{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:20:48Z","timestamp":1784164848502,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lucane SL"},{"name":"Immedica Pharma Spain"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The present study updates the Spanish registry of patients with urea cycle disorders (UCD), originally established in 2013, to provide comprehensive epidemiological data and evaluate the impact of therapeutic strategies and newborn screening (NBS) on clinical outcomes. Methods: This retrospective, multicenter study focuses on 255 Spanish UCD patients. It includes all living and deceased cases up to February 2024, analyzing demographic, clinical, and biochemical variables. Results: The incidence of UCD in Spain over the past decade was 1:36,063 births. The most common defects were ornithine transcarbamylase deficiency (OTCD) and argininosuccinate synthetase deficiency. Early-onset (EO) cases comprised 32.7%, and 10.6% were diagnosed through NBS. Global mortality was 14.9%, higher in carbamoylphosphate synthetase 1 deficiency (36.8%) and male OTCD patients (32.1%) compared to other defects (p = 0.013). EO cases presented a higher mortality rate (35.8%) than late-onset (LO) cases (7.1%) (p &lt; 0.0001). The median ammonia level in deceased patients was higher at 1058 \u00b5mol\/L (IQR 410\u20131793) than in survivors at 294 \u00b5mol\/L (IQR 71\u2013494) (p &lt; 0.0001). Diagnosis through NBS improved survival and reduced neurological impairment compared to symptomatic diagnosis. Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. Conclusions: This updated analysis highlights the positive impact of NBS and advanced treatments on mortality and neurologic outcomes. Persistent neurological challenges underscore the need for further therapeutic strategies.<\/jats:p>","DOI":"10.3390\/nu17071173","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T03:35:28Z","timestamp":1743132928000},"page":"1173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry"],"prefix":"10.3390","volume":"17","author":[{"given":"Elena","family":"Mart\u00edn-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"P\u00e9rez-Mohand","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9704-9534","authenticated-orcid":false,"given":"Patricia","family":"Correcher Medina","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Metabolopat\u00edas, Hospital Universitario La F\u00e9, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4008-3747","authenticated-orcid":false,"given":"Javier","family":"Blasco-Alonso","sequence":"additional","affiliation":[{"name":"Unidad de Gastroenterolog\u00eda, Hepatolog\u00eda y Nutrici\u00f3n Pedi\u00e1trica, Laboratorio de Bioqu\u00edmica, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7507-9743","authenticated-orcid":false,"given":"Ana","family":"Morais-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n Infantil y Enfermedades Metab\u00f3licas, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5663-537X","authenticated-orcid":false,"given":"Javier","family":"de las Heras","sequence":"additional","affiliation":[{"name":"Hereditary Metabolic Diseases Unit, Hospital Universitario Cruces, MetabERN, Biobizkaia Health Research Institute, 48903 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Mar\u00eda","family":"Meavilla Olivas","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital San Joan de D\u00e9u, MetabERN, CIBERER, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8865-2438","authenticated-orcid":false,"given":"Lucy","family":"Dougherty-de Miguel","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Vall d\u2019Hebr\u00f3n, MetabERN, VHIR, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-9905","authenticated-orcid":false,"given":"Maria Luz","family":"Couce","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Cl\u00ednico Universitario de Santiago, MetabERN, IDIS, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6610-5644","authenticated-orcid":false,"given":"Elvira Ca\u00f1edo","family":"Villarroya","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Enfermedades Metab\u00f3licas, Hospital Universitario Ni\u00f1o Jes\u00fas, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Concepci\u00f3n","family":"Garc\u00eda Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Unidad de Metabolismo, Servicio de Pediatr\u00eda, Hospital Miguel Servet, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5501-5272","authenticated-orcid":false,"given":"Pedro Juan","family":"Moreno-Lozano","sequence":"additional","affiliation":[{"name":"Unidad de Errores Cong\u00e9nitos del Metabolismo en el Adulto, Medicina Interna, Hospital Cl\u00ednic, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Vives","sequence":"additional","affiliation":[{"name":"Gastroenterolog\u00eda Pedi\u00e1trica, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-0242","authenticated-orcid":false,"given":"Mercedes","family":"Gil-Campos","sequence":"additional","affiliation":[{"name":"Unidad de Metabolismo, Hospital Universitario Reina