to analyze responses. Results Sixty‐three dietitians managing ≥5 patients with PKU in U.S.‐based metabolic centers responded to the survey. Ninety‐eight percent of survey respondents reported using some version of the Simplified Diet in clinical practice. The survey identified areas of strong agreement, including introduction of the Simplified Diet at 6 to 12 months of age. The survey also identified areas of widespread variability, including specific Phe or protein thresholds for free/uncounted foods, and whether or not to set daily quantity limits on these foods. Conclusions Significant variability related to implementation of the Simplified Diet exists across U.S.‐based metabolic centers. This practice variability may contribute to differences in the patient experience across centers and may indicate a need for development of clinical guidelines.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism. Besides dietary treatment, some patients are responsive to and treated with tetrahydrobiopterin (BH4). Our primary objective was to examine whether the 48-hour BH4 loading test misses BH4-responsive PKU patients. Secondary, we assessed if it would be beneficial to 1) use a cut-off value of 20% Phe reduction instead of commonly used 30%, and 2) extend the loading test to 7 days.METHODS: 24 patients with a 20-30% decrease of blood Phe levels during their initial 48-hour BH4 loading test or at least one mutation associated with long-term BH4 responsiveness, were invited to participate. 22 of them underwent the 7-day BH4 loading test. During the BH4 loading test, BH4 was administered orally once daily for 7 days (20 mg/kg/day). Blood samples on filter paper were collected at 13 time points. Potential BH4 responders (≥20% decrease in blood Phe concentrations at ≥1 moment within the first 48 h or ≥30% at ≥1 moment during the entire test) underwent a treatment trial to assess true long-term responsiveness (≥30% decrease of Phe levels compared to baseline and/or ≥50% increase in natural protein tolerance in accordance with the Dutch guidelines before 2017). The duration of the treatment trial varied from 2 to 18 months.RESULTS: Of the 22 patients who completed the 7-day BH4 loading test, 2 were excluded, 8 had negative tests and 12 were considered to be potential BH4 responders. Of these 12 potential BH4-responsive PKU patients, 5 turned out to be false positive, 6 true-responder and 1 was withdrawn.CONCLUSION: Even though the 48-hour BH4 loading test has proven its efficacy in the past, a full week may be necessary to detect all responders. So, if blood Phe concentrations during the 48-hour BH4 test shows a clear tendency, but not sufficient decrease, a full week (with only measurements each 24 h) could be offered. A threshold of ≥20% decrease within 48 h is not useful for predicting true BH4 responsiveness.

Phenylketonuria (PKU) is a condition that results in the build-up of phenylalanine in the blood. This can cause severe brain damage and neurological issues if left untreated. Management can be complex and many individuals may turn to the internet to access further information. It is important that resources are understood as misinterpretation could result in harm to health. The aim of this study was to assess the readability of online resources for PKU and to assess their visual appearance using a communication sciences assessment framework. We searched the top five websites through Google using the search term “phenylketonuria/PKU”. We then analysed the text content of the identified websites using five readability formulae to determine the USA and UK reading grade. The median readability level across the five websites was US grade/UK grade 10.6/11.6, with individual grades ranging from 10/11 to 13.3/14.3. We found wide differences in the focus, layout and general appearance of the websites. The readability of resources was much higher than the recommended US 6th grade level. Online resources for PKU need to be simplified to ensure they can be easily understood.

PurposeDefective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients.MethodsTwelve males with classical PKU (aged 18–41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined.ResultsAerobic capacity (VO2max) was significantly lower in the PKU group (p = 0.018); however, relative VO2maxwas similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls (p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups.ConclusionPKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.

Background and Aim:Phenylketonuria is a type of autosomal recessive congenital and genetically induced fungal disease that has not been converted to tyrosine by the lack or lack of the phenylalanine hydroxylase enzyme and has been shown to increase phenylalanine levels in the blood, especially in the brain. The aim of this study was to compare the IQ scores of children with phenylketonuria and healthy children referring to Besat hospital clinic in Sanandaj in 2017-2018.Methods:This historic cohort study wasperformed on all of the patients at the time of birth, referred to PKU and pediatric clinics, as well as healthy children (for phenylketonuria) referred to other clinics of the children's hospital. The control group was done.Goodinow’s intelligence test was used to measure cognitive, mental and children's intelligence. Finally, the results of the two groups were analyzed by the statistical consult.Results:The results showed that 46 (69.7%) were male and 20 (30.3%) were female. The mean age of the subjects was 6.34±2.52of years. Result from the current study showed that there was not significant differences between IQ mean in two groups of study(p>0.05).Conclusion:According to the results of this study, the timely identification and treatment of patients with phenylketonuria has been able to prevent the complications of this disease to a large extent, and keep the children's IQs intact, thereby providing timely andaccurate identification and treatment of this disease is necessary among children.

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.

Children spend a substantial part of their childhood in school, so provision of dietary care and inclusion of children with phenylketonuria (PKU) in this setting is essential. There are no reports describing the dietary support children with PKU receive whilst at school. The aim of this cross-sectional study was to explore the experiences of the dietary management of children with PKU in schools across the UK. Data was collected using an online survey completed by parents/caregivers of children with PKU. Of 159 questionnaire responses, 92% (n = 146) of children attended state school, 6% (n = 10) private school and 2% (n = 3) other. Fourteen per cent (n = 21/154) were at nursery/preschool, 51% (n = 79/154) primary and 35% (n = 54/154) secondary school. Sixty-one per cent (n = 97/159) said their child did not have school meals, with some catering services refusing to provide suitable food and some parents distrusting the school meals service. Sixty-one per cent of children had an individual health care plan (IHCP) (n = 95/155). Children were commonly unsupervised at lunchtime (40%, n = 63/159), with snacks (46%, n = 71/155) and protein substitute (30%, n = 47/157), with significantly less supervision in secondary than primary school (p &lt, 0.001). An IHCP was significantly associated with improved supervision of food and protein substitute administration (p &lt, 0.01), and better communication between parents/caregivers and the school team (p &lt, 0.05). Children commonly accessed non-permitted foods in school. Therefore, parents/caregivers described important issues concerning the school provision of low phenylalanine food and protein substitute. Every child should have an IHCP which details their dietary needs and how these will be met safely and discreetly. It is imperative that children with PKU are supported in school.

