{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:06:54Z","timestamp":1793196414274,"version":"4.5.0"},"reference-count":32,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54HD061221"],"award-info":[{"award-number":["U54HD061221"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["U54HD083092"],"award-info":[{"award-number":["U54HD083092"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001204","name":"Kettering Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001204","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild\u2010to\u2010moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course\u00a0so far, we aimed to design a reliable disease prediction model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48\n                      <jats:italic>ASS1<\/jats:italic>\n                      gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E\u2010IMD databases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L\u2010citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification\u2010based guidance of therapeutic decision\u2010making based on residual enzymatic ASS1 activity in the future.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity\u2010adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.50886","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T08:32:30Z","timestamp":1567153950000},"page":"1858-1871","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Early prediction of phenotypic severity in Citrullinemia Type 1"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-2914","authenticated-orcid":false,"given":"Matthias","family":"Zielonka","sequence":"first","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"},{"name":"Heidelberg Research Center for Molecular Medicine (HRCMM) Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gleich","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"St\u00fctzenberger","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"}],"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 Texas Children's Hospital Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Gropman","sequence":"additional","affiliation":[{"name":"Children's National Health System The George Washington School of Medicine District of Columbia Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg F.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven F.","family":"Garbade","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 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":"Center for Pediatric and Adolescent Medicine Division of Pediatric Neurology and Metabolic Medicine University Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"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":[[2019,8,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.07.008"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12031"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9839-3"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9840-x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9901-1"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25492"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-016-9938-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-017-0132-5"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2015_408"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2010.01.014"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23184"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.10"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.133"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25069"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12013"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv454"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2013.12.024"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-9868.2010.00749.x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1198\/106186006X133933"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.07.042"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.06.007"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.10.009"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502845200"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-017-0661-x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066596"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.04.031"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-103937"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.1.2.189"},{"key":"e_1_2_11_30_1","unstructured":"US Food and Drug Administration.Center for drug evaluation and research. 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