Evaluating Therapy and Growth in Children with Phenylketonuria: A Retrospective Longitudinal Study from Two Romanian Centers.

Background and Objectives: Phenylketonuria (PKU) is a rare genetic disorder characterized by the inability to convert the essential amino acid phenylalanine into tyrosine. Early dietary treatment can successfully prevent complications, but controversies still exist regarding the attainment of normal growth in these patients. Materials and Methods: Eighteen patients with PKU from two Romanian reference centers were compared to eighteen non-PKU controls, matched for age and gender. The comparisons used weight-for-height, weight-for-age, height/length-for-age, and body mass index-for-age z-scores from birth to three years of age. Results: The PKU study group consisted of nine boys and nine girls, with a median follow-up period of thirty-six months (interquartile range = 9.75). While median values of all four growth metrics remained within the normal range across the entire study period, weight-for-age z-scores were significantly lower in PKU patients throughout most of the study (p < 0.001). Conclusions: The persistent lower weight-for-age z-scores of the PKU patients compared to controls indicate that ongoing monitoring and potential adjustments in dietary therapy may be necessary to further optimize growth outcomes.

Phenylalanine-Free Infant Formula in Patients with Phenylketonuria: A Retrospective Study.

The long-term efficacy and use of phenylalanine-free infant amino acid formula (PFIF) is understudied. This retrospective, longitudinal study evaluated PFIF (PKU Start: Vitaflo International) in children with phenylketonuria, collecting data on metabolic control, growth, dietary intake, and symptoms and the child's experience with PFIF. Twenty-five children (12 males, 48%) with a median age of 3.6 years (2.0-6.2 years) were included. During 24 months follow-up, children maintained normal growth and satisfactory metabolic control. The protein intake from protein substitutes increased from 2.7 at 6 months to 2.8 g/kg/day at 24 months, while natural protein decreased from 0.6 to 0.4 g/kg/day. By 24 months, most children (n = 16, 64%) had stopped PFIF, while nine (36%) continued with a median intake of 450 mL/day (Q1:300 mL, Q3: 560 mL). Children who continued PFIF after 24 months of age had higher energy and fat intakes with higher weight/BMI z-scores compared with those who stopped earlier (p < 0.05). Constipation was reported in 44% of infants but improved with age. Initial difficulty with PFIF acceptance was reported in 20% of infants but also improved with time. Prolonged use of PFIF in pre-school children may contribute to poor feeding patterns and overweight; thus, replacing the majority of the protein equivalent provided by PFIF with a weaning protein substitute by 12 months and discontinuing PFIF before 2 years is recommended.

No Impairment in Bone Turnover or Executive Functions in Well-Treated Preschoolers with Phenylketonuria-A Pilot Study.

Patients with phenylketonuria (PKU) present signs of impaired executive functioning and bone health in adolescence and adulthood, depending in part on the success of therapy in childhood. Therefore, nine children with well-treated PKU (4-7 years old, 22.2% ♀, seven with a full set of data, two included into partial analysis) and 18 age-, gender- and season-matched controls were analyzed for differences in executive functioning and bone parameters in plasma. Plasma was analyzed with commercially available kits. Cognitive performance in tonic alertness, visuo-spatial working memory, inhibitory control and task switching was assessed by a task battery presented on a touch screen. Regarding cognition, only the performance in incongruent conditions in inhibitory control was significantly better in children with PKU than in controls. No further differences in cognitive tests were detected. Furthermore, no significant difference in the bone turnover markers osteocalcin, undercarboxylated osteocalcin and CTX were detected between children with PKU and controls, while children with PKU had a significantly higher vitamin D concentration (69.44 ± 12.83 nmol/L vs. 41.87 ± 15.99 nmol/L, p < 0.001) and trended towards lower parathyroid hormone concentrations than controls (48.27 ± 15.16 pg/mL vs. 70.61 ± 30.53 pg/mL, p = 0.066). In this small group of well-treated preschoolers with PKU, no impairments in cognitive performance and bone turnover were observed, while vitamin D supplementation of amino acid supplements seems to be sufficient to achieve good vitamin D status.

Insurance Reimbursement for Special Foods and Phenylalanine Levels in Patients With PKU in China.

