{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:25:10Z","timestamp":1787315110364,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"APR Applied Pharma Research SA"},{"id":[{"id":"https:\/\/ror.org\/05c2q0q08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Achieving optimal metabolic control in phenylketonuria (PKU) remains challenging, particularly in adolescents and adults. Conventional free amino acid\u2013based protein substitutes are absorbed rapidly, whereas prolonged-release formulations are designed to provide a more gradual amino acid release profile. Whether this translates into more favorable 24 h Phe and Tyr profiles and improved short-term biochemical parameters of metabolic control remains uncertain. This study evaluated whether a prolonged-release amino acid\u2013based protein substitute (PR-AA) could improve 24 h metabolic control compared with standard protein substitutes. Methods: This randomized, controlled, open-label crossover study included adolescents and adults with PKU aged \u226516 years. Participants received either conventional protein substitutes (standard of care; SC) or PR-AA three times daily for two consecutive days, followed by crossover to the alternate treatment. Blood spot samples were collected at five time points over 24 h on the second day of each treatment period. The primary outcome was the 24 h blood Phe profile. Secondary outcomes included blood Tyr, Phe\/Tyr ratio, and exploratory assessment of branched-chain amino acids (BCAAs). Results: Twenty-one patients were enrolled, of whom 16 were included in the intention-to-treat analysis and 12 in the per-protocol analysis. PR-AA treatment resulted in significantly lower mean blood Phe levels over 24 h compared with SC (522 \u00b1 194 vs. 561 \u00b1 165 \u00b5mol\/L; p = 0.0009), corresponding to a reduction of approximately 6\u20137%. The effect was consistently observed throughout the 24-h assessment period, particularly during the early morning, and became detectable after only two days of treatment. PR-AA was also associated with significantly higher blood Tyr levels (approximately +18\u201320%; p &lt; 0.05) and a lower Phe\/Tyr ratio (approximately \u221220%; p &lt; 0.001) compared with SC. Exploratory analyses demonstrated modestly lower and more stable BCAA profiles with PR-AA. No significant carryover effects or treatment-related safety concerns were observed. Conclusions: Short-term treatment with a prolonged-release protein substitute was associated with modest but consistent improvements in short-term biochemical parameters of metabolic control in adolescents and adults with PKU, including lower blood Phe and higher Tyr levels, resulting in a reduced Phe\/Tyr ratio. These findings suggest that optimizing amino acid delivery kinetics may represent a promising strategy to improve short-term metabolic control in PKU. Given the preliminary nature of these findings and the limited number of participants who completed the study protocol, larger studies with longer follow-up, including direct clinical and neurocognitive outcomes and formal variability metrics, are needed to determine the clinical relevance of these biochemical effects.<\/jats:p>","DOI":"10.3390\/nu18162738","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:37:34Z","timestamp":1787312254000},"page":"2738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of a Prolonged-Release Protein Substitute on 24-h Phenylalanine and Tyrosine Profiles in Phenylketonuria: A Randomized Crossover Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7703-8635","authenticated-orcid":false,"given":"Valentina","family":"Rovelli","sequence":"first","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7177-7982","authenticated-orcid":false,"given":"Graziella","family":"Cefalo","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0528-4968","authenticated-orcid":false,"given":"Alice Re","family":"Dionigi","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Finizii","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Paci","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juri","family":"Zuvadelli","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Banderali","sequence":"additional","affiliation":[{"name":"Clinical Department of Pediatrics, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(10)60961-0","article-title":"Phenylketonuria","volume":"376","author":"Blau","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41572-021-00267-0","article-title":"Phenylketonuria","volume":"7","author":"Blau","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1001\/archneur.1973.00490190063008","article-title":"Saturation of Blood Brain Barrier Transport of Amino Acids in Phenylketonuria","volume":"28","author":"Oldendorf","year":"1973","journal-title":"Arch. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Huijbregts, S., and Romani, C. (2026). Cognitive Functioning in Phenylketonuria: A Lifespan Perspective. Nutrients, 18.","DOI":"10.3390\/nu18010146"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109125","DOI":"10.1016\/j.ymgme.2025.109125","article-title":"European Guidelines on Diagnosis and Treatment of Phenylketonuria: First Revision","volume":"145","author":"MacDonald","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/s13023-020-01391-y","article-title":"PKU Dietary Handbook to Accompany PKU Guidelines","volume":"15","author":"MacDonald","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Scala, I., Riccio, M.P., Marino, M., Bravaccio, C., Parenti, G., and Strisciuglio, P. (2020). Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria. Nutrients, 12.","DOI":"10.3390\/nu12041092"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s10545-010-9069-7","article-title":"Large Neutral Amino Acids in Daily Practice","volume":"33","author":"Ahring","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ymgme.2007.02.002","article-title":"The Effects of Large Neutral Amino Acid Supplements in PKU: An MRS and Neuropsychological Study","volume":"91","author":"Schindeler","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_10","first-page":"805","article-title":"Sapropterin Dihydrochloride (Kuvan\/Phenoptin), an Orally Active Synthetic Form of BH4 for the Treatment of Phenylketonuria","volume":"10","author":"Burnett","year":"2007","journal-title":"IDrugs Investig. Drugs J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1111\/bcp.13886","article-title":"Efficacy and Safety of Sapropterin Dihydrochloride in Patients with Phenylketonuria: A Meta-Analysis of Randomized Controlled Trials","volume":"85","author":"Qu","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1177392819857089","DOI":"10.1177\/1177392819857089","article-title":"A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria","volume":"13","author":"Hydery","year":"2019","journal-title":"Drug Target Insights"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1080\/14656566.2025.2498477","article-title":"Sepiapterin for the Treatment of Phenylketonuria","volume":"26","author":"Williams","year":"2025","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40265-025-02247-0","article-title":"Sepiapterin: First Approval","volume":"86","author":"Lamb","year":"2026","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0140-6736(02)09334-0","article-title":"How Practical Are Recommendations for Dietary Control in Phenylketonuria?","volume":"360","author":"Walter","year":"2002","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ymgme.2017.01.001","article-title":"Adherence to Clinic Recommendations among Patients with Phenylketonuria in the United States","volume":"120","author":"Jurecki","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/ejcn.2010.258","article-title":"Blood Phenylalanine Control in Phenylketonuria: A Survey of 10 European Centres","volume":"65","author":"Ahring","year":"2011","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1080\/03007995.2020.1847717","article-title":"The Management of Phenylketonuria in Adult Patients in Italy: A Survey of Six Specialist Metabolic Centers","volume":"37","author":"Burlina","year":"2021","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_19","first-page":"39","article-title":"Living with Phenylketonuria in Adulthood: The PKU ATTITUDE Study","volume":"16","author":"Cazzorla","year":"2018","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.2147\/PPA.S512719","article-title":"Phenylketonuria as an Adherence Disease","volume":"19","author":"Reach","year":"2025","journal-title":"Patient Prefer. Adherence"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ymgme.2019.12.007","article-title":"5-Year Retrospective Analysis of Patients with Phenylketonuria (PKU) and Hyperphenylalaninemia Treated at Two Specialized Clinics","volume":"129","author":"Levy","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_22","first-page":"101026","article-title":"Adherence to PKU Guidelines among Patients with Phenylketonuria: A Cross-Sectional National Multicenter Survey-Based Study in Argentina, Brazil, and Mexico","volume":"38","author":"Chiesa","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_23","first-page":"54","article-title":"Treatment Adherence during Childhood in Individuals with Phenylketonuria: Early Signs of Treatment Discontinuation","volume":"11","author":"Araya","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Pinto, A., Ahring, K., Almeida, M.F., Ashmore, C., B\u00e9langer-Quintana, A., Burlina, A., Co\u015fkun, T., Daly, A., van Dam, E., and Dursun, A. (2024). Blood Phenylalanine Levels in Patients with Phenylketonuria from Europe between 2012 and 2018: Is It a Changing Landscape?. Nutrients, 16.","DOI":"10.3390\/nu16132064"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106969","DOI":"10.1016\/j.ymgme.2022.106969","article-title":"The Impact of Metabolic Control on Cognition, Neurophysiology, and Well-Being in PKU: A Systematic Review and Meta-Analysis of the within-Participant