{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:52:41Z","timestamp":1791161561304,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2026,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n Dual inherited defects affecting urea cycle function are exceptionally rare. We report the first case, to our knowledge, of the coexistence of argininosuccinic aciduria (ASA) and citrin deficiency (CD). A girl born to consanguineous Tunisian parents presented at 6\u2009months of age with recurrent seizures, vomiting, developmental delay, and severe hyperammonemic encephalopathy. Laboratory investigations revealed hyperammonemia, respiratory alkalosis, transaminitis, dyslipidemia, hyperglutaminemia, and mild hypercitrullinemia. Brain imaging showed delayed myelination and basal ganglia abnormalities. Management involved arginine supplementation, ammonia scavengers, protein restriction and antiepileptic drugs. The patient died at 33\u2009months of age from severe hyperammonemia and lactic acidosis. Next\u2010generation sequencing identified two homozygous variants affecting distinct urea cycle\u2013related genes:\n The known pathogenic ASL<\/jats:italic>\n variant c.1153C>T p.(Arg385Cys), responsible for ASA, and a previously unreported likely pathogenic\n SLC25A13<\/jats:italic>\n variant, c.1474C>T, p.(Arg492Trp), consistent with CD. Segregation analysis confirmed biallelic inheritance of both variants. This unique association illustrates how multilocus pathogenic variation can generate an atypical phenotype. From a pathophysiological perspective, CD may aggravate urea cycle dysfunction by reducing cytosolic aspartate availability and ASS1 activity, while ASL deficiency blocks the downstream conversion of argininosuccinate, resulting in a profound impairment of ureagenesis. This dual defect creates diagnostic and therapeutic challenges, highlighting the importance of integrating comprehensive biochemical investigations with molecular testing to enable accurate diagnosis and personalized metabolic management.\n <\/jats:p>","DOI":"10.1002\/jmd2.70129","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:31:00Z","timestamp":1791160260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Urea Cycle Dysfunction Caused by Coexisting Argininosuccinic Aciduria and Citrin Deficiency: Clinical, Biochemical, and Molecular Insights From an Exceptional Case"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2889-3328","authenticated-orcid":false,"given":"Mouna","family":"Zribi","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1281-6682","authenticated-orcid":false,"given":"Mariem","family":"Bhouri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0485-1416","authenticated-orcid":false,"given":"Safa","family":"Khatrouch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4368-927X","authenticated-orcid":false,"given":"Hela","family":"Boudabous","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-091X","authenticated-orcid":false,"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Division of Metabolism & Children's Research University Children's Hospital Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Slim","family":"Abdelmoula","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7880-3215","authenticated-orcid":false,"given":"Amel Ben","family":"Chehida","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Diseases La Rabta Hospital Tunis Tunisia"},{"name":"Faculty of Medicine of Tunis University Tunis El Manar Tunis Tunisia"},{"name":"Research Laboratory LR12SP02: \u201cInherited Metabolic Diseases, Investigation and Management\u201d Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038\u2010019\u20100614\u20104"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100036\u20101586454"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12100"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20102944(79)90077\u20102"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.07.017"},{"key":"e_1_2_11_7_1","first-page":"1909","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Brusilow S. W.","year":"2001"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.62438\/tunismed.v102i5.4787"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100380200046"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.2595\u201023"},{"issue":"5","key":"e_1_2_11_11_1","first-page":"1024","article-title":"A Search for the Primary Abnormality in Adult\u2010Onset Type II Citrullinemia","volume":"53","author":"Kobayashi K.","year":"1993","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010017\u20100022\u2010x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17596"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30289"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12047"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1020108002877"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12768"}],"container-title":["JIMD Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmd2.70129","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jmd2.70129","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmd2.70129","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:31:02Z","timestamp":1791160262000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmd2.70129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,4]]},"references-count":16,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/jmd2.70129"],"URL":"https:\/\/doi.org\/10.1002\/jmd2.70129","archive":["Portico"],"relation":{},"ISSN":["2192-8312","2192-8312"],"issn-type":[{"value":"2192-8312","type":"print"},{"value":"2192-8312","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,4]]},"assertion":[{"value":"2026-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70129"}}