Sof\u00eda, IMIBIC, UCO, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0340-4580","authenticated-orcid":false,"given":"Sinziana","family":"Stanescu","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Ram\u00f3n y Cajal, MetabERN, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Ceberio-Hualde","sequence":"additional","affiliation":[{"name":"Hereditary Metabolic Diseases Unit, Hospital Universitario Cruces, MetabERN, Biobizkaia Health Research Institute, 48903 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Camprod\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Vall d\u2019Hebr\u00f3n, MetabERN, VHIR, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8604-2230","authenticated-orcid":false,"given":"Elisenda","family":"Cort\u00e8s-Saladelafont","sequence":"additional","affiliation":[{"name":"Unidad de Neurolog\u00eda Pedi\u00e1trica y Enfermedades Metab\u00f3licas, Hospital Germans Trias i Pujol, 08916 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2355-3041","authenticated-orcid":false,"given":"Rafael","family":"L\u00f3pez-Urdiales","sequence":"additional","affiliation":[{"name":"Departamento de Endocrinolog\u00eda y Nutrici\u00f3n, Hospital de Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-2600","authenticated-orcid":false,"given":"Mercedes","family":"Murray Hurtado","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Metabolopat\u00edas, Pediatr\u00eda, Hospital Universitario de Canarias, 38320 Santa Cruz de Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"M\u00e1rquez Armenteros","sequence":"additional","affiliation":[{"name":"Gastroenterolog\u00eda Infantil, Hospital Materno-Infantil de Badajoz, 06010 Badajoz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concha","family":"Sierra C\u00f3rcoles","sequence":"additional","affiliation":[{"name":"Neurolog\u00eda Pedi\u00e1trica, Hospital Universitario de Ja\u00e9n, 23007 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6052-5894","authenticated-orcid":false,"given":"Luis","family":"Pe\u00f1a-Quintana","sequence":"additional","affiliation":[{"name":"Gastroenterolog\u00eda y Nutrici\u00f3n Pedi\u00e1trica, Complejo Hospitalario Universitario Insular-Materno Infantil, CIBEROBN-ISCIII, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Ruiz-Pons","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Enfermedades Metab\u00f3licas, Pediatr\u00eda, Hospital Universitario Virgen de la Candelaria, 38010 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Alcalde","sequence":"additional","affiliation":[{"name":"Servicio de Pediatr\u00eda, Hospital Universitario R\u00edo Ortega, 47012 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-5343","authenticated-orcid":false,"given":"Fernando","family":"Castellanos-Pinedo","sequence":"additional","affiliation":[{"name":"Neurolog\u00eda, Hospital Virgen del Puerto, Plasencia, 10600 C\u00e1ceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Dios","sequence":"additional","affiliation":[{"name":"Endocrinolog\u00eda y Enfermedades Metab\u00f3licas, MetabERN, Hospital Virgen del Roc\u00edo, 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0171-3830","authenticated-orcid":false,"given":"Delia","family":"Barrio-Carreras","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Mart\u00edn-Caza\u00f1a","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Garc\u00eda-Peris","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Metabolopat\u00edas, Hospital Universitario La F\u00e9, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 David","family":"Andrade","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n Infantil y Enfermedades Metab\u00f3licas, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Garc\u00eda-Volpe","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital San Joan de D\u00e9u, MetabERN, CIBERER, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariela","family":"de los Santos","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital San Joan de D\u00e9u, MetabERN, CIBERER, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angels","family":"Garc\u00eda-Cazorla","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital San Joan de D\u00e9u, MetabERN, CIBERER, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8163-1853","authenticated-orcid":false,"given":"Mireia","family":"del Toro","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Vall d\u2019Hebr\u00f3n, MetabERN, VHIR, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Felipe-Ruci\u00e1n","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Vall d\u2019Hebr\u00f3n, MetabERN, VHIR, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Comino Monroy","sequence":"additional","affiliation":[{"name":"Unidad de Metabolismo, Hospital Universitario Reina Sof\u00eda, IMIBIC, UCO, 14004 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4992-1305","authenticated-orcid":false,"given":"Paula","family":"S\u00e1nchez-Pintos","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Cl\u00ednico Universitario de Santiago, MetabERN, IDIS, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9184-8079","authenticated-orcid":false,"given":"Ana","family":"Matas","sequence":"additional","affiliation":[{"name":"Unidad