Literature","volume":"138","author":"Thomas","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1186\/s13023-019-1225-z","article-title":"Adult Cognitive Outcomes in Phenylketonuria: Explaining Causes of Variability beyond Average Phe Levels","volume":"14","author":"Romani","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108544","DOI":"10.1016\/j.ymgme.2024.108544","article-title":"Executive Functions & Metabolic Control in Phenylketonuria (PKU) and Mild Hyperphenylalaninemia (MHPA)","volume":"143","author":"Tomm","year":"2024","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107684","DOI":"10.1016\/j.ymgme.2023.107684","article-title":"Metabolic Control and Clinical Outcome in Adolescents with Phenylketonuria","volume":"140","author":"Nardecchia","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/jimd.12413","article-title":"Long-Term Cognitive and Psychosocial Outcomes in Adults with Phenylketonuria","volume":"44","author":"Aitkenhead","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00415-024-12840-0","article-title":"Neuropsychological Profile of French Adults with Early-Treated Phenylketonuria: A Multicenter Study","volume":"272","author":"Brachet","year":"2024","journal-title":"J. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1017\/S1355617722000686","article-title":"A Comprehensive Assessment of Neurocognitive and Psychological Functioning in Adults with Early-Treated Phenylketonuria","volume":"29","author":"Clocksin","year":"2023","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ymgme.2018.12.011","article-title":"Neurocognitive Functioning in Adults with Phenylketonuria: Report of a 10-Year Follow-Up","volume":"126","author":"Feldmann","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1007\/s10519-017-9863-1","article-title":"Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study","volume":"47","author":"Jahja","year":"2017","journal-title":"Behav. Genet."},{"key":"ref_34","first-page":"502356","article-title":"Clinical Characteristics and Management of Spanish Adult Patients with Phenylketonuria","volume":"225","year":"2025","journal-title":"Rev. Clin. Esp."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1186\/s13023-024-03203-z","article-title":"Systematic Literature Review of the Somatic Comorbidities Experienced by Adults with Phenylketonuria","volume":"19","author":"Whitehall","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/s13023-025-03830-0","article-title":"Intelligence Quotient Scores among Early-Treated Phenylketonuria Patients: Results from a Systematic Literature Review","volume":"20","author":"Tomazos","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1080\/13803395.2019.1696753","article-title":"Emotional Health in Early-Treated Adults with Phenylketonuria (PKU): Relationship with Cognitive Abilities and Blood Phenylalanine","volume":"42","author":"Palermo","year":"2020","journal-title":"J. Clin. Exp. Neuropsychol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109210","DOI":"10.1016\/j.ymgme.2025.109210","article-title":"Meta-Analysis of Cognitive Outcomes in Children and Adults with Early Treated Phenylketonuria\u2014Results across Functions","volume":"146","author":"Romani","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tomm, A., Thiele, A.G., Rohde, C., Schl\u00f6gl, H., Kiess, W., and Beblo, S. (2025). Executive Functions and Long-Term Metabolic Control in Adults with Phenylketonuria (PKU). Metabolites, 15.","DOI":"10.3390\/metabo15030197"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ymgme.2014.01.012","article-title":"Variability in Phenylalanine Control Predicts IQ and Executive Abilities in Children with Phenylketonuria","volume":"111","author":"Hood","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ymgme.2014.11.007","article-title":"Prolonged Exposure to High and Variable Phenylalanine Levels over the Lifetime Predicts Brain White Matter Integrity in Children with Phenylketonuria","volume":"114","author":"Hood","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/apa.14517","article-title":"Children and Adolescents with Phenylketonuria Display Fluctuations in Their Blood Phenylalanine Levels","volume":"108","author":"Feldmann","year":"2019","journal-title":"Acta Paediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1203\/00006450-199604001-00857","article-title":"Factors Affecting Cognitive, Motor, Executive And Behavioral Functioning In Children With Phenylketonuria (PKU). 835","volume":"39","author":"Arnold","year":"1996","journal-title":"Pediatr. Res."},{"key":"ref_44","first-page":"80","article-title":"Blood Phenylalanine Instability Strongly Correlates with Anxiety in Phenylketonuria","volume":"14","author":"Didycz","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1177\/10815589221143485","article-title":"The Role of Phenylalanine Levels in the Neuropsychological and Neuroanatomical Status of Adult Patients with Phenylketonuria: The Impact of Fluctuations","volume":"71","year":"2023","journal-title":"J. Investig. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1111\/1467-8624.00370","article-title":"Associations between Phenylalanine-to-Tyrosine Ratios and Performance on Tests of Neuropsychological Function in Adolescents Treated Early and Continuously for Phenylketonuria","volume":"72","author":"Luciana","year":"2001","journal-title":"Child Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1080\/87565640903325725","article-title":"A Preliminary Investigation of the Role of the Phenylalanine:Tyrosine Ratio in Children with Early and Continuously Treated Phenylketonuria: Toward Identification of \u201cSafe\u201d Levels","volume":"35","author":"Sharman","year":"2010","journal-title":"Dev. Neuropsychol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.gene.2012.05.007","article-title":"Depressive Symptoms in Adolescents with Early and Continuously Treated Phenylketonuria: Associations with Phenylalanine and Tyrosine Levels","volume":"504","author":"Sharman","year":"2012","journal-title":"Gene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1177\/014860719101500148","article-title":"Effect of Simultaneous Ingestion of L-Amino Acids and Whole Protein on Plasma Amino Acid and Urea Nitrogen Concentrations in Humans","volume":"15","author":"Gropper","year":"1991","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"nzaa049_066","DOI":"10.1093\/cdn\/nzaa049_066","article-title":"Ingestion of Free Amino Acids as Opposed to Intact Protein Increases Amino Acid Absorption but Does Not Further Augment Postprandial Muscle Protein Synthesis Rates","volume":"4","author":"Weijzen","year":"2020","journal-title":"Curr. Dev. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1093\/jn\/nxab305","article-title":"Ingestion of Free Amino Acids Compared with an Equivalent Amount of Intact Protein Results in More Rapid Amino Acid Absorption and Greater Postprandial Plasma Amino Acid Availability Without Affecting Muscle Protein Synthesis Rates in Young Adults in a Double-Blind Randomized Trial","volume":"152","author":"Weijzen","year":"2022","journal-title":"J. Nutr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/PL00014226","article-title":"Utilisation of amino acid mixtures in adolescents with phenylketonuria","volume":"155","author":"Herrmann","year":"1996","journal-title":"Eur. J. Pediatr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14930","DOI":"10.1073\/pnas.94.26.14930","article-title":"Slow and Fast Dietary Proteins Differently Modulate Postprandial Protein Accretion","volume":"94","author":"Boirie","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E340","DOI":"10.1152\/ajpendo.2001.280.2.E340","article-title":"The Digestion Rate of Protein Is an Independent Regulating Factor of Postprandial Protein Retention","volume":"280","author":"Dangin","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1136\/gut.24.1.78","article-title":"Comparison of an Elemental and Polymeric Enteral Diet in Patients with Normal Gastrointestinal Function","volume":"24","author":"Jones","year":"1983","journal-title":"Gut"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1017\/S0954422418000173","article-title":"Optimising Amino Acid Absorption: Essential to Improve Nitrogen Balance and Metabolic Control in Phenylketonuria","volume":"32","author":"Macdonald","year":"2019","journal-title":"Nutr. Res. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2326409818783780","DOI":"10.1177\/2326409818783780","article-title":"A New Phe-Free Protein Substitute Engineered to Allow a Physiological Absorption of Free Amino Acids for Phenylketonuria","volume":"6","author":"Giarratana","year":"2018","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Giarratana, N., Giardino, L., Bighinati, A., Reiner, G., and Rocha, J.C. (2022). In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU). Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042227"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Scheinin, M., Junnila, J., Reiner, G., Macdonald, A., and Muntau, A.C. (2021). Nitrogen Balance after the Administration of a Prolonged-Release Protein Substitute for Phenylketonuria as a Single Dose in Healthy Volunteers. Nutrients, 13.","DOI":"10.3390\/nu13093189"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Scheinin, M., Barassi, A., Junnila, J., Lovr\u00f3, Z., Reiner, G., Sarkkinen, E., and Macdonald, A. (2020). Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers. Nutrients, 12.","DOI":"10.3390\/nu12061653"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1203\/00006450-199009000-00019","article-title":"Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome","volume":"28","author":"Thompson","year":"1990","journal-title":"Pediatr. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.nut.2007.03.009","article-title":"Protein Metabolism in Adult Patients with Phenylketonuria","volume":"23","author":"Hoeksma","year":"2007","journal-title":"Nutrition"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Daly, A., Evans, S., Chahal, S., Santra, S., Pinto, A., Gingell, C., Rocha, J.C., van Spronsen, F., Jackson, R., and Macdonald, A. (2019). The Effect of Glycomacropeptide versus Amino Acids on Phenylalanine and Tyrosine Variability over 24 Hours in Children with PKU: A Randomized Controlled Trial. Nutrients, 11.","DOI":"10.3390\/nu11030520"},{"key":"ref_64","unstructured":"MSSO (2026, June 23). Introductory Guide MedDRA Version 27.1. Available online: https:\/\/www.meddra.org\/how-to-use\/support-documentation\/english\/welcome."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1093\/ajcn\/22.12.1568","article-title":"Diurnal Variations of Serum Phenylalanine in Phenylketonuric Children on Low Phenylalanine Diet","volume":"22","author":"Olesen","year":"1969","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1016\/j.ymgme.2011.08.010","article-title":"Diurnal Variations in Blood Phenylalanine of PKU Infants under Different Feeding Regimes","volume":"104","author":"Hoeksma","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1542\/peds.92.4.570","article-title":"Plasma Phenylalanine and Tyrosine Responses to Different Nutritional Conditions (Fasting\/Postprandial) in Patients With Phenylketonuria: Effect of Sample Timing","volume":"92","author":"Smit","year":"1993","journal-title":"Pediatrics"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1136\/adc.78.2.122","article-title":"Does a Single Plasma Phenylalanine Predict Quality of Control in Phenylketonuria?","volume":"78","author":"MacDonald","year":"1998","journal-title":"Arch. Dis. Child."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1136\/adc.74.5.412","article-title":"Factors Affecting the Variation in Plasma Phenylalanine in Patients with Phenylketonuria on Diet","volume":"74","author":"MacDonald","year":"1996","journal-title":"Arch. Dis. Child."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1037\/neu0000336","article-title":"The Impact of Phenylalanine Levels on Cognitive Outcomes in Adults with Phenylketonuria: Effects across Tasks and Developmental Stages","volume":"31","author":"Romani","year":"2017","journal-title":"Neuropsychology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ymgme.2011.05.011","article-title":"Effect of Tetrahydrobiopterin on Phe\/Tyr Ratios and Variation in Phe Levels in Tetrahydrobiopterin Responsive PKU Patients","volume":"104","author":"Humphrey","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"9559","DOI":"10.1038\/s41598-023-36550-1","article-title":"Blood Phenylalanine Fluctuation in Phenylketonuric Children Treated by BH4 or Low-Phenylalanine Diet from Birth","volume":"13","author":"Theron","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ymgme.2021.02.008","article-title":"Effect of BH4 on Blood Phenylalanine and Tyrosine Variations in Patients with Phenylketonuria","volume":"133","author":"Evers","year":"2021","journal-title":"Mol. Genet. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Daly, A., Pinto, A., Evans, S., Geberhiwot, T., Jackson, R., Rocha, J.C., Tang, J.C.Y., and MacDonald, A. (2025). Protein Substitute Absorption: A Randomised Controlled Trial Comparing CGMP vs. Amino Acids vs. Micellar Casein in Healthy Volunteers. Nutrients, 17.","DOI":"10.3390\/nu17162671"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13023-026-04264-y","article-title":"Randomized investigation to evaluate phenylalanine fluctuation after overnight fasting in PKU patients treated with prolonged-release versus standard amino acid protein substitute","volume":"21","author":"Daly","year":"2026","journal-title":"Orphanet. J. Rare. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1023\/A:1025186217369","article-title":"Administration of Protein Substitute and Quality of Control in Phenylketonuria: A Randomized Study","volume":"26","author":"MacDonald","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1475-2891-12-60","article-title":"Diurnal Variation of Phenylalanine and Tyrosine Concentrations in Adult Patients with Phenylketonuria: Subcutaneous Microdialysis Is No Adequate Tool for the Determination of Amino Acid Concentrations","volume":"12","author":"Brichta","year":"2013","journal-title":"Nutr. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1515\/jpem-2020-0025","article-title":"Morning Specimen Is Not Representative of Metabolic Control in Tunisian Children with Phenylketonuria: A Repeated Cross-Sectional Study","volume":"33","author":"Tangour","year":"2020","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/1750-1172-8-133","article-title":"Phenylketonuria: Reduced Tyrosine Brain Influx Relates to Reduced Cerebral Protein Synthesis","volume":"8","author":"Hoeksma","year":"2013","journal-title":"Orphanet J. Rare Dis."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2738\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:46:11Z","timestamp":1787312771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":79,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18162738"],"URL":"https:\/\/doi.org\/10.3390\/nu18162738","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]}}}