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Introduction Maple Syrup Urine Disease (MSUD) is a rare metabolic disorder requiring lifelong restriction of branched-chain amino acids (BCAAs), and targeted supplementation with valine and isoleucine to maintain metabolic stability. Methods A prospective, open-label, observational study was conducted over 56 days in 5 paediatric patients mean age 8.8 years (range 3–14) with classical MSUD. In Phase 1 (Days 0–28), participants received the ready to use (RTU) liquid valine formulation, while continuing their usual powdered isoleucine supplement. In Phase 2 (Days 29–56), participants returned to powdered valine and changed to the ready to use RTU liquid isoleucine supplement. Weekly plasma BCAAs were monitored. Acceptability, gastrointestinal tolerance, adherence, and dietary intake were assessed through questionnaires and food diaries. Results RTU liquid valine and isoleucine supplements were well tolerated and accepted by all participants. Plasma leucine decreased when taking both liquid valine (mean leucine 253 µmol/L) and isoleucine (mean leucine 219 µmol/L) compared to baseline (mean leucine 356 µmol/L). Required doses of valine and isoleucine decreased by 30% and 18%, respectively, suggesting improved adherence or enhanced efficacy. Palatability and ease of use were rated more favourably for the RTU products, with no adverse effects or adherence issues reported. Dietary intake remained stable throughout the study. Discussion These preliminary findings suggest that RTU valine and isoleucine formulations may offer potential advantages in MSUD management, simplifying administration, and enhancing user satisfaction. While limited by sample size and short-term evaluation, their practicality and patient-centered design warrant further investigation in larger, more diverse populations to establish long-term efficacy and broader applicability.

Background Effective management of phenylketonuria (PKU) requires consistent blood phenylalanine (Phe) control. However, patients, particularly those with classical PKU, often experience diurnal fluctuations, particularly with early morning Phe levels after an overnight fast. These fluctuations have been linked to neurocognitive and psychological impairments. This 4-week, randomized, controlled crossover study evaluated the efficacy of a prolonged-release amino acid (PR-AA) compared to a conventional free amino acid-based protein substitute (AA) in reducing early morning blood Phe levels in patients with classical PKU. Methods Participants on a low-Phe diet supplemented with protein substitutes were randomly assigned to one of two treatment arms: Arm A, participants received the PR-AA as a single evening dose for 7 days, followed by a 2-week washout period, then crossed over to receive their usual AA protein substitute for all daily doses for another 7 days. Arm B, the order was reversed. All other daily protein substitute doses remained unchanged, using the patients’ usual Phe-free L-AA protein substitute throughout the study. Blood Phe and tyrosine (Tyr) levels, Phe/Tyr ratio, branched-chain amino acids (BCAAs), urinary nitrogen and creatinine excretion, tolerability, and patient acceptability were assessed. Results From 16 eligible patients, 13 children with classical PKU ( n= 8 females, 62%) with a mean age of 11.8 ± 3.2 years completed the study. Administration of the PR-AA significantly reduced early morning Phe levels compared to AA (mean difference from baseline to the end of treatment with PR-AA: 63.6 ± 28.93 µmol/L; −17.8%; p =  0.0484; with AA: 95.5 ± 28.9 µmol/L; +27.6%; p =  0.0063). Subgroup analyses indicated greater benefit in patients < 12 years and in those with higher baseline Phe level (>360 μmol/L). PR-AA also significantly increased blood Tyr levels, and improved the Phe/Tyr ratio. No significant differences were observed for other parameters. PR-AA was well tolerated, with high adherence. Conclusions PR-AA demonstrated improved metabolic control, particularly in reducing early morning Phe levels. PR-AA may be a useful alternative protein substitute for patients with classical PKU, particularly those with poor metabolic control. Further long-term studies are warranted to assess sustained efficacy, adherence, and neurocognitive outcomes.

Background In phenylketonuria (PKU), attending multidisciplinary clinic reviews is an important aspect of life-long care. Since the COVID-19 pandemic, video and telephone clinics are used as alternative methods for people with PKU to have contact with their care team. There is limited research concerning patient preference, experience and perceptions of alternative types of clinic review. Individuals from the UK with PKU and their caregivers were invited to complete an online questionnaire, hosted on the National Society for PKU (NSPKU) website and social media platform. Results Data was available from 203 respondents. Forty one per cent of respondents ( n  = 49/119) preferred in-person clinics; 41% ( n  = 49) a hybrid of in-person, video and telephone clinics; 9% ( n  = 11) video clinics only, 6% ( n  = 7) telephone only and 3% ( n =  3) were unsure. The main respondent obstacles to in-person clinics were costs, travel and time, but this was balanced by the benefits of a physical examination and better patient engagement/motivation. Twenty one per cent ( n  = 36/169) of respondents were uncomfortable with the number of healthcare professionals (HCPs) in a clinic room. Patients were less likely to consult with a doctor on video (64%, n  = 91/143) or phone (50%, n =  59/119) reviews compared to in-person (80%, n  = 146/183). Issues with video and telephone reviews included the shorter time length of review, distractions, technical issues and poor patient engagement. Conclusions Online video and telephone clinic platforms were effective in overcoming the challenging circumstances in management, monitoring and treatment of patients with PKU during the COVID-19 pandemic. However, in-person clinics remain the preferred respondent option. It is important that HCPs are flexible, enabling people with PKU a choice of clinic options according to their individual clinical need and circumstances.