Importance: Recent changes in China's social medical insurance reimbursement policy have impacted the financial burden of patients with phenylketonuria (PKU) for special foods. However, whether this policy change is associated with their blood phenylalanine (PHE) concentration is unclear. Objective: To investigate the association between the reimbursement policy and blood PHE concentration in patients with PKU. Design, Setting, and Participants: This cohort study measured the blood PHE concentrations of 167 patients with PKU across 4 newborn screening centers in China from January 2018 to December 2021. The reimbursement policy for special foods for patients with PKU at 2 centers was canceled in 2019 and restored from 2020 onwards. In contrast, the other 2 centers consistently implemented the policy. Data were analyzed from September 10 to December 6, 2023. Exposures: The implementation and cancelation of the reimbursement policy for special foods of patients with PKU. Main Outcomes and Measures: The blood PHE concentration was regularly measured from 2018 to 2021. A 1-sided Z test was used to compare the mean of the blood PHE concentration between different years. Results: Among 167 patients with PKU (mean [SD] age, 84.4 [48.3] months; 87 males [52.1%]), a total of 4285 measurements of their blood PHE concentration were collected from 2018 to 2021. For patients at the center that canceled the reimbursement policy in 2019, the mean (SD) of the blood PHE concentrations in 2019 was 5.95 (5.73) mg/dL, significantly higher than 4.84 (4.11) mg/dL in 2018 (P < .001), 5.06 (5.21) mg/dL in 2020 (P = .006), and 4.77 (4.04) mg/dL in 2021 (P < .001). Similarly, for patients at the other center that canceled the policy in 2019, the mean (SD) of the blood PHE concentrations in 2019 was 5.95 (3.43) mg/dL, significantly higher than 5.34 (3.45) mg/dL in 2018 (P = .03), 5.13 (3.15) mg/dL in 2020 (P = .003), and 5.39 (3.46) mg/dL in 2021 (P = .03). On the contrary, no significant difference was observed between any of the years for patients at the 2 centers that consistently implemented the policy. Conclusions and Relevance: In this cohort study of patients with PKU from multiple centers, the implementation of the reimbursement policy for special foods was associated with controlling the blood PHE concentration. Special foods expenditure for patients with PKU should be included in the scope of long-term social medical insurance reimbursement.

Morphofunctional Assessment beyond Malnutrition: Fat Mass Assessment in Adult Patients with Phenylketonuria-Systematic Review.

Morphofunctional assessment was developed to evaluate disease-related malnutrition. However, it can also be used to assess cardiometabolic risk, as excess adiposity increases this risk. Phenylketonuria (PKU) is the most prevalent inherited metabolic disease among adults, and obesity in PKU has recently gained interest, although fat mass correlates better with cardiometabolic risk than body mass index. In this systematic review, the objective was to assess whether adult patients with PKU have higher fat mass than healthy controls. Studies of adult PKU patients undergoing dietary treatment in a metabolic clinic reporting fat mass were included. The PubMed and EMBASE databases were searched. Relevance of articles, data collection, and risk of bias were evaluated by two independent reviewers. Ten articles were evaluated, six with a control group, including 310 subjects with PKU, 62 with mild hyperphenylalaninemia, and 157 controls. One study reported a significant and four a tendency towards an increased fat mass in all patients or only females with PKU. Limitations included not having a healthy control group, not reporting sex-specific results and using different techniques to assess fat mass. Evaluation of fat mass should be included in the morphofunctional assessment of cardiometabolic risk in adult patients with PKU.

Comparison of Cost Analysis in Patients with Tetrahydrobiopterin-Responsive and Non-Responsive Phenylketonuria in Turkey.

Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.

A phenylalanine-free recombinant nutritional protein for the dietary management of phenylketonuria.

Phenylketonuria (PKU) is a congenital metabolic disorder that causes the systemic elevation of phenylalanine (Phe), which is neurotoxic and teratogenic. PKU is currently incurable, and management involves lifelong adherence to an unpalatable protein-restricted diet based on Phe-free amino acid mixtures. Seeking a palatable dietary alternative, we identified a Bacillus subtilis protein (GSP16O) with a well-balanced but low-Phe amino acid profile. We optimized the sequence and expressed a modified Phe-free version (GSP105) in Pseudomonas fluorescens, achieving yields of 20 g/L. The purified GSP105 protein has a neutral taste and smell, is highly soluble, and remains stable up to 80°C. Homozygous enu2 mice, a model of human PKU, were fed with diets containing either GSP105 or normal protein. The GSP105 diet led to normalization of blood Phe levels and brain monoamine neurotransmitter metabolites, and prevented maternal PKU. The GSP105 diet thus provides an alternative and efficacious dietary management strategy for PKU.

Evaluation of a New 'Mix-In' Style Glycomacropeptide-Based Protein Substitute for Food and Drinks in Patients with Phenylketonuria and Tyrosinemia.