Phenylketonuria (PKU) and Hyperphenylalaninemia (HPA) are inborn errors of metabolism (IEM) due to mutations in the PAH gene resulting in increased blood phenylalanine (Phe) concentrations. Depending on the Phe levels, a lifelong dietary intervention may be needed. During the COVID-19 pandemic, finding new strategies to ensure follow-up and metabolic control for such patients became mandatory and telehealth was identified as the most eligible tool to provide care and assistance beyond barriers. The aim of this study was to evaluate how telehealth use may have impacted disease follow-ups. Seven hundred and fifty-five patients affected by PKU/HPA in follow-ups at the Clinical Department of Pediatrics (San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Italy) were included in this study. The data regarding the used telehealth model, type of performed consultations and patients’ perspectives were retrospectively collected and analyzed after a one-year experience of implemented follow-ups. The results demonstrated that telehealth seemed to be a useful tool to improve the adherence to treatment and that it could guarantee continuous assistance and care beyond the surrounding epidemiological status. Patients expressed great satisfaction with the offered services and requested that they were implemented in standards of care on a long-term basis. Our results suggested the implementation of telehealth in the management guidelines for PKU/HPA patients.

Funding Information: Outside the submitted work, the authors disclose the following. Bausell H received personal fees from BioMarin, Ultragenyx, Horizon and Vitaflo. Bélanger-Quintana A reports personal fees from BioMarin, Nutricia, Vitaflo, Orphan Europe, Takeda and Genzyme. Rocha JC received research grants from BioMarin, Glutamine and Cambrooke, as well as personal fees from BioMarin, Applied Pharma Research, Nutricia, Merck Serono, Vitaflo, Cambrooke, PIAM and Lifediet. MacDonald A reports research funding from BioMarin, Nutricia, Applied Pharma Research, Vitaflo, Galen, Metax, Mevalia and Arla, as well as lecture fees from BioMarin, Applied Pharma Research, Nutricia and Vitaflo, and consultancy fees from BioMarin, Applied Pharma Research, Arla, Nutricia and Vitaflo. Met Ed reports grant funding from BioMarin, Nutricia, Vitaflo and Horizon Pharmaceuticals. Bernstein L and Rohr F report lecture fees from Vitaflo. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Background: The metabolic dietitian/nutritionist (hereafter ‘dietitian’) plays an essential role in the nutritional management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional management and counselling of pegvaliase-treated patients. Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional evaluation and management of patients receiving pegvaliase. The consensus group consisted of 10 PKU experts: six dietitians and one paediatrician from Europe and three dietitians from the US. One European and three US dietitians had experience with pegvaliase-treated patients. Results: The consensus group recommended that a physician, dietitian and nurse are part of the pegvaliase treatment team. Additionally, a psychologist/counsellor should be included if available. Practical proposals for the nutritional evaluation of pegvaliase-treated patients at baseline, during the induction and titration phases and for long-term maintenance were developed. The consensus group suggested assessment of blood Phe at least monthly or every 2 weeks in the event of low blood Phe (i.e., blood Phe

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism, causing a build-up of Phe in the body. Treatment consists of a Phe-restricted diet for life and regular determination of blood Phe levels to monitor the intake of Phe. Despite the fact that diet is the cornerstone of treatment, there are no studies examining common knowledge about food items and whether they are allowed as part of the PKU diet. Improving parents’ and patients’ knowledge and competence about the diet enables them to make appropriate food choices. This study validates a food-knowledge questionnaire first developed in Spanish and modified for English speaking populations. The questionnaire potentially helps parents to prepare appropriate meals and healthcare providers to create individualized educational programs about PKU for children and adolescents with this disorder.

This study aimed to describe the current practices in the diagnosis and dietary management of phenylketonuria (PKU) in Latin America, as well as the main barriers to treatment. We developed a 44-item online survey aimed at health professionals. After a pilot test, the final version was sent to 25 practitioners working with inborn errors of metabolism (IEM) in 14 countries. Our results include 22 centers in 13 countries. Most countries (12/13) screened newborns for PKU. Phenylalanine (Phe) targets at different ages were very heterogeneous among centers, with greater consistency at the 0–1 year age group (14/22 sought 120–240 µmol/L) and the lowest at &gt, 12 years (10 targets reported). Most countries had only unflavored powdered amino acid substitutes (10/13) and did not have low-protein foods (8/13). Only 3/13 countries had regional databases of the Phe content of foods, and only 4/22 centers had nutrient analysis software. The perceived obstacles to treatment were: low purchasing power (62%), limited/insufficient availability of low-protein foods (60%), poor adherence, and lack of technical resources to manage the diet (50% each). We observed a heterogeneous scenario in the dietary management of PKU, and most countries experienced a lack of dietary resources for both patients and health professionals.

There is agreement that the pandemic has affected the healthcare system and behaviour of patients. This study aims to identify problems encountered by patients with phenylketonuria (PKU) and their parents/caregivers during the six-week pandemic lockdown in Poland (15 March to 30 April 2020). To determine the factors that influenced health and treatment-related issues, as well as the respondents’ perception of the impact of the pandemic, study participants were asked to complete a non-validated online questionnaire comprising 31 questions (including 27 single-choice, two multiple-choice and two open-ended ones). A total of 571 patients or their parents completed the questionnaire, with 9.5% of respondents not performing any blood phenylalanine (Phe) test in the analysed period, 21.3% declaring a blood Phe increase, and 15.3% a decrease. Increased problems in contacting the doctor or dietitian were reported by 26.1% of subjects, whereas 39.3% of them felt restricted access to dietary products. Most (63.4%) participants were satisfied with remote contact with their PKU clinic. Better compliance was associated with higher odds of acceptance of remote contact and of reporting fewer problems with contacting the doctor, and with lower odds of missing Phe testing. Self-reported high stress was associated with higher odds of reporting the limited availability of low-Phe products and Phe-free formulas, as well as with increased Phe concentrations and non-PKU-related health problems. These patients also had poor dietary compliance and experienced more problems in contacting specialists. Health and treatment-related problems experienced during the pandemic lockdown were related to a higher intensity of stress in patient’s family and worse therapy compliance before the pandemic. Previous experience of remote visits resulted in a better perception of this method of contact. It seems that this form of communication should be popularized and improved to increase therapy effectiveness in case of different limitations in the future. Special attention should be paid to vulnerable patients who may be at extra risk when the provision of standard care is affected.