Background Phenylalanine-free infant formula is an essential source of safe protein in a phenylalanine restricted diet, but its efficacy is rarely studied. We report a multicentre, open, longitudinal, prospective intervention study on a phenylalanine-free infant formula (PKU Start: Vitaflo International Ltd.). Results This was a 2-part study: part I (28 days short term evaluation) and part II (12 months extension). Data was collected on infant blood phenylalanine concentrations, dietary intake, growth, and gastrointestinal tolerance. Ten infants ( n  = 8 males, 80%), with a median age of 14 weeks (range 4–36 weeks) were recruited from 3 treatment centres in the UK. Nine of ten infants completed the 28-day follow-up (one caregiver preferred the usual phenylalanine-free formula and discontinued the study formula after day 14) and 7/9 participated in study part II. The phenylalanine-free infant formula contributed a median of 57% (IQR 50–62%) energy and 53% (IQR 33–66%) of total protein intake from baseline to the end of the part II extension study. During the 12-month follow-up, infants maintained normal growth and satisfactory blood phenylalanine control. Any early gastrointestinal symptoms (constipation, colic, vomiting and poor feeding) improved with time. Conclusion The study formula was well tolerated, helped maintain good metabolic control, and normal growth in infants with PKU. The long-term efficacy of phenylalanine-free infant formula should continue to be observed and monitored.

Background In children with phenylketonuria (PKU), transitioning protein substitutes at the appropriate developmental age is essential to help with their long-term acceptance and ease of administration. We assessed the parental experiences in transitioning from a second stage to third stage liquid or powdered protein substitute in patients with PKU. Results Sixteen interviews (23 open-ended questions) were carried out with parents/caregivers of children with PKU (8 females, 50%) with a median age of 8 years (range 5–11 years), continuously treated with diet, and on a third stage protein substitute. Parents/caregivers identified common facilitators and barriers during the third stage protein substitute transition process. The main facilitators were: child and parent motivation, parent knowledge of the transition process, a role model with PKU, low volume and easy preparation of the third stage protein substitute (liquid/powder), anticipation of increasing child independence, lower parent workload, attractive packaging, better taste and smell, school and teacher support, dietetic plans and guidance, PKU social events, child educational materials and written resources. The main barriers were child aversion to new protein substitutes, poor child behaviour, child aged > 5 years, parental fear of change, the necessity for  parental time and persistence, loss of parental control, high product volume, different taste, smell, and texture of new protein substitutes, and peer bullying. Conclusion A stepwise, supportive approach is necessary when transitioning from second to third stage protein substitutes in PKU. Future studies are needed to develop guidance to assist parents/caregivers, health professionals, and teachers during the transition process.

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.

Background In the treatment of phenylketonuria (PKU), there was disparity between UK dietitians regarding interpretation of how different foods should be allocated in a low phenylalanine diet (allowed without measurement, not allowed, or allowed as part of phenylalanine exchanges). This led to variable advice being given to patients. Methodology In 2015, British Inherited Metabolic Disease Group (BIMDG) dietitians ( n  = 70) were sent a multiple-choice questionnaire on the interpretation of protein from food-labels and the allocation of different foods. Based on majority responses, 16 statements were developed. Over 18-months, using Delphi methodology, these statements were systematically reviewed and refined with a facilitator recording discussion until a clear majority was attained for each statement. In Phase 2 and 3 a further 7 statements were added. Results The statements incorporated controversial dietary topics including: a practical ‘scale’ for guiding calculation of protein from food-labels; a general definition for exchange-free foods; and guidance for specific foods. Responses were divided into paediatric and adult groups. Initially, there was majority consensus (≥86%) by paediatric dietitians ( n  = 29) for 14 of 16 statements; a further 2 structured discussions were required for 2 statements, with a final majority consensus of 72% ( n  = 26/36) and 64% ( n  = 16/25). In adult practice, 75% of dietitians agreed with all initial statements for adult patients and 40% advocated separate maternal-PKU guidelines. In Phase 2, 5 of 6 statements were agreed by ≥76% of respondents with one statement requiring a further round of discussion resulting in 2 agreed statements with a consensus of ≥71% by dietitians in both paediatric and adult practice. In Phase 3 one statement was added to elaborate further on an initial statement, and this received 94% acceptance by respondents. Statements were endorsed by the UK National Society for PKU. Conclusions The BIMDG dietitians group have developed consensus dietetic statements that aim to harmonise dietary advice given to patients with PKU across the UK, but monitoring of statement adherence by health professionals and patients is required.

