{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:21:36Z","timestamp":1787509296644,"version":"build-2736575974"},"reference-count":55,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T00:00:00Z","timestamp":1711843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001720","name":"Nutricia Research Foundation","doi-asserted-by":"publisher","award":["2019N0174"],"award-info":[{"award-number":["2019N0174"]}],"id":[{"id":"10.13039\/501100001720","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl\u2010phenylalanine, glutamyl\u2010glutamyl\u2010phenylalanine, N\u2010lactoyl\u2010phenylalanine, N\u2010acetyl\u2010phenylalanine, the dipeptides phenylalanyl\u2010phenylalanine and phenylalanyl\u2010leucine, phenylalanine\u2013hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well\u2010defined PKU patient\u2010COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age\u2010 and sex\u2010matched controls were analyzed using ultra\u2010high performance liquid chromatography quadrupole time\u2010of\u2010flight mass spectrometry. Group differences were tested using the Mann\u2013Whitney\n                    <jats:italic>U<\/jats:italic>\n                    test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro\u2010)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl\u2010phenylalanine, N\u2010lactoyl\u2010phenylalanine, N\u2010acetyl\u2010phenylalanine, phenylalanine\u2013hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N\u2010lactoyl\u2010phenylalanine were associated with DSM\u2010VI Attention deficit\/hyperactivity (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.195,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.039 and\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.335,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002, respectively) of the ASR questionnaire. In addition, N\u2010lactoyl\u2010phenylalanine showed significant associations with ASR DSM\u2010VI avoidant personality (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.265,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.010), internalizing (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.192,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.046) and externalizing problems (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.217,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    between 0.178 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.048) and 0.204 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.033). Even though the strength of the models was not considered strong, N\u2010lactoyl\u2010phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12732","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T22:15:01Z","timestamp":1711923301000},"page":"624-635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The clinical relevance of novel biomarkers as outcome parameter in adults with phenylketonuria"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-4833","authenticated-orcid":false,"given":"A. M. J.","family":"van Wegberg","sequence":"first","affiliation":[{"name":"Division of Metabolic Diseases University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. C.","family":"van der Weerd","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Laboratory of Metabolic Diseases, University of Groningen, University Medical Centre Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U. F. H.","family":"Engelke","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Translational Metabolic Laboratory, Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. L. M.","family":"Coene","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Chemistry and Hematology, M\u00e1xima Medical Centre  Veldhoven The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Jahja","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. J. L.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Groningen, University Medical Center Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. C. J.","family":"Huijbregts","sequence":"additional","affiliation":[{"name":"Department of Clinical Child and Adolescent Studies\u2010Neurodevelopmental Disorders Faculty of Social Sciences, Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2278-9746","authenticated-orcid":false,"given":"R. A.","family":"Wevers","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Translational Metabolic Laboratory, Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. R.","family":"Heiner\u2010Fokkema","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Laboratory of Metabolic Diseases, University of Groningen, University Medical Centre Groningen  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3773-1929","authenticated-orcid":false,"given":"F. 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