The present study assessed patients’ metabolic control of phenylketonuria (PKU) during the first 2020 COVID-19 lockdown in Poland. Blood (phenylalanine) Phe results of the tests of 535 patients, performed in 2019 and in the first months of 2020, were analysed. The six-week lockdown period was compared to the preceding six-week period as well as to the two corresponding periods of 2019 (three non-lockdown periods). More patients failed to perform Phe tests in the lockdown period (32.7%) than in non-lockdown periods (15.6%, 15.1%, 17.2%, p &lt, 0.001 for all). The median Phe levels for those patients who performed testing in all the four periods did not differ between periods. However, these patients tended to perform only one test during the lockdown (ORs: 1.43 to 1.60, 95% CI: from 1.01–2.04 to 1.11–2.30, p-value 0.02 to 0.005). Patients who did not take blood during the lockdown (46.7%) performed significantly fewer blood tests in the remaining periods (median &lt, IQR&gt, 1 &lt, 0–1&gt, vs. 2 &lt, 1–4&gt, 0.001). In conclusion, direct assessment of patients’ compliance based upon Phe levels during the pandemic lockdown was not possible. Pre-pandemic non-compliant patients frequently failed to perform the test during the lockdown, whereas the previously compliant ones were more likely to perform only one test. This strongly suggests that metabolic control might have worsened.

Funding Information: Funding: This research was funded by Vitaflo International as part of Ph.D. grant. Funding Information: Conflicts of Interest: A.D. research funding from Vitaflo International, financial support from Nutri-cia, Mevalia & Vitaflo International to attend study days & conferences. S.E. research funding from Nutricia, financial support from Nutricia & Vitaflo International to attend study days & conferences. A.P. has received an educational grant from Cambrooke Therapeutics and grants from Vitaflo International, Nutricia, Merck Serono, Biomarin and Mevalia to attend scientific meetings. C.A. received honoraria from Nutricia and Vitaflo International to attend study days and conferences. J.C.R. member of the European Nutritionist Expert Panel (Biomarin), the Advisory Board for Applied Pharma Research and Nutricia, and received honoraria as a speaker from APR, Merck Serono, Biomarin, Nutricia, Vitaflo, Cambrooke, PIAM and Lifediet. A.M. research funding & honoraria from Nutricia, Vitaflo International & Merck Serono, Member of European Nutrition Expert Panel (Merck Serono international), member of Sapropterin Advisory Board (Merck Serono international), member of the Advisory Board Element (Danone-Nutricia). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. Aims: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. Methodology: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5–6 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5–16years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5–16years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5–15years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. Results: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2–L4 BMDa g/cm2 ), bone mineral apparent density (L2–L4 BMAD g/cm3 ) and total body less head BMDa (TBLH g/cm2 ). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. Conclusions: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs. publishersversion published

Phenylketonuria (PKU) requires tight control to prevent neurocognitive impairment but reports show that patients may present mild cognitive defects related to higher impulsivity. We hypothesize that chronic intervention may influence the parents and child bonding and the child´s resources to face problems. To describe the PKU parenting styles perceived by the children (PS) and their coping strategies (CS) assessing their relationship with impulsivity, 30 early diagnosed and adequately treated PKU children and 30 non PKU aged-paired controls (CG) were compared. The Argentine Children´s Coping Questionnaire, Argentine Scale Perception of the Relationship with Parents, WISC IV Comprehension Subtest, and CPT II test were administered. PKU PS were based on control: strict to pathologic in the mother and acceptable in the father (both p

Contains fulltext : 235312.pdf (Publisher’s version ) (Open Access) BACKGROUND: Reliable measurement of phenylalanine (Phe) is a prerequisite for adequate follow-up of phenylketonuria (PKU) patients. However, previous studies have raised concerns on the intercomparability of plasma and dried blood spot (DBS) Phe results. In this study, we made an inventory of differences in (pre-)analytical methodology used for Phe determination across Dutch laboratories, and compared DBS and plasma results. METHODS: Through an online questionnaire, we assessed (pre-)analytical Phe measurement procedures of seven Dutch metabolic laboratories. To investigate the difference between plasma and DBS Phe, participating laboratories received simultaneously collected plasma-DBS sets from 23 PKU patients. In parallel, 40 sample sets of DBS spotted from either venous blood or capillary fingerprick were analyzed. RESULTS: Our data show that there is no consistency on standard operating procedures for Phe measurement. The association of DBS to plasma Phe concentration exhibits substantial inter-laboratory variation, ranging from a mean difference of -15.5% to +30.6% between plasma and DBS Phe concentrations. In addition, we found a mean difference of +5.8% in Phe concentration between capillary DBS and DBS prepared from venous blood. CONCLUSIONS: The results of our study point to substantial (pre-)analytical variation in Phe measurements, implicating that bloodspot Phe results should be interpreted with caution, especially when no correction factor is applied. To minimize variation, we advocate pre-analytical standardization and analytical harmonization of Phe measurements, including consensus on application of a correction factor to adjust DBS Phe to plasma concentrations.