Background: During adolescence, the brain is undergoing anatomical and physiological maturation processes with changes to cognitive development. However, in adolescents with phenylketonuria (PKU), executive function and mental health are adversely affected by high blood phenylalanine (Phe) levels. Objectives: We aim to describe clinical outcomes in adolescents with PKU. Methods: Cross-sectional questionnaires were performed on quality of life (EuroQol “EQ-5D-5L” questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale- HADS) and food neophobia in a single PKU centre. Retrospective data on metabolic control (previous 12 months) and medical history, and current data on anthropometry, dietary treatment, and comorbidities were collected. Results: In total, 33 adolescents with PKU participated with a mean age of 13.5 ± 1.3 y (16 boys, 17 girls). All were on a Phe restricted diet, with 3 also prescribed sapropterin. Questionnaires were self-completed by n = 25/33 (76%) adolescents. A mean of 36 ± 26 blood Phe spots were performed over 12 months. There was a mean of 83% of blood Phe < 600 µmol/L and 49% < 360 µmol/L. In total, 39% (n = 13/33) of adolescents were overweight/obese, 18% (n = 6/33) overweight and 21% (n = 7/33) obese. Medical history documented mental health disorders (anxiety/depression) in 7 cases, low mood, suicidal thoughts and self-harming in 5, and neuro diversity in 4 (autism and/or attention-deficit hyperactivity disorder (ADHD). In the HADS questionnaire, 12% (n = 3/25) of adolescents scored borderline abnormal for anxiety and 12% (n = 3/25) abnormal for depression. Mean anxiety scores for females were almost twice as high compared to males. No significant correlation was found between blood Phe and anxiety/depression scores. However, higher Phe levels showed a trend towards reduced enjoyment and emotional responsiveness, including lower scores on measures of pleasure, cheerfulness, and emotional reactivity. Although not statistically significant, these findings suggest a potential subtle association between poorer metabolic control and mood disturbances in adolescents with PKU. No food neophobia was identified in our study. Conclusions: Adolescents with PKU presented with high levels of depression and anxiety. Long term studies focusing on quality of life and neurocognition even when achieving the PKU European guidelines are necessary. Different therapeutic options are needed to improve the outcome of patients with PKU.

Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of phenylketonuria (PKU) and other amino acid disorders, allowing the antagonistic amino acid to be removed but with the safe provision of all other amino acids necessary for maintaining normal physiological function. They were first formulated by a chemist and used experimentally on a 2-year-old girl with PKU and their nutritional formulations and design have improved over time. Since 2008, a bioactive macropeptide has been used as a base for protein substitutes in PKU, with potential benefits of improved bone and gut health, nitrogen retention, and blood phenylalanine control. In 2018, animal studies showed that physiomimic technology coating the amino acids with a polymer allows a slow release of amino acids with an improved physiological profile. History has shown that in PKU, the protein substitute’s efficacy is determined by its nutritional profile, amino acid composition, dose, timing, distribution, and an adequate energy intake. Protein substitutes are often given little importance, yet their pharmacological actions and clinical benefit are pivotal when managing PKU.

: Sapropterin dihydrochloride is an established treatment option for individuals with phenylketonuria (PKU) who demonstrate responsiveness, but uncertainty persists regarding dosing frequency, timing relative to meals, the influence of dietary composition, and efficacy of different formulations. Despite widespread use in the UK, real-world administration behaviours have not previously been characterised. This study aimed to characterise sapropterin administration behaviours among people with PKU in the UK. : A 31-item questionnaire was developed and disseminated via the National Society for Phenylketonuria website and social media channels. The survey captured demographic information, dosing schedules, formulation use, administration techniques, co-ingestion with food, and changes in natural protein tolerance following initiation of generic sapropterin. : 124 current sapropterin users completed the survey. Most respondents were caregivers of children or adolescents (68.5% aged 0-18 years). Once-daily dosing was most common (66.1%, = 82), typically administered at breakfast, followed by twice-daily (32.3%, = 40) and three-times-daily (1.6%, = 2). Tablets were the predominant formulation (92.7%, = 115); 50.4% ( = 58/115) swallowed tablets whole, while the remaining (49.6%, = 57/115) crushed or dissolved them in water or juice. Nine respondents (7.3%, = 9/124) used powder sachets. Most participants (75%, = 93/124) took sapropterin with food, with both low-fat (36.6%, = 34/93) and high-fat (26.9%, = 24/93) meals reported. Over a third of participants (33.9%, = 42/124) tolerated a natural protein intake >30 g/day when this was measured, and a further 15.3% ( = 19) were able to maintain a fully unrestricted protein intake without protein substitute supplementation. The magnitude of protein intake improvement was significantly greater among adults ( < 0.001), those with higher baseline natural protein intake (≥30 exchanges/day) ( < 0.001), and individuals who swallowed sapropterin tablets whole ( = 0.038). Although 71.8% ( = 89/124) were pleased with their increased natural protein allowance, many expressed a desire for further improvement. : Substantial heterogeneity in dosing schedules, formulation handling, and co-ingestion practices highlights the absence of standardised guidance. These findings emphasise the need for clearer clinical recommendations to optimise treatment effectiveness and support consistent, equitable care.