(1) Background: Poor palatability, large volume, and lack of variety of some liquid and powdered protein substitutes (PSs) for patients with phenylketonuria (PKU) and tyrosinemia (TYR) can result in poor adherence. This study aimed to evaluate a new unflavoured, powdered GMP-based PS designed to be mixed into drinks, foods, or with other PSs, in patients with PKU and TYR. (2) Methods: Paediatric and adult community-based patients were recruited from eight metabolic centres and prescribed ≥1 sachet/day (10 g protein equivalent (PE)) of the Mix-In-style PS over 28 days. Adherence, palatability, GI tolerance, and metabolic control were recorded at baseline and follow-up. Patients who completed at least 7 days of intervention were included in the final analysis. (3) Results: Eighteen patients (3-45 years, nine males) with PKU (n = 12) and TYR (n = 6) used the Mix-In-style PS for ≥7 days (mean 26.4 days (SD 4.6), range 11-28 days) alongside their previous PS, with a mean intake of 16.7 g (SD 7.7) PE/day. Adherence was 86% (SD 25), and GI tolerance was stable, with n = 14 experiencing no/no new symptoms and n = 3 showing improved symptoms compared to baseline. Overall palatability was rated satisfactory by 78% of patients, who successfully used the Mix-In-style PS in various foods and drinks, including smoothies, squash, and milk alternatives, as a top-up to meet their protein needs. There was no concern regarding safety/metabolic control during the intervention. (4) Conclusions: The 'Mix-In'-style PS was well adhered to, accepted, and tolerated. Collectively, these data show that providing a flexible, convenient, and novel format of PS can help with adherence and meet patients' protein needs.

A food pyramid for adult patients with phenylketonuria and a systematic review on the current evidences regarding the optimal dietary treatment of adult patients with PKU.

Early dietary treatment is mind-saving in patients with phenylketonuria. A "diet-for-life" is advocated, aimed to prevent effects of chronic exposure to hyperphenylalaninemia. While adherence to diet is significant during childhood as patients are followed-up at specialized metabolic centers, during adolescence and adulthood percentage of patients discontinuing diet and/or lost at follow-up is still high. The process of passing skills and responsibilities from pediatric team to adult team is defined "transition". The goal of transition clinics is to set up specific multidisciplinary care pathways and guarantee continuity of care and compliance of patients to care. In 2017, "The complete European guidelines on phenylketonuria" were published. These guidelines, however, do not provide an easy way to illustrate to adult patients how to follow correct dietary approach. The purpose of this review is to evaluate current evidence on optimum dietary treatment of adults with phenylketonuria and to provide food pyramid for this population. The pyramid built shows that carbohydrates should be consumed every day (3 portions), together with fruits and vegetables (5 portions), extra virgin olive oil, and calcium water (almost 1 L/day); weekly portions can include 150 g potatoes walnuts and hazelnuts (20 g). At top of pyramid, there are two pennants. The green means that, based on individual metabolic phenotype and daily phenylalanine tolerance, patients need personalized supplementation (specific phenylalanine free amino acid mixtures, vitamins and omega 3 fatty acids); the one red indicates foods that are banned from diet (aspartame and protein foods exceeding individual dietary phenylalanine tolerance).

The effect of casein glycomacropeptide versus free synthetic amino acids for early treatment of phenylketonuria in a mice model.

INTRODUCTION: Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. OBJECTIVE: The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. MATERIAL AND METHODS: 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. RESULTS: Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). CONCLUSION: CGMP can be a relevant supplement for the treatment of PKU.

Adecuación del aporte de proteína natural en el tratamiento de la fenilcetonuria: una revisión bibliográfica / Adequacy of natural protein intake in patients with phenylketonuria: bibliographic review

Introducción: la fenilcetonuria (PKU) es el error congénito del metabolismo de las proteínas más frecuente. El tratamiento dietético consiste en un plan de alimentación con una ingesta de proteínas naturales restringida, un sustituto proteico libre o de bajo contenido en fenilalanina (Phe) y el aporte de alimentos muy bajos en proteínas. El objetivo principal de este trabajo fue investigar si es posible aumentar la ingesta de proteína natural (PN) que se indica a los pacientes con PKU manteniendo los dosajes de Phe en sangre en rangos de seguridad. Materiales y método: se buscaron en 6 bases de datos electrónicas artículos publicados. Se identificaron un total de 154 artículos de Pub Med por intervalo de años desde 1999 a 2020. Se eligieron 15 artículos que se adaptaron a los criterios de inclusión y exclusión y respondían al objeto de estudio de esta revisión bibliográfica. Resultados: hay varios factores que pueden influenciar la estimación de la tolerancia de Phe como la severidad del fenotipo del paciente, la edad, el rango de seguridad de Phe en sangre, la prescripción de Phe y la adherencia al sustituto proteico. Si los niveles de Phe en sangre se mantienen en forma constante dentro del rango adecuado y por un período determinado, se debería considerar un incremento de la ingesta de Phe. El aumento de la ingesta de PN deberá ser realizado de manera controlada, individual y evaluando en forma constante el impacto en los dosajes de Phe en sangre. Conclusión: optimizar la ingesta de PN ofrece una mejora en la calidad de vida de pacientes con PKU, facilita la capacidad del paciente para socializar y contribuye a una mejor adherencia a la dieta(AU).

