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

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...

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Bibliographic Details
Published in:	PloS one Vol. 17; no. 1; p. e0261150
Main Authors:	Ahring, Kirsten K, Dagnæs-Hansen, Frederik, Brüel, Annemarie, Christensen, Mette, Jensen, Erik, Jensen, Thomas G, Johannsen, Mogens, Johansen, Karen S, Lund, Allan M, Madsen, Jesper G, Brøndum-Nielsen, Karen, Pedersen, Michael, Sørensen, Lambert K, Kjolby, Mads, Møller, Lisbeth B
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 11-01-2022 Public Library of Science (PLoS)
Subjects:	Acetic acid Amino acids Amino Acids - blood Amino Acids - chemical synthesis Amino Acids - therapeutic use Animals Biology and Life Sciences Body mass Bone and Bones - diagnostic imaging Bone and Bones - metabolism Bone Density Bone mineral content Brain Brain - metabolism Brain - pathology Brain research Casein Caseins - therapeutic use Chymosin Departments Diet Diet therapy Dietary intake Dietary Supplements Dihydroxyphenylacetic acid Disease Models, Animal Dopamine Drinking water Dual energy X-ray absorptiometry Female Food Food intake Glycomacropeptide Health aspects Hospitals Lean body mass Maze Learning Medicine and Health Sciences Metabolic disorders Metabolites Mice Mice, Inbred C57BL Mutation Pediatrics Peptide Fragments - therapeutic use Peptides Phenylalanine Phenylalanine - analysis Phenylalanine - blood Phenylalanine Hydroxylase - deficiency Phenylalanine Hydroxylase - genetics Phenylketonuria Phenylketonurias - diet therapy Proteins Research and Analysis Methods Serotonin Serotonin - blood Teeth Tyrosine - blood Water intake Water intakes Whey Denmark Aarhus Denmark
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Summary:	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. 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?. 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. 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)). CGMP can be a relevant supplement for the treatment of PKU.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: Erik Jensen was the industrial supervisor for the above described PhD project, and his mandatory obligation was to contribute with inputs to study design, formulation of test diets and study manuscript according to agreements and ethical standard. However, Erik Jensen did not have the final decision about these issues and this affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. Erik Jensen has sent a written signed statement regarding this (separate file).
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0261150