de Errores Cong\u00e9nitos del Metabolismo en el Adulto, Medicina Interna, Hospital Cl\u00ednic, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-2780","authenticated-orcid":false,"given":"David","family":"Gil Ortega","sequence":"additional","affiliation":[{"name":"Gastroenterolog\u00eda Pedi\u00e1trica, Hospital Cl\u00ednico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-1069","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Mart\u00edn-Rivada","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Metabolopat\u00edas, Pediatr\u00eda, Hospital Universitario de Canarias, 38320 Santa Cruz de Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Bergua","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n Infantil y Enfermedades Metab\u00f3licas, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-8956","authenticated-orcid":false,"given":"Amaya","family":"Belanger-Quintana","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Metab\u00f3licas, Hospital Ram\u00f3n y Cajal, MetabERN, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isidro","family":"Vitoria","sequence":"additional","affiliation":[{"name":"Unidad de Nutrici\u00f3n y Metabolopat\u00edas, Hospital Universitario La F\u00e9, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-1563","authenticated-orcid":false,"given":"Raquel","family":"Yahyaoui","sequence":"additional","affiliation":[{"name":"Unidad de Gastroenterolog\u00eda, Hepatolog\u00eda y Nutrici\u00f3n Pedi\u00e1trica, Laboratorio de Bioqu\u00edmica, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga-IBIMA, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-1958","authenticated-orcid":false,"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, IdiPAZ, CIBERER, Universidad Aut\u00f3noma Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Morales-Conejo","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1026-4854","authenticated-orcid":false,"given":"Pilar","family":"Quijada-Fraile","sequence":"additional","affiliation":[{"name":"Unidad de Enfermedades Mitocondriales-Metab\u00f3licas Hereditarias, Hospital Universitario 12 de Octubre, Instituto de Investigaci\u00f3n Imas12, MetabERN, CIBERER, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,28]]},"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. Inherit. Metab. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/jimd.12348","article-title":"An international classification of inherited metabolic disorders (ICIMD)","volume":"44","author":"Ferreira","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1067\/mpd.2002.122394","article-title":"Inborn errors of metabolism in the Italian pediatric population: A national retrospective survey","volume":"140","author":"Rizzo","year":"2002","journal-title":"J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1111\/j.1651-2227.2008.00923.x","article-title":"Hereditary urea cycle diseases in Finland","volume":"97","author":"Keskinen","year":"2008","journal-title":"Acta Paediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ymgme.2013.07.008","article-title":"European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). The incidence of urea cycle disorders","volume":"110","author":"Summar","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13023-017-0661-x","article-title":"Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland","volume":"12","author":"Nettesheim","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/ajmg.1320390226","article-title":"Estimated frequency of urea cycle enzymopathies in Japan","volume":"39","author":"Nagata","year":"1991","journal-title":"Am. J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s10545-011-9427-0","article-title":"Long-term outcome and intervention of urea cycle disorders in Japan","volume":"35","author":"Kido","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s10545-015-9839-3","article-title":"The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: The initial presentation","volume":"38","author":"Valayannopoulos","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10545-015-9840-x","article-title":"The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: The evolving clinical phenotype","volume":"38","author":"Valayannopoulos","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Garc\u00eda Vega, M., Andrade, J.D., Morais, A., Frauca, E., Mu\u00f1oz Bartolo, G., Lled\u00edn, M.D., Bergua, A., and Hierro, L. (2023). Urea cycle disorders and indications for liver transplantation. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1103757"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102405","DOI":"10.1016\/j.eclinm.2023.102405","article-title":"Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): A phase 3, randomized, double-blind, placebo-controlled, multi-centre trial","volume":"68","author":"Russo","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/jimd.12609","article-title":"Gene therapy for urea cycle defects: An update from historical perspectives to future prospects","volume":"47","author":"Duff","year":"2024","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ymgme.2014.08.001","article-title":"A longitudinal study of urea cycle disorders","volume":"113","author":"Batshaw","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1002\/jimd.12146","article-title":"Neuropsychological attributes of urea cycle disorders: A systematic review of the literature","volume":"42","author":"Waisbren","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10545-017-0132-5","article-title":"Biochemical markers and neuropsychological functioning in distal urea cycle disorders","volume":"41","author":"Waisbren","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/s41390-023-02722-y","article-title":"Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders","volume":"94","author":"Sanz","year":"2023","journal-title":"Pediatr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s10545-018-0157-4","article-title":"The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders","volume":"41","author":"Hediger","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s13023-014-0187-4","article-title":"Urea cycle disorders in Spain: An observational, cross-sectional and multicentric study of 104 cases","volume":"9","author":"Couce","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_20","unstructured":"(2024, September 19). Urea Cycle Disorders Consortium. Available online: https:\/\/www1.rarediseasesnetwork.org\/cms\/UCDC."},{"key":"ref_21","unstructured":"(2024, September 19). European Registry and Network for Intoxication Type Metabolic Diseases. Available online: https:\/\/www.e-imd.org."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/jimd.12031","article-title":"Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders\u2014A successful strategy for clinical research of rare diseases","volume":"42","author":"Posset","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/jimd.12384","article-title":"Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan","volume":"44","author":"Kido","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_24","unstructured":"Carrascosa, A., Fern\u00e1ndez, J.M., Fern\u00e1ndez, M., L\u00f3pez-Siguero, J.P., L\u00f3pez, D., S\u00e1nchez, E., and Grupo Colaborador (2024, May 14). Estudios Espa\u00f1oles de Crecimiento 2010. Available online: http:\/\/www.aeped.es\/noticias\/estudios-espanoles-crecimiento-2010."},{"key":"ref_25","unstructured":"Instituto Nacional de Estad\u00edstica (2024, May 14). Demograf\u00eda y Poblaci\u00f3n. Available online: https:\/\/www.ine.es\/."},{"key":"ref_26","unstructured":"WHO\/FAO\/UNU Expert Consultation (2007). Protein and Amino Acid Requirements in Human Nutrition."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1365-277X.2012.01259.x","article-title":"Dietary management of urea cycle disorders: UK practice","volume":"25","author":"Adam","year":"2012","journal-title":"J. Hum. Nutr. Diet."},{"key":"ref_28","first-page":"25","article-title":"Liver transplantation prevents progressive neurological impairment in argininemia","volume":"11","author":"Silva","year":"2013","journal-title":"JIMD Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1111\/j.1651-2227.2008.00952.x","article-title":"Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes","volume":"97","author":"Summar","year":"2008","journal-title":"Acta Paediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ymgme.2010.01.013","article-title":"Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria","volume":"100","author":"Moeslinger","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/jimd.12678","article-title":"The challenge of understanding and predicting phenotypic diversity in urea cycle disorders","volume":"46","author":"Posset","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1002\/acn3.50886","article-title":"Early prediction of phenotypic severity in Citrullinemia Type 1","volume":"6","author":"Zielonka","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.ymgme.2020.10.013","article-title":"Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders","volume":"131","author":"Posset","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ymgme.2009.06.011","article-title":"Argininosuccinate lyase deficiency: Long-term outcome of 13 patients detected by newborn screening","volume":"98","author":"Ficicioglu","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s10545-017-0022-x","article-title":"Expanding the phenotype in argininosuccinic aciduria: Need for new therapies","volume":"40","author":"Baruteau","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/jimd.12047","article-title":"Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects","volume":"42","author":"Baruteau","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.ymgme.2017.06.003","article-title":"Newborn screening for hyperargininemia due to arginase 1 deficiency","volume":"121","author":"Therrell","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Burlina, A., Gasperini, S., la Marca, G., Pession, A., Siri, B., Spada, M., Ruoppolo, M., and Tummolo, A. (2023). Long-term management of patients with mild urea cycle disorders identified through the newborn screening: An expert opinion for clinical practice. Nutrients, 16.","DOI":"10.3390\/nu16010013"},{"key":"ref_39","unstructured":"Posset, R., Garbade, S.F., Gleich, F., Gropman, A.L., de Lonlay, P., Hoffmann, G.F., Garcia-Cazorla, A., Nagamani, S.C.S., Baumgartner, M.R., and Schulze, A. (2020). Long-term effects of MM on growth and weight in individuals with urea cycle disorders. Sci. Rep., 10."