Many countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS. ispartof: JOURNAL OF PEDIATRICS vol:239 pages:231-+ ispartof: location:United States status: published

ObjectiveTo evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.MethodsIn this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.ResultsNineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p= 0.003), total tau (p< 0.001), and phosphorylated tau (p= 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r= 0.64,p= 0.003), neuropsychiatric symptoms (r= 0.73,p< 001), motor evoked potential latency (r= 0.48,p= 0.030), and parietal lobe atrophy.ConclusionsOur study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

Objectives: The present study describes clinical, biochemical, molecular genetic data, current treatment strategies and follow-up in nine patients with tetrahydrobiopterin (BH4) deficiency due to various inherited genetic defects. Methods: We analyzed clinical, biochemical, and molecular data of nine patients with suspected BH4 deficiency. All patients were diagnosed at Ege University Faculty of Medicine in Izmir, Turkey and comprised data collected from 2006 to 2019. The diagnostic laboratory examinations included blood phenylalanine and urinary or plasma pterins, dihydropteridine reductase (DHPR) enzyme activity measurement in dried blood spots, folic acid and monoamine neurotransmitter metabolites in cerebrospinal fluid, as well as DNA sequencing. Results: Among the nine patients, we identified one with autosomal recessive GTP cyclohydrolase I (ar GTPCH) deficiency, two with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, three with sepiapterin reductase (SR) deficiency, and three with DHPR deficiency. Similar to previous observations, the most common clinical symptoms are developmental delay, intellectual disability, and movement disorders. All patients received treatment with l-dopa and 5-hydroxytryptophan, while only the ar GTPCH, the PTPS, and one DHPR deficient patients were supplemented in addition with BH4. The recommended dose range varies among patients and depends on the type of disease. The consequences of BH4 deficiencies are quite variable; however, early diagnosis and treatment will improve outcomes. Conclusions: As BH4 deficiencies are rare group of treatable neurometabolic disorders, it is essential to diagnose the underlying (genetic) defect in newborns with hyperphenylalaninemia. Irreversible brain damage and progressive neurological deterioration may occur in untreated or late diagnosed patients. Prognosis could be satisfying in the cases with early diagnose and treatment. © 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

The nutritional composition of special low protein foods (SLPFs) is controlled under EU legislation for &lsquo, Foods for Special Medical Purposes (FSMP)&rsquo, They are designed to meet the energy needs of patients unable to eat a normal protein containing diet. In phenylketonuria (PKU), the macronutrient contribution of SLPFs has been inadequately examined. Aim: A 3-year longitudinal prospective study investigating the contribution of SLPFs to the macronutrient intake of children with early treated PKU. Methods: 48 children (27 boys) with a mean recruitment age of 9.3 y were studied. Semi-quantitative dietary assessments and food frequency questionnaires (FFQ) were collected three to four times/year for 3 years. Results: The mean energy intake provided by SLPFs was 33% (SD &plusmn, 8), and this figure was 42% (SD &plusmn, 13) for normal food and 21% (SD &plusmn, 5) for protein substitutes (PS). SLPFs supplied a mean intake of 40% carbohydrate (SD &plusmn, 10), 51% starch (SD &plusmn, 18), 21% sugar (SD &plusmn, 8), and 38% fat (SD &plusmn, 13). Fibre intake met 83% of the Scientific Advisory Committee on Nutrition (SACN) reference value, with 50% coming from SLPFs with added gums and hydrocolloids. Low protein bread, pasta and milk provided the highest energy contribution, and the intake of sweet SLPFs (e.g., biscuits, cakes, and chocolate) was minimal. Children averaged three portions fruit/vegetable daily, and children aged &ge, 12 y had irregular meal patterns. Conclusion: SLPFs provide essential energy in phenylalanine restricted diets. Optimising the nutritional quality of SLPFs deserves more attention.

Protein is the most satiating macronutrient, increasing secretion of gastrointestinal hormones and diet induced thermogenesis. In phenylketonuria (PKU), natural protein is restricted with approximately 80% of intake supplied by a synthetic protein source, which may alter satiety response. Casein glycomacropeptide (CGMP-AA), a carbohydrate containing peptide and alternative protein substitute to amino acids (AA), may enhance satiety mediated by its bioactive properties. Aim: In a three-year longitudinal, prospective study, the effect of AA and two different amounts of CGMP-AA (CGMP-AA only (CGMP100) and a combination of CGMP-AA and AA (CGMP50) on satiety, weight and body mass index (BMI) were compared. Methods: 48 children with PKU completed the study. Median ages of children were: CGMP100, (n = 13), 9.2 years, CGMP50, (n = 16), 7.3 years, and AA (n = 19), 11.1 years. Semi-quantitative dietary assessments and anthropometry (weight, height and BMI) were measured every three months. Results: The macronutrient contribution to total energy intake from protein, carbohydrate and fat was similar across the groups. Adjusting for age and gender, no differences in energy intake, weight, BMI, incidence of overweight or obesity was apparent between the groups. Conclusion: In this three-year longitudinal study, there was no indication to support a relationship between CGMP and satiety, as evidenced by decreased energy intake, thereby preventing overweight or obesity. Satiety is a complex multi-system process that is not fully understood.

The story of phenylketonuria (PKU) started in 1934 with Asbjørn Følling’s examination of two mentally retarded siblings from a Norwegian family. However, if their mother had not been so persistent in her search for somebody who could give her a reason why both her children were retarded, Asbjørn Følling’s name might never have been associated with PKU and surely the history of PKU would have started differently. In the short review below, the authors give a partly personal and therefore rare account of the early history of PKU, its treatment and the start of neonatal screening. Prof. Woolf is a pioneer of both the dietary treatment of PKU and neonatal screening; Mr. Adams is a long-time advocate for PKU patient interests.

Background: The implementation of neonatal screening and the early initiation of lifelong therapy have helped to prevent severe complications and enabled much more favorable outcomes for early-treated phenylketonuria (ETPKU) patients. However, PKU patients tend to develop subtle cognitive and psychosocial abnormalities and the strict dietary therapy can present financial and social burden. Thus, PKU is expected to affect the quality of life (QoL) of these patients. There is insufficient evidence regarding the relationship between metabolic control and Health-Related QoL (HRQoL). We aimed to assess the effect of short- and long-term therapy on QoL among Hungarian adult PKU patients using the standardized PKU-specific PKU-QoL questionnaire. Methods: We conducted a single-centre, cross-sectional, observational study in Hungary. We included adult PKU patients treated with diet and amino acid supplements only. Patients reported HRQoL using the standardized adult PKU-QoL questionnaire and mean blood Phe concentrations were assessed for three different time periods: the previous 10 years, the previous year and concentration at the time of completing the questionnaire. The correlation between patients’ QoL scores and their Phe levels was assessed. The classical PKU group was further divided into “good” and “suboptimal” adherence groups based on individual mean Phe levels in the examined time period. We evaluated differences in QoL among the two subgroups of classical PKU patients. QoL scores between classical and non-classical patients were also compared. Results: Data from 88 adult patients were analysed (66 had classical PKU). No median PKU-QoL score reached major or severe impact/frequent symptoms in any domain. The highest scores (meaning larger burden) were mostly related to emotional impact of PKU and disease management. When performing correlation analysis between Phe levels and QoL scores by all patients we found weak to fair positive correlation in several domains either short or long term. Patients with classical PKU reported greater financial impact of PKU than patients with less severe PKU. Classical PKU patients with good therapy adherence tended to report better HRQoL scores than patients with suboptimal adherence. Conclusion: We conclude that patients showed good HRQoL using the PKU-specific questionnaire. Our study demonstrates that suboptimal metabolic control is negatively associated with patients' HRQoL.

