{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:14:02Z","timestamp":1787944442776,"version":"build-2784847793"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ArlaFoodsIngredients"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>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<jats:sup>\u00ae<\/jats:sup> CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins\/peptides.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>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?.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Material and methods<\/jats:title>\n<jats:p>45 female mice homozygous for the <jats:italic>Pah<\/jats:italic><jats:sup><jats:italic>enu2<\/jats:italic><\/jats:sup> 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>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)).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>CGMP can be a relevant supplement for the treatment of PKU.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0261150","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T18:48:02Z","timestamp":1641926882000},"page":"e0261150","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["The effect of casein glycomacropeptide versus free synthetic amino acids for early treatment of phenylketonuria in a mice 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Shedlovsky","year":"1993","journal-title":"Genetics"},{"issue":"2","key":"pone.0261150.ref024","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1538\/expanim.58.141","article-title":"Genetic differences among C57BL\/6 substrains","volume":"58","author":"K Mekada","year":"2009","journal-title":"Exp Anim"},{"key":"pone.0261150.ref025","author":"K Ahring","journal-title":"Effect of offering Phenylketonuria (PKU) mice Glycomacropeptide (GMP) before normal or low protein (LP) diet on growth, serum-phenylalanine (phe)-concentration, bone structure, performance and concentration of phe in the brain"},{"issue":"3","key":"pone.0261150.ref026","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1093\/jn\/124.3.451","article-title":"Protein and amino acid requirements for maintenance and amino acid requirements for growth of laboratory rats","volume":"124","author":"NJ Benevenga","year":"1994","journal-title":"J 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