{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:28:59Z","timestamp":1783542539962,"version":"3.55.0"},"reference-count":20,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T00:00:00Z","timestamp":1487116800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T00:00:00Z","timestamp":1487116800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100011852","name":"Paracelsus Medical University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011852","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in <jats:italic>UMPS<\/jats:italic>, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability\/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in <jats:italic>UMPS<\/jats:italic>. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous <jats:italic>UMPS<\/jats:italic> variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We therefore conclude that heterozygous <jats:italic>UMPS\u2010<\/jats:italic>mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS\u2010deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-017-0015-9","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T12:19:17Z","timestamp":1487161157000},"page":"423-431","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Mild orotic aciduria in <i>UMPS<\/i> heterozygotes: a metabolic finding without clinical consequences"],"prefix":"10.1002","volume":"40","author":[{"given":"Saskia B.","family":"Wortmann","sequence":"first","affiliation":[{"name":"Department of Pediatrics Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU) Mullner Hauptstrasse 48 Salzburg 5020 Austria"},{"name":"Institute of Human Genetics Helmholtz Zentrum Munich Neuherberg Germany"},{"name":"Institute of Human Genetics Technical University Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Chen","sequence":"additional","affiliation":[{"name":"Prevention Genetics Marshfield WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Colombo","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Faculty of Medicine Catholic University of the Sacred Heart Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Pontoglio","sequence":"additional","affiliation":[{"name":"Center for the Study of Rare Hereditary Diseases Niguarda Ca\u2019 Granda Metropolitan Hospital Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader","family":"Alhaddad","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Technical University Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo D.","family":"Botto","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Utah School of Medicine Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Yuzyuk","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Utah Salt Lake City UT USA"},{"name":"ARUP Laboratories Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis R.","family":"Coughlin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Colorado Denver Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Descartes","sequence":"additional","affiliation":[{"name":"Departments of Genetics and Pediatrics University of Alabama School of Medicine Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Gr\u0171newald","sequence":"additional","affiliation":[{"name":"Metabolic Medicine Department Great Ormond Street Hospital for Children NHS Foundation Trust, and UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Maranda","sequence":"additional","affiliation":[{"name":"CHUS Genetic Services University of Sherbrooke Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippa B.","family":"Mills","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine Programme UCL Great Ormond Street Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Pitt","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Royal Children's Hospital Parkville Australia"},{"name":"Department of Paediatrics University of Melbourne Parkville Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Potente","sequence":"additional","affiliation":[{"name":"Ambry Genetics Aliso Viejo CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Rodenburg","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A. 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