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Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity\u2010adjusted classification system based on in\u00a0vitro residual enzymatic OTC activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Applying a cell\u2010based expression system, residual enzymatic OTC activities of 71 pathogenic <jats:italic>OTC<\/jats:italic> variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC\u2010D (mOTC\u2010D) as reported in the UCDC and E\u2010IMD registries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC\u2010D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Residual enzymatic OTC activity reliably predicts the disease severity in mOTC\u2010D and could thus serve as a tool for severity\u2010adjusted evaluation of therapeutic strategies and counselling patients and parents.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51668","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T05:27:44Z","timestamp":1665466064000},"page":"1715-1726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2619-8727","authenticated-orcid":false,"given":"Svenja","family":"Scharre","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2249-3980","authenticated-orcid":false,"given":"Roland","family":"Posset","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven F.","family":"Garbade","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gleich","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie J.","family":"Seidl","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Catrin","family":"Druck","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen G.","family":"Okun","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Gropman","sequence":"additional","affiliation":[{"name":"Division of Neurodevelopmental Pediatrics and Neurogenetics, Children's National Health System and The George Washington School of Medicine  Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandesh C. S.","family":"Nagamani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine and Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg F.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-2914","authenticated-orcid":false,"given":"Matthias","family":"Zielonka","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"},{"name":"Heidelberg Research Center for Molecular Medicine (HRCMM)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E\u2010IMD) Consortia Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.08.001"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-017-0661-x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.07.008"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2012.06.065"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-003-1188-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9901-1"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066596"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12146"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12100"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9839-3"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9840-x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12013"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-016-9938-9"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25492"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2008.00952.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2015.04.003"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50886"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23983"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12031"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1198\/106186006X133933"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.1.2.189"},{"key":"e_1_2_9_23_1","volume-title":"Guidance for Industry and Staff; 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