Background Accumulation of phenylalanine (Phe) due to deficiency in the enzyme phenylalanine hydroxylase (PAH), responsible for the conversion of Phe into tyrosine leads to Phenylketonuria (PKU), a rare autosomal recessive inborn error of metabolism with a mean prevalence of approximately 1:10,000 to 1:15,000 newborns. Physical, neurocognitive and psychiatric symptoms include neurodevelopmental disorder as intellectual disability and autism spectrum disorder. The most common treatments such as low-Phe diet and supplements may decrease blood Phe concentrations, but neuropsychological, behavioral and social issues still occur in some patients. This study aimed to better understand (i) the Brazilian population's knowledge about newborn screening (NBS), the main diagnostic method for PKU, as well as (ii) the impacts of phenylketonuria in the daily lives of patients and parents. Methods Two surveys in Real World Data format gathering of Brazilian residents by online questionnaires with (i) 1000 parents of children up to 5 years old between March and April 2019; (ii) 228 PKU patients and caregivers in March 2019. The survey was conducted in partnership with Abril Publisher and two Brazilian patient associations: Metabolic Mothers and SAFE Brasil, for families with rare diseases and PKU patients, respectively. Results The first questionnaire shows that 93% of parents recognize the importance of NBS and 92% report that their children have undergone the test. Still, two out of ten participants did not know what the exam is or what it is for. From the second questionnaire nine out of ten patients had their PKU diagnosis by NBS. Although strict dietary controls for PKU were claimed by 44% of respondents from second questionnaire, 55% assume not following all nutritionist recommendations and 52% did not maintain routinely Phe control levels. In addition, 53% said they had high spending on medical appointments, therapies and purchase of special foods. Conclusions Despite the lack of understanding, the awareness of NBS importance is present in the studied population. The early diagnosis of most PKU patients in the study corroborates with neonatal screening central role of PKU early detection. The difficulty in adhering to dietary adjustments and the possibility that current and new therapeutic strategies other than diet could be determinant to achieve the recommended Phe levels.

BackgroundThe population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain.MethodsThe PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial.ParticipantsThirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life.Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach.ObjectivesThe primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland.RandomizationCentral randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician.Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment.DiscussionUsing a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed.Trial registrationThe study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

Background Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes. Methods We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death. Results For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles. Conclusions Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.

Phenylketonuria (PKU, OMIM 261600) is predominantly caused by mutations in the PAH gene. One hundred and three Argentine PKU patients were studied by Sanger sequencing; 101 were completely characterized (90.3% were compound heterozygotes). Fifty-four different pathogenic variants were identified. Mutations were distributed all along the PAH gene but concentrated in exon 7 (26%), 12 (12%), 11 (10%), and 6 (10%). 77% were missense, and 77% affected the enzyme catalytic domain, nine mutations accounted for 57% of 179 studied alleles: p.Arg261Gln (Allele frequency(AF):10.6%), c.1066-11G>A (AF:9,5%), p.Arg408Trp (AF:8,3%), p.Tyr414Cys (AF:5,5%), p.Ala403Val, p.Val388Met, and p.Arg158Gln (AF: 5% each), p.Leu48Ser, and p.Ile65Thr (AF:4% each). The predicted phenotype was assigned by Guldberg´s arbitrary value (AV) and compared with the clinical phenotype based in tolerance to Phe intake. 29.1% (n:30) were hyperphenylalaninemias, 18.5% (n:19) mild-PKU, 27.2% (n:28) moderate-PKU and 25.2 % (n:26) classical-PKU. Genotype/phenotype correlation was statistically significant (p

Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AlN-93M control diet for 6 weeks. In addition, adult wild-type mice on AlN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning. (C) 2017 Elsevier Inc. All rights reserved.

Phenylalanine (Phe) is a key nutrient in the dietary management of the metabolic disease phenylketonuria (PKU). To give more freedom to PKU patients, we propose a numerical process to estimate the Phe content of a commercial food using the information printed on the label (Nutritional Fact Label and ordered ingredient list). The process is amenable to implementation as a smart phone/Web app and could be integrated into a personalized dietary management software. Our tests show that the results are very accurate (±13 mg per serving) in the vast majority of foods considered. Our approach can be modified to handle any other amino acid for the management of other inborn errors of metabolism. A similar approach can also be used for improving the precision (i.e., increasing the quantization resolution) of the nutrients already listed (e.g., protein).

Background Phenylketonuria (PKU) is an inherited error of metabolism, screened at 48–72 h of life since 1975 in Hungary. The patients have to keep a strict lifelong protein-restricted diet, resulting in PKU and its treatment can lead to social and financial burdens. The current study aimed to evaluate the health-related quality of life (HRQoL) of children living with PKU. Patients and methods A single-centre, cross-sectional, observational study was conducted at the Center of Newborn Screening and Inherited Metabolic Disorders of Budapest, Hungary, using the PKU-quality of life (PKU-QoL) questionnaire. Responses of 59 parents and 11 teenagers were collected. Numerous aspects regarding HRQoL were analysed according to clinical compliance and severity. The patients were classified into groups with good or suboptimal adherence based on regular phenylalanine (Phe) values. The online officially translated versions of the adolescent or parental PKU-QoL questionnaire were used and analysed anonymously. Differences in HRQoL were compared - PKU vs. Hyperphenylalaninaemia (HPA) and good vs. suboptimal adherence. Results Twenty-five of 32 examined parameters had no or little impact on HRQoL. The most frequently reported symptom was irritability. Food enjoyment was the most impacted domain, with a major severity score in the adolescent group (median 62,5, IQR: 25–75). The emotional impact was scored at moderate severity by both the adolescents and parents. Classical PKU patients with good metabolic control were more frequently tired than HPA patients (0,0027). The group with poor metabolic adherence showed more frequent tiredness (p = 0,03), slow thinking (p = 0,018) and anxiety (p = 0,015). Conclusion Overall, our patients showed an excellent HRQoL; most domains (29/36) were reported as little/no impacted. Worse QoL was found in patients with suboptimal metabolic control. Particular attention should be paid to the emotional health of PKU patients.

