{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:49:01Z","timestamp":1793148541703,"version":"4.5.0"},"reference-count":26,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26ek0109865"],"award-info":[{"award-number":["JP26ek0109865"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"award":["JP26ek0109865"],"award-info":[{"award-number":["JP26ek0109865"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Health Labour and Welfare","award":["23FC1034"],"award-info":[{"award-number":["23FC1034"]}]},{"award":["23FC1034"],"award-info":[{"award-number":["23FC1034"]}],"id":[{"id":"https:\/\/ror.org\/03mwa7s65","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Proximal urea-cycle disorders (PUCDs), including N-acetylglutamate synthase deficiency (NAGSD), ornithine transcarbamylase deficiency (OTCD), and carbamoyl phosphate synthase 1 deficiency (CPS1D), cause hyperammonemia and impair neurological outcomes. Early detection of late-onset forms allows presymptomatic intervention to prevent hyperammonemia; however, reliable newborn screening (NBS) markers are lacking. This prospective pilot study in Hyogo Prefecture, Japan, evaluated hypocitrullinemia as a screening marker for late-onset PUCDs. Newborns with citrulline levels below the 0.05th percentile on NBS between June 2020 and May 2024 were enrolled in the study. Confirmatory diagnosis of PUCDs was performed using plasma amino acids, urinary organic acids, and genetic testing. During the first period (101,172 newborns), 11 newborns exhibited hypocitrullinemia; 10 underwent further evaluation. One newborn was diagnosed with CPS1D (compound heterozygous CPS1 variants); another was later diagnosed with Leigh syndrome. The remaining eight cases were false positives, often associated with prematurity, poor feeding, or gastrointestinal disorders. A second dried blood spot (DBS) card protocol was introduced in the second period (34,694 newborns), reducing false positives. One neonatal-onset OTCD case was detected, and citrulline levels were normalized in six of the seven other cases. In summary, hypocitrullinemia can identify presymptomatic PUCDs, and requesting a second DBS card reduces false positives, supporting its feasibility for incorporation into NBS programs.<\/jats:p>","DOI":"10.3390\/ijns12020039","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:11:04Z","timestamp":1780593064000},"page":"39","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Four-Year Prospective Pilot Study of Newborn Screening for Late-Onset Proximal Urea-Cycle Disorders in Hyogo Prefecture in Japan"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-1202","authenticated-orcid":false,"given":"Tomoko","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Hyogo Medical University, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hyogo Medical University, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hyogo Medical University, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Bo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-4142","authenticated-orcid":false,"given":"Hiroyuki","family":"Awano","sequence":"additional","affiliation":[{"name":"Organization for Research Initiative and Promotion, Tottori University, Yonago 683-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Toyooka Hospital, Toyooka 668-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Toyooka Hospital, Toyooka 668-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Minato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Toyooka Hospital, Toyooka 668-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9091-3521","authenticated-orcid":false,"given":"Hironori","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Laboratories Division, Shimane University Hospital, Izumo 693-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Laboratories Division, Shimane University Hospital, Izumo 693-8501, Japan"},{"name":"Department of Pediatrics, Matsue Red Cross Hospital, Matsue 690-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Juntendo University, Tokyo 113-8421, Japan"},{"name":"Department of Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6468-7185","authenticated-orcid":false,"given":"Yasuhiro","family":"Takeshima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hyogo Medical University, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1002\/jimd.12100","article-title":"Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision","volume":"42","author":"Burlina","year":"2019","journal-title":"J. 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