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1002\/jimd.12066","article-title":"Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders: On the basis of information from a European multicenter registry","volume":"42","author":"Molema","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/jimd.12318","article-title":"Liver and\/or kidney transplantation in amino and organic acid-related inborn errors of metabolism: An overview on European data","volume":"44","author":"Molema","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10545-016-9938-9","article-title":"Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders","volume":"39","author":"Posset","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/ana.25492","article-title":"Impact of diagnosis and therapy on cognitive function in urea cycle disorders","volume":"86","author":"Posset","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/jimd.12564","article-title":"The role and control of arginine levels in arginase 1 deficiency","volume":"46","author":"Diaz","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/gim.2012.166","article-title":"Argininosuccinic aciduria: From a monogenic to a complex disorder","volume":"15","author":"Erez","year":"2013","journal-title":"Genet. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108112","DOI":"10.1016\/j.ymgme.2023.108112","article-title":"Impact of supplementation with L-citrulline\/arginine after liver transplantation in individuals with urea cycle disorders","volume":"141","author":"Posset","year":"2024","journal-title":"Mol. Genet. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bernstein, L.E., Rohr, F., and van Calcar, S. (2022). Nutrition management in urea cycle disorders. Nutrition Management in Inherited Metabolic Diseases, Springer.","DOI":"10.1007\/978-3-030-94510-7"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.ymgme.2013.09.003","article-title":"Dietary management of urea cycle disorders: European practice","volume":"110","author":"Adam","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1007\/s10545-007-0718-4","article-title":"Nutritional management of patients with urea cycle disorders","volume":"30","author":"Singh","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ymgme.2012.07.009","article-title":"Optimizing therapy for argininosuccinic aciduria","volume":"107","author":"Nagamani","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/ped.13163","article-title":"Citrulline for urea cycle disorders in Japan","volume":"59","author":"Tanaka","year":"2017","journal-title":"Pediatr. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s13023-023-02800-8","article-title":"Citrulline in the management of patients with urea cycle disorders","volume":"18","author":"Imbard","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Hern\u00e1ndez, E., Quijada-Fraile, P., Correcher, P., Meavilla, S., S\u00e1nchez-Pintos, P., de Las Heras Montero, J., Blasco-Alonso, J., Dougherty, L., Marquez, A., and Pe\u00f1a-Quintana, L. (2022). Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain. J. Clin. Med., 11.","DOI":"10.3390\/jcm11175045"},{"key":"ref_54","first-page":"137","article-title":"Direct replacement of oral sodium benzoate with glycerol phenylbutyrate in children with urea cycle disorders","volume":"63","author":"Yeo","year":"2022","journal-title":"JIMD Rep."},{"key":"ref_55","first-page":"317","article-title":"Clinical experience with glycerol phenylbutyrate in 20 patients with urea cycle disorders at a UK paediatric centre","volume":"64","author":"Yeo","year":"2023","journal-title":"JIMD Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"107558","DOI":"10.1016\/j.ymgme.2023.107558","article-title":"Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders","volume":"138","author":"Cederbaum","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ah Mew, N., McCarter, R., Izem, R., Markus, A., Gerstein, M., Rice, K., Sanz, J., Le Mons, C., Bartos, J., and Tuchman, M. (2020). Comparing Treatment Options for Urea Cycle Disorders, Patient-Centered Outcomes Research Institute (PCORI).","DOI":"10.25302\/12.20.CER.150227816"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/7\/1173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:03:59Z","timestamp":1760029439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/7\/1173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":57,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["nu17071173"],"URL":"https:\/\/doi.org\/10.3390\/nu17071173","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]}}}