There is a consensus on the importance of early and life-long treatment for PKU patients. Still, differences exist on target blood phenylalanine (Phe) concentrations for children with PKU in different countries and treatment centers. For the first time, long-term metabolic control and child development and cognitive functioning is compared between children with mean phenylalanine concentrations under 240 μmol/L (group A), between 240 and 360 μmol/L (group B) or over 360 μmol/L (group C) during their first year of life. METHODS: 70 patients diagnosed with PKU through neonatal screening with Phe > 900 μmol/L, were divided into 3 groups: A, B and C, according to mean Phe concentrations and standard deviation (SD). Metabolic control during childhood, psychomotor development and IQ were compared. RESULTS: In group A, Phe was maintained within the recommended range until 6 years of age, in Group B, until 3 years of age, and in group C, Phe was always over the recommended range. No significant differences were found between the three groups in mental development index (MDI) and motor development index (PDI) scores at 12, 24, and 30 months of age, but group C had the lowest scores on MDI at all age periods. At preschool and school age, IQ was higher in group A compared to group C. CONCLUSION: Results show that mean blood Phe concentrations between 120 and 240 μmol/L during first year of life have a positive impact in metabolic control and cognitive functioning during childhood., Highlights • Protecting early brain development through adequate metabolic control is critical during the first years of life in PKU patients. • Metabolic control and cognitive functioning is compared between children with mean phenylalanine concentrations under 240; between 240–360 and over 360 μmol/L during their first year of life. • Mean blood phenylalanine concentrations under 240 μmol/L during first year of life have a positive impact on posterior metabolic control and cognitive functioning. • A blood phenylalanine target concentration between 120–240 μmol/L is proposed during the first year of life for the treatment of PKU patients.

Introduction Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a deficiency in phenylalanine (Phe) hydroxylase activity. Early diagnosis and continuous treatment with a low Phe diet prevents severe neurological and cognitive impairment. Aims 1. Analyze how treatment adherence evolves through infancy, childhood, and early adolescence in individuals with PKU. 2. Identify early signs of treatment discontinuation. Methodology This longitudinal, retrospective study included 75 children diagnosed through newborn screening, ages 7 to 13 years. Data on blood Phe concentration, number of blood samples sent, proportion of samples with Phe concentrations over the recommended range, and number of visits to the metabolism clinic were recorded. Logistic regression analysis was used to identify the variables that predict treatment discontinuation before 13 years of age. Results A progressive increase in mean blood Phe concentrations with age was identified. The greatest increase occurred between the first and second years of life. By age ten, mean Phe blood concentration of the group was above the recommended range. The proportion of samples with Phe concentrations over the recommended range also increased with age, from an average of 13% during the first year of life to 67% in early adolescence. Sixty-eight percent of the children attended the outpatient clinic and sent samples from birth to the time of the study. Individuals who discontinued follow-up showed significantly higher mean blood Phe concentrations (360 vs. 220.9 μmol/L; p = 0.004) and the proportion of samples over the recommended range (37% vs. 12% p = 0.002) was significantly higher during the second year of life. Mean age for children who discontinued treatment was 5.5 years of age. Blood Phe concentration values at 12 to 23 months of age and at 6 to 8 years of age significantly predicted treatment discontinuation before 13 years of age. Conclusion Treatment adherence in PKU diminishes with age. Early signs of treatment discontinuation can be identified during the second year of life, allowing preventive interventions in high risk groups.

Introduction: In phenylketonuria (PKU), a natural protein-restricted dietary treatment prevents severe cognitive impairment. Nutrient deficiencies may occur due to strict diet. This study is aimed at evaluating the dietary intake and blood concentrations of micronutrients and essential fatty acids (FA), bone mineral density (BMD) and fracture history in patients on long-term dietary treatment. Methods: Sixty early diagnosed Dutch patients (aged 1-39 years) were included in a multi-center cross-sectional study. Their dietary intake, blood concentrations of micronutrients, FA, fracture history and BMD were assessed. Results: Selenium dietary intake and serum concentrations were low in 14 and 46% of patients, respectively. The serum 25-OH vitamin D2 + D3 concentration was low in 14% of patients while 20% of patients had a low vitamin D intake. Zinc serum concentrations were below normal in 14% of patients, despite adequate intake. Folic acid serum concentrations and intake were elevated. Despite safe total protein and fat intake, arginine plasma concentrations and erythrocyte eicosapentaenoic acid were below reference values in 19 and 6% of patients, respectively. Low BMD (Z-score Conclusions: Dutch patients with PKU on long-term dietary treatment have a near normal nutrient status. Supplementation of micronutrients of which deficiency may be deleterious (e.g., vitamin D and selenium) should be considered. BMD warrants further investigation.

Phenylketonuria (PKU) is a well-described inborn error of amino acid metabolism that has been treated for >60 years. Enzyme deficiency causes accumulation of phenylalanine (Phe) and if left untreated will lead to profound and irreversible intellectual disability in most children. Traditionally, it has been managed with a low-Phe diet supplemented with a Phe-free protein substitute although newer treatment options mainly in combination with diet are available for some subgroups of patients with PKU, for example, sapropterin, large neutral amino acids, and glycomacropeptide. The diet consists of three parts: 1) severe restriction of dietary Phe; 2) replacement of non-Phe l-amino acids with a protein substitute commonly supplemented with essential fatty acids and other micronutrients; and 3) low-protein foods from fruits, some vegetables, sugars, fats and oil, and special low-protein foods (SLPF). The prescription of diet is challenging for health professionals. The high-carbohydrate diet supplied by a limited range of foods may program food preferences and contribute to obesity in later life. Abnormal tasting and satiety-promoting protein substitutes are administered to coincide with peak appetite times to ensure their consumption, but this practice may impede appetite for other important foods. Intermittent dosing of micronutrients when combined with l-amino acid supplements may lead to their poor bioavailability. Much work is required on the ideal nutritional profiling for special SLPF and Phe-free l-amino acid supplements. Although non-diet treatments are being studied, it is important to continue to fully understand all the consequences of diet therapy as it is likely to remain the foundation of therapy for many years.

