{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:46:48Z","timestamp":1788425208378,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"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>Many phenylketonuria (PKU) patients cannot adhere to the severe dietary restrictions as advised by the European PKU guidelines, which can be accompanied by aggravated neuropsychological impairments that, at least in part, have been attributed to brain monoaminergic neurotransmitter deficiencies. Supplementation of large neutral amino acids (LNAA) to an unrestricted diet has previously been shown to effectively improve brain monoamines in PKU mice of various ages. To determine the additive value of LNAA supplementation to a liberalized phenylalanine-restricted diet, brain and plasma monoamine and amino acid concentrations in 10 to 16-month-old adult C57Bl\/6 PKU mice on a less severe phenylalanine-restricted diet with LNAA supplementation were compared to those on a non-supplemented severe or less severe phenylalanine-restricted diet. LNAA supplementation to a less severe phenylalanine-restricted diet was found to improve both brain monoamine and phenylalanine concentrations. Compared to a severe phenylalanine-restricted diet, it was equally effective to restore brain norepinephrine and serotonin even though being less effective to reduce brain phenylalanine concentrations. These results in adult PKU mice support the idea that LNAA supplementation may enhance the effect of a less severe phenylalanine-restricted diet and suggest that cerebral outcome of PKU patients treated with a less severe phenylalanine-restricted diet may be helped by additional LNAA treatment.<\/jats:p>","DOI":"10.3390\/nu11092252","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T10:55:21Z","timestamp":1568890521000},"page":"2252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Benefit of Large Neutral Amino Acid Supplementation to a Liberalized Phenylalanine-Restricted Diet in Adult Phenylketonuria Patients: Evidence from Adult Pah-Enu2 Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Danique","family":"van Vliet","sequence":"first","affiliation":[{"name":"Beatrix Children\u2019s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"van der Goot","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiggert G.","family":"van Ginkel","sequence":"additional","affiliation":[{"name":"Beatrix Children\u2019s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn H. J. R.","family":"van Faassen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pim","family":"de Blaauw","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido P.","family":"Kema","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1643-6506","authenticated-orcid":false,"given":"Aurora","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Rebecca","family":"Heiner-Fokkema","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy A.","family":"van der Zee","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francjan J.","family":"van Spronsen","sequence":"additional","affiliation":[{"name":"Beatrix Children\u2019s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S2213-8587(16)30320-5","article-title":"Key European guidelines for the diagnosis and management of patients with phenylketonuria","volume":"5","author":"Ahring","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1037\/neu0000337","article-title":"Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains","volume":"31","author":"Palermo","year":"2017","journal-title":"Neuropsychology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1080\/02643294.2017.1320278","article-title":"Speed of processing and executive functions in adults with phenylketonuria: Quick in finding the word, but not the ladybird","volume":"35","author":"Romani","year":"2017","journal-title":"Cogn. Neuropsychol."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1037\/neu0000358","article-title":"Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study","volume":"31","author":"Jahja","year":"2017","journal-title":"Neuropsychology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10545-016-9918-0","article-title":"Social-cognitive functioning and social skills in patients with early treated phenylketonuria: A PKU-COBESO study","volume":"39","author":"Jahja","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1017\/S0033291717001398","article-title":"Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria","volume":"47","author":"Boot","year":"2017","journal-title":"Psychol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.3945\/ajcn.116.135996","article-title":"Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model","volume":"104","author":"Bruinenberg","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jnutbio.2017.09.020","article-title":"Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: Evidence from adult Pah-enu2 mice","volume":"53","author":"Bruinenberg","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_10","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_11","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_12","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrendo.2010.125","article-title":"Phenylketonuria: A 21st century perspective","volume":"6","year":"2010","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s10545-010-9216-1","article-title":"Large neutral amino acids in the treatment of PKU: From theory to practice","volume":"33","author":"Hoeksma","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1111\/j.1651-2227.2005.tb02078.x","article-title":"Behavioural effects of phenylalanine-free amino acid tablet supplementation in intellectually disabled adults with untreated phenylketonuria","volume":"94","author":"Kalkanoglu","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1542\/peds.112.S4.1570","article-title":"Future role of large neutral amino acids in transport of phenylalanine into the brain","volume":"112","author":"Matalon","year":"2003","journal-title":"Pediatrics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1007\/s10545-006-0395-8","article-title":"Large neutral amino acids in the treatment of phenylketonuria (PKU)","volume":"29","author":"Matalon","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10545-007-0556-4","article-title":"Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine","volume":"30","author":"Matalon","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1542\/peds.112.S4.1575","article-title":"Brain phenylalanine concentrations in phenylketonuria: Research and treatment of adults","volume":"112","author":"Moats","year":"2003","journal-title":"Pediatrics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1172\/JCI5017","article-title":"Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria","volume":"103","author":"Pietz","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jpeds.2012.10.015","article-title":"Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: A new biomarker","volume":"162","author":"Yano","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yano, S., Moseley, K., Fu, X., and Azen, C. (2016). Evaluation of tetrahydrobiopterin therapy with large neutral amino acid supplementation in phenylketonuria: Effects on potential peripheral biomarkers, melatonin and dopamine, for Brain monoamine neurotransmitters. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160892"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Van Vliet, D., Bruinenberg, V.M., Mazzola, P.N., van Faassen, M.H., de Blaauw, P., Kema, I.P., Heiner-Fokkema, M.R., van Anholt, R.D., van der Zee, E.A., and van Spronsen, F.J. (2015). Large neutral amino acid supplementation exerts its effect through three synergistic mechanisms: Proof of principle in phenylketonuria mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143833"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","article-title":"AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet","volume":"123","author":"Reeves","year":"1993","journal-title":"J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-017-0685-2","article-title":"The complete European guidelines on phenylketonuria: Diagnosis and treatment","volume":"12","author":"MacDonald","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.4155\/bio.11.170","article-title":"Quantitative determination of free and total dopamine in human plasma by LC-MS\/MS: The importance of sample preparation","volume":"3","author":"Hendriks","year":"2011","journal-title":"Bioanalysis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jpeds.2014.03.061","article-title":"Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: Effects of tryptophan and tyrosine supplementation","volume":"165","author":"Yano","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_28","first-page":"52","article-title":"Central tetrahydrobiopterin concentration in neurodevelopmental disorders","volume":"4","author":"Frye","year":"2010","journal-title":"Front. Neurosci."},{"key":"ref_29","first-page":"216","article-title":"The methylation, neurotransmitter, and antioxidant connections between folate and depression","volume":"13","author":"Miller","year":"2008","journal-title":"Altern. Med. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Berguig, G.Y., Martin, N.T., Creer, A.Y., Murphy, R., Pacheco, G., Xie, L., Zhang, L., Bullens, S., Obertz, J., and Weng, H.H. (2019). Of mice and men: Plasma phenylalanine reduction in PKU corrects neurotransmitter pathways in the brain. Molecular Genetics and Metabolism, Elsevier.","DOI":"10.1016\/j.ymgme.2019.08.004"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1093\/brain\/awv224","article-title":"Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency","volume":"138","author":"Korner","year":"2015","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S109","DOI":"10.1007\/PL00014370","article-title":"The neurochemistry of phenylketonuria","volume":"159","author":"Surtees","year":"2000","journal-title":"Eur. J. Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/gim.2013.157","article-title":"Phenylalanine hydroxylase deficiency: Diagnosis and management guideline","volume":"16","author":"Vockley","year":"2014","journal-title":"Genet. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3945\/ajcn.116.135293","article-title":"Glycomacropeptide for nutritional management of phenylketonuria: A randomized, controlled, crossover trial","volume":"104","author":"Ney","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/jhn.12438","article-title":"Glycomacropeptide in children with phenylketonuria: Does its phenylalanine content affect blood phenylalanine control?","volume":"30","author":"Daly","year":"2017","journal-title":"J. Hum. Nutr. Diet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/j.jand.2012.05.004","article-title":"Food products made with glycomacropeptide, a low-phenylalanine whey protein, provide a new alternative to amino Acid-based medical foods for nutrition management of phenylketonuria","volume":"112","author":"Ney","year":"2012","journal-title":"J. Acad. Nutr. Diet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.copbio.2016.10.009","article-title":"Designing medical foods for inherited metabolic disorders: Why intact protein is superior to amino acids","volume":"44","author":"Ney","year":"2017","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E885","DOI":"10.1152\/ajpendo.00647.2011","article-title":"Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria","volume":"302","author":"Solverson","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1909101","DOI":"10.1155\/2017\/1909101","article-title":"Amino acid medical foods provide a high dietary acid load and increase urinary excretion of renal net acid, calcium, and magnesium compared with glycomacropeptide medical foods in phenylketonuria","volume":"2017","author":"Stroup","year":"2017","journal-title":"J. Nutr. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121762","DOI":"10.1172\/jci.insight.121762","article-title":"Inhibiting neutral amino acid transport for the treatment of phenylketonuria","volume":"3","author":"Belanger","year":"2018","journal-title":"JCI Insight"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/9\/2252\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:21:50Z","timestamp":1760188910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/9\/2252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,19]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["nu11092252"],"URL":"https:\/\/doi.org\/10.3390\/nu11092252","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,19]]}}}