{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:54:33Z","timestamp":1779234873102,"version":"3.51.4"},"reference-count":63,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free\/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.<\/jats:p>","DOI":"10.3390\/nu13031040","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T23:59:41Z","timestamp":1616543981000},"page":"1040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"13","author":[{"given":"Fatma","family":"Ilgaz","sequence":"first","affiliation":[{"name":"Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, 06100 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-6359","authenticated-orcid":false,"given":"Cyril","family":"Marsaux","sequence":"additional","affiliation":[{"name":"Danone Nutricia Research, 3584CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Dietetics, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rani","family":"Singh","sequence":"additional","affiliation":[{"name":"Metabolic Genetics Nutrition Program, Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Rohde","sequence":"additional","affiliation":[{"name":"Department of Paediatrics of the University Clinics Leipzig, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erdem","family":"Karabulut","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00fclya","family":"G\u00f6kmen-\u00d6zel","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, 06100 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirjam","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Danone Nutricia Research, 3584CT Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Department of Dietetics, Birmingham Women\u2019s and Children\u2019s Hospital, Birmingham B4 6NH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,23]]},"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":"234","DOI":"10.1016\/j.ajhg.2020.06.006","article-title":"The Genetic Landscape and Epidemiology of Phenylketonuria","volume":"107","author":"Hillert","year":"2020","journal-title":"Am. 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