Phenylketonuria (PKU) is a disorder of phenylalanine metabolism, characterized by a neurotoxic phenylalanine (Phe) accumulation, and treatable with a life-long Phe-restricted diet. Though early and continuously treated PKU (ETPKU) patients exhibit normal IQ, their cognitive outcome remains suboptimal. In this longitudinal study, we aimed at assessing the determinants of IQ subscales and quality of metabolic control in ETPKU children.We collected blood Phe levels, numbers of blood samples for Phe determination, parents' socio-professional categories and school achievement data of 39 classical and moderate ETPKU patients who underwent two cognitive evaluations performed by the same neuropsychologist (at 6.5 and 10y of mean age). We then sought to evaluate the determinants of 1) the changes in their IQ between the two testings (delta IQ) and 2) the quality of metabolic control (evaluated by the median Phe levels during the year before the second test) with multivariate regression analysis.Though in the normal range, mean total IQ slightly decreased between the two evaluations, and we observed a better verbal than performance outcome. Modeling the determining factors of the delta IQ, we found a significant influence of the number of blood samples (β = 0.46, 95%CI = 0.13 to 0.79, p

Background Phenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN’s goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families. Objectives We investigated Canadian metabolic dietitians’ perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines. Methods We invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency. Results We received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ≥360 μmol/L (6 mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360 μmol/L (2–6 mg/dL) as the optimal treatment range for blood Phe in children 0–9 years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3 day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin. Conclusion While Canadian dietitians’ practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.

Background Phenylketonuria (PKU) is due to the deficit of the enzyme phenylalanine hydroxylase, the first step of dopamine synthesis. If not early treated the disease results in severe neurological impairment. Minor neurological signs have been reported in early treated PKU (ETPKU) subjects. Prolactin level is affected by (and reflects) brain dopamine availability. Object of the study was to assess the occurrence, age at onset, distribution, associated neurological signs, and possible pathogenetic biomarkers of tremor in ETPKU. Methods Fifty-nine ETPKU and 43 control subjects (age range 7–54) underwent individual and familiar tremor history, clinical assessment of tremor by means of the Fahn-Tolosa-Marin Tremor Rating Scale, and IQ evaluation. Historical and concomitant biochemical data (blood levels of Phe) and serum prolactin were included in the analysis. Results Thirty-two percent of ETPKU patients were affected by postural and kinetic tremor. We found a significant correlation between severity of tremor and: prolactin level at the day of examination (part A: rs = 0.320; p = .014; part C: rs = 0.319; p = .014), Phe fluctuations from 12 years onwards (part B: rs = 0.300; p = .036). We also found a significant correlation between prolactin (18.2 ± 9.6 ng/ml) and Phe levels (852 ± 472 μmol/l) on the day of assessment (rs = 0.470; p Conclusions The main clinical features of tremor in ETPKU evoke those of essential tremor, although with a higher prevalence and an earlier onset than in general population. The severity of tremor was related to concomitant prolactin rather than Phe levels. This pattern suggests that metabolic alterations associated with PKU may result in an anticipation of the tremor onset in subjects who are possibly prone to this disorder.

Background: Creatine (Cr) levels are strongly dependent on diets, including animal-derived proteins. Cr is an important metabolite as it represents a source of stored energy to support physical performance and potentially sustain positive effects such as improving memory or intelligence. This study was planned to assess Cr levels in PKU children adhering to a diet low in phenylalanine (Phe) content and compared with those of children with mild hyperphenylalaninemia (MHP) on a free diet. Methods: This retrospective pilot study analyzed Cr levels from Guthrie cards in 25 PKU and 35 MHP subjects. Anthropomorphic and nutritional data of the study populations were assessed, compared and correlated. Results: Cr levels of PKU subjects were significantly lower than those of MHP subjects and correlated to the low intake of animal proteins. Although no deficiencies in PKU subjects were identified, PKU subjects were found to have a 26-fold higher risk of displaying Cr levels

Background: COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread. Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential modifiers. Methods: Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into subgroups according to age (GROUP A 600 umol/l and a − 8% of patients with 100% DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed time-periods. On the contrary, GROUP B demonstrated significant reductions in mean blood Phe concentrations (p

Phenylketonuria (PKU) is an inherited metabolic disorder due to phenylalanine hydroxylase (PAH) deficiency resulting in an elevation of Phe [1]. High blood phenylalanine (Phe) is associated with developmental disability, seizures and eczema that are prevented if blood Phe is controlled from infancy within 120–360 μmol/L [2]. The primary treatment for PKU is a Phe-restricted diet that eliminates high protein food and relies on the use of low or Phe-free medical foods. The diet is difficult to follow, and this results in sub-optimal blood Phe, especially in adults [3], with associated adverse neuropsychological outcomes [4]. Consequently, additional non-dietary therapies have been developed. The first of these to be approved was saproterin dihydrochloride,1 a synthetic form of the PAH cofactor tetrahydrobiopterin (BH4). In pharmacological amounts this oral therapy usually serves as adjunctive to diet by enhancing PAH activity in a subpopulation of those with PKU, thereby allowing for a degree of diet liberalization in those patients [5]. A second and more recently approved therapy is pegvaliase pqpz1 (pegvaliase), an injectable enzyme substitution therapy that converts phenylalanine to trans-cinnamic acid and ammonia and can replace dietary therapy in those with PKU who respond to this treatment [6]. Untreated PKU during pregnancy (maternal PKU) results in poor offspring outcomes, including low birth weight, microcephaly, congenital heart defects and developmental disability [7,8]. During clinical trials of pegvaliase, subjects were required to use two forms of birth control and to discontinue the study drug for pregnancy and breastfeeding but the approved label in the U.S. does not contraindicate its use during pregnancy or breastfeeding [9]. Therefore, this decision is left to the judgment of prescribing clinicians. However, there are no human data available regarding the use of pegvaliase during pregnancy or breastfeeding. This case describes the challenges for a woman with PKU who transitioned from pegvaliase therapy and an unrestricted diet to a phe-restricted diet for pregnancy and breastfeeding and the re-introduction of drug therapy after breastfeeding.