Introduction: phenylketonuria (PKU) is the most frequent inborn error of protein metabolism. The dietary treatment consists of a diet with a restricted natural protein intake, a free or low phenylalanine (Phe) protein substitute, and the intake of low protein food. The main objective of this work is to analyze if it is possible to increase the natural protein (NP) intake prescribed to PKU patients while maintaining blood Phe dosages within safe range. Materials and method: studies published were searched in 6 electronic data- basis. A total of 154 Pub Med articles were identified by range of years from 1999 to 2020. Fifteen articles which met the inclusion and exclusion criteria and responded to the objective of this bibliographic review were chosen. Results: several factors may influence Phe tolerance, such as severity of the patient´s phenotype, age, blood Phe safe range, Phe prescription and adherence to protein substitute. If Phe blood levels remain constantly within safe range and for a certain period, an increase of Phe intake should be considered. Increase of NP intake must be carried out in a controlled manner, individually and constantly evaluating blood Phe levels. Conclusion: optimizing NP intake offers the PKU patient an improvement in quality of life, facilitates the patient´s ability to socialize and contributes to a better adherence to the diet(AU).

Provision and Supervision of Food and Protein Substitute in School for Children with PKU: Parent Experiences.

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 < 0.001). An IHCP was significantly associated with improved supervision of food and protein substitute administration (p < 0.01), and better communication between parents/caregivers and the school team (p < 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.

Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (n = 142) were examined. Their costs in comparison to regular protein-containing (n = 182) and 'free-from' products (n = 135) were also analysed. Similar foods were grouped into subgroups (n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (n = 39/40) were more expensive than regular and 'free-from' food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis.

Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

Nitrogen Balance after the Administration of a Prolonged-Release Protein Substitute for Phenylketonuria as a Single Dose in Healthy Volunteers.

Nitrogen balance is the difference between nitrogen excreted as urea and nitrogen ingested, mainly in proteins. Increased circulating concentrations of amino acids (AA) in the bloodstream are usually associated with proportional increases in the production and excretion of urea. Previously, we reported results from a randomized, controlled, single-dose, crossover trial in healthy adult volunteers (n = 30) (Trial Registration: ISRCTN11016729), in which a Test product (prolonged-release AA mixture formulated with Physiomimic Technology™ (PT™)) significantly slowed down the release and reduced the peak plasma concentrations of essential AAs compared with a free AA mixture (Reference product) while maintaining essential AA bioavailability. Here, we report an assessment of the nitrogen balance from the same study. The amount of nitrogen contained in plasma AAs, levels of blood urea nitrogen (BUN) (p < 0.0001) and changes in BUN (p < 0.0001) were smaller after the Test product compared with the Reference product. These findings suggest that the production of urea in proportion to systemic AA availability was significantly smaller after the administration of the Test product compared with the Reference product and that the test product conferred the increased utilization of AAs for protein synthesis and reduced their oxidation and conversion to urea. In the clinical setting, it is possible that the effects of PT™ observed on the disposition of free AAs in this study may translate to health benefits in terms of physiological body composition and growth if used for the treatment of subjects with phenylketonuria (PKU). Further investigation in patients with PKU is warranted.

Adaptation and Validation of a Questionnaire to Evaluate Knowledge of the Low Phe Diet in PKU.

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.

Current Practices and Challenges in the Diagnosis and Management of PKU in Latin America: A Multicenter Survey.

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 >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.

A Three-Year Longitudinal Study Comparing Bone Mass, Density, and Geometry Measured by DXA, pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes.

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 5-16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5-16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5-16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5-15 years) (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.

The Impact of the First 2020 COVID-19 Lockdown on the Metabolic Control of Patients with Phenylketonuria.

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 < 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 : 1 <0-1> vs. 2 <1-4>; p < 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.

Long-term cognitive and psychosocial outcomes in adults with phenylketonuria.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty-four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty-nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.