{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:50:46Z","timestamp":1791561046294,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well\u2010controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes excess phenylalanine to accumulate. This accumulation can competitively block some other amino acids from entering the brain. This may reduce production of key neurotransmitters like dopamine and serotonin, which can affect brain function and development. However, direct correlations between blood Phe levels and central nervous system (CNS) neurotransmitter concentrations have not been established, and reliable CNS biomarkers are lacking. Positron emission tomography (PET) enables in\u00a0vivo assessment of brain metabolism and neurotransmitter\u2010related processes; therefore, we aim to investigate its potential value as a biomarker. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 25, 2026. Studies evaluating brain PET imaging in individuals with PKU or hyperphenylalaninemia were included. Data on study design, patient characteristics, PET tracers, and key findings were extracted and synthesized qualitatively. A total of 380 records were screened, and 13 studies were included, with a mean sample size of 8.8 (median 6). PET tracers included\n                    <jats:sup>18<\/jats:sup>\n                    fluorodeoxyglucose (FDG), amino acids, including tyrosine\u2010, methionine\u2010, leucine\u2010, aminocyclohexanecarboxylate\u2010based tracers, and fluorodopa\u2010related tracers. FDG PET studies demonstrated regionally heterogeneous abnormalities in brain glucose metabolism, independent of plasma Phe levels. Amino acid PET studies demonstrated reduced cerebral protein synthesis associated with impaired large neutral amino acid transport and increased brain Phe levels. Fluorodopa\u2010related PET studies indicated reduced dopaminergic activity, with no significant correlation between plasma Phe levels and striatal fluorodopa utilization. PET is a promising tool to bridge the gap between peripheral biochemical markers and CNS dysfunction in PKU. Further studies are needed to overcome limitations which include small sample sizes, heterogeneous metabolic control, restricted availability of tracer types, predominantly cross\u2010sectional study designs, and lack of correlation with clinical signs and symptoms.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70238","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:34:08Z","timestamp":1782498848000},"page":"2420-2432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Positron Emission Tomography (\n                    <scp>PET<\/scp>\n                    ) in Phenylketonuria: A Systematic Review of Brain Metabolism Beyond Phenylalanine"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7278-8242","authenticated-orcid":false,"given":"Yutaka","family":"Furuta","sequence":"first","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Yano","sequence":"additional","affiliation":[{"name":"Genetics Division, Pediatrics, Los Angeles General Hospital University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"John A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics and Genomic Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7093-8844","authenticated-orcid":false,"given":"Rory J.","family":"Tinker","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Genomics Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8391-4067","authenticated-orcid":false,"given":"Eishi","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center Wayne State University  Detroit Michigan USA"},{"name":"Department of Neurology, Children's Hospital of Michigan, Detroit Medical Center Wayne State University  Detroit Michigan USA"},{"name":"Translational Imaging Laboratory, University Health Center, Detroit Medical Center  Detroit Michigan USA"},{"name":"Translational Neuroscience Program Wayne State University  Detroit Michigan USA"},{"name":"Department of Pediatrics Central Michigan University  Mt. 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