Background: Phenylketonuria (PKU) leads to an accumulation of phenylalanine (Phe) in the blood and subsequent neurologic, cognitive, psychiatric, and behavioral dysfunction. Many patients report social isolation and decreased quality of life. Pegvaliase is an enzyme substitution therapy that reduces blood Phe levels in patients with PKU and is associated with a risk of hypersensitivity reactions. Objective: To define the minimum acceptable benefit (MAB) of pegvaliase, i.e., the minimum probability of achieving a blood Phe level 600 μmol/L participated in a patient-preference web survey using two surveys: adapted swing-weighting and thresholding. Participants were asked to make ordinal choices between varying clinical benefit and severity levels for hypersensitivity. Disease effects and treatment satisfaction were also assessed. Results: Among 45 participants, the mean (standard deviation) self-reported blood Phe level was 976.9 (429.9) μmol/L; only 28.8% reported satisfaction with their current treatment. Most (84.4%) indicated difficulty in following a PKU diet; 60% reported that the PKU diet was burdensome, and 58% reported feeling socially isolated. Most (≥69%) reported their MAB to be less than the expected clinical benefit provided by pegvaliase; the mean MAB was 22.7% and 34.4% in the swing-weighting and thresholding surveys, respectively. Conclusion: Most participants felt the burden of PKU on their daily lives, were dissatisfied with current treatments, and were willing to accept the risks of hypersensitivity reactions to achieve recommended blood Phe levels with pegvaliase treatment. Keywords: Phenylketonuria, PKU, Pegvaliase, Minimum acceptable benefit, Benefit-risk analysis, Patient preference

WOS: 000442229500021, PubMed ID: 30101073, Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. Methods: We sent a cross sectional, survey monkey (R) questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months. 53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, >= 26 weeks in 12% and < 17 weeks in 3%. Discussion: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development., Vitaflo, We thank Vitaflo for supporting the publication cost of this paper.

We assessed the relationship between anxiety and long-term metabolic control in adolescents with phenylketonuria (PKU). We used a standardized psychological test to measure anxiety level and analyzed lifelong blood phenylalanine stability in a selected group of 25 PKU teenagers with treatment adherence problems. We demonstrated significant correlations of anxiety with variability of blood phenylalanine concentrations and with severity of hyperphenylalaninemia. Avoiding blood phenylalanine fluctuations in childhood can probably reduce anxiety in PKU adolescents.

Background Inherited metabolic diseases (IMD) are a large group of rare single-gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Methods This two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum. Discussion This protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy-makers. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2327-3) contains supplementary material, which is available to authorized users.

Background In phenylketonuria, dietary treatment prevents most of the severe brain disease. However, patients have to follow a diet restricted in several natural components, what may cause decreased bone density and obesity. Exercise is known to improve both mental functioning and bone density also avoiding obesity, and could optimize aspects of central and peripheral outcome, regardless changes in phenylalanine (Phe) levels. However, the acute effects of exercise on metabolic parameters in phenylketonuria patients are unknown and thereby long-term adaptations are unclear. Therefore, this study aimed to evaluate patients' basal metabolic rate (BMR), and their acute response to an aerobic exercise session on plasma concentrations of Phe, tyrosine (Tyr), and branched-chain amino acids (BCAA), as well as metabolic and hormonal responses. Methods Five early- and four late diagnosed phenylketonuria patients aged 21 ± 4 years and 17 sex-, age-, and BMI-matched controls were evaluated for BMR, peak oxygen consumption (VO 2peak ) and plasma amino acid, glucose, lipid profile and hormonal levels. At least one week later, participants performed a 30-min aerobic exercise session (intensities individually calculated using the VO 2peak results). Blood samples were collected in fasted state (moment 1, M1) and immediately after a small breakfast, which included the metabolic formula for patients but not for controls, and the exercise session (moment 2, M2). Results Phenylketonuria patients and controls showed similar BMR and physical capacities. At M1, patients presented higher Phe concentration and Phe/Tyr ratio; and lower levels of BCAA and total cholesterol than controls. Besides that, poorly controlled patients tended to stay slightly below the prescribed VO 2 during exercise. Both patients and controls showed increased levels of total cholesterol and LDL at M2 compared with M1. Only controls showed increased levels of Tyr, lactate, and HDL; and decreased Phe/Tyr ratio and glucose levels at M2 compared to values at M1. Conclusions Acute aerobic exercise followed by a Phe-restricted breakfast did not change Phe concentrations in treated phenylketonuria patients, but it was associated with decreased Phe/Tyr only in controls. Further studies are necessary to confirm our results in a higher number of patients.

To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86 %) contacted countries (N = 8600 patients). The main results’ analysis was based on completed questionnaires obtained from 31 centres (53 %) within 15 countries (68 %). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84 % of centres, respectively. In 26 % of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48 % of centres, with 24-h responsiveness tests most common (36 %). Only one centre among the five countries lacking newborn screening provided a completed questionnaire. Conclusion: Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe.“What is Known”• PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. • Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches. “What is New”• PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the region. • Key areas for improvement identified in surveyed centres include a need for comprehensive screening in all countries, increased number of metabolic dietitians and specialised adult PKU clinics, delayed time to treatment initiation, appropriate Phe thresholds, Phe targets and monitoring frequencies, and universal access to currently available treatment options. Electronic supplementary material The online version of this article (doi:10.1007/s00431-015-2622-5) contains supplementary material, which is available to authorized users.

Contains fulltext : 182674.pdf (Publisher’s version ) (Open Access) Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAH(enu2) (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments.

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children, SCOPUS: ar.j, info:eu-repo/semantics/published