{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:12:23Z","timestamp":1769645543629,"version":"3.49.0"},"reference-count":22,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100011302","name":"Children's Hospital Foundation","doi-asserted-by":"publisher","award":["2315"],"award-info":[{"award-number":["2315"]}],"id":[{"id":"10.13039\/100011302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ornithine transcarbamylase (OTC) deficiency can present during the neonatal period, infancy, or adulthood. Late\u2010onset phenotypes are influenced by residual enzyme activity and\n                    <jats:italic>OTC<\/jats:italic>\n                    gene expression. The objective of this study was to assess the pathogenicity of a rare promoter region variant, c.\u2010106C&gt;A. We reviewed three independent pedigrees harboring the c.\u2010106C&gt;A variant. Retrospective chart reviews were conducted for 16 affected males to evaluate biochemical and clinical features. Functional OTC enzyme data were obtained from the liver biopsy of three affected males. The median age of diagnosis for symptomatic males was 15\u2009years (range: 0.08\u201355). All 21 heterozygous females have been asymptomatic to date. Of the 16 hemizygous males, seven have experienced at least one episode of hyperammonemia, and eight have remained asymptomatic. The proband from Family A presented at age 55, with a peak ammonia level of 694\u2009\u03bcmol\/L. His OTC activity was 8.2\u2009\u03bcmol\/g\u2009liver\/min (control: 94.9\u2009\u03bcmol\/g\u2009liver\/min). The proband from Family B presented at age 15 with an ammonia level of 1568\u2009\u03bcmol\/L and later died from cerebral edema. His OTC activity was 2.2\u2009\u03bcmol\/g\u2009liver\/min (control: 73.2\u2009\u03bcmol\/g\u2009liver\/min). The proband from Family C presented at age 24 with hyperammonemia and later died following withdrawal of care. His liver punch biopsy OTC enzyme activity was measured to be 0\u2009\u03bcmol\/g\u2009liver\/min (control range: 25\u201331.7\u2009\u03bcmol\/g\u2009liver\/min). For most affected males, ammonia scavenger therapy has successfully prevented recurrent decompensation. The combined biochemical, clinical, and enzymatic data strongly support the pathogenicity of the c.\u2010106C&gt;A\n                    <jats:italic>OTC<\/jats:italic>\n                    promoter region variant in late\u2010onset OTC deficiency.\n                  <\/jats:p>","DOI":"10.1002\/jmd2.70064","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T07:49:58Z","timestamp":1768549798000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biochemical, Clinical, and Functional Characterization of a Rare c.\u2010\n                    <scp>106C<\/scp>\n                    &gt;A Promoter Region Variant in Late\u2010Onset Ornithine Transcarbamylase Deficiency: A Multifamily Case Series"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-9377","authenticated-orcid":false,"given":"Samuel Quinn","family":"Tholl","sequence":"first","affiliation":[{"name":"Western University  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"McCaul","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biochemistry London Health Sciences Centre  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Rupar","sequence":"additional","affiliation":[{"name":"Western University  London Ontario Canada"},{"name":"Department of Pathology and Biochemistry London Health Sciences Centre  London Ontario Canada"},{"name":"Department of Paediatrics London Health Sciences Centre  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie P.","family":"Napier","sequence":"additional","affiliation":[{"name":"GeneDx  Gaithersburg Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalya","family":"Karp","sequence":"additional","affiliation":[{"name":"Western University  London Ontario Canada"},{"name":"Department of Paediatrics London Health Sciences Centre  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea C.","family":"Yu","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario  Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"Ratko","sequence":"additional","affiliation":[{"name":"Department of Paediatrics London Health Sciences Centre  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aneal","family":"Khan","sequence":"additional","affiliation":[{"name":"Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"M.A.G.I.C. (Metabolics and Genetics in Canada) Clinic  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Geraghty","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario  Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6007-7251","authenticated-orcid":false,"given":"Chitra","family":"Prasad","sequence":"additional","affiliation":[{"name":"Western University  London Ontario Canada"},{"name":"Department of Paediatrics London Health Sciences Centre  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"Ornithine Transcarbamylase Deficiency","author":"Orphanet","year":"2024"},{"key":"e_1_2_11_3_1","volume-title":"GeneReviews","author":"Lichter\u2010Konecki U.","year":"2013"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.PCC.0000216682.56067.23"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/2050313X14546348"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.54"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmd2.12289"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10035"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20339"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0266-1"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23394"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/088307389501000506"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.2443"},{"issue":"1","key":"e_1_2_11_14_1","first-page":"80","article-title":"A Promoter Variant in the OTC Gene Associated With Late and Variable Age of Onset Hyperammonemia","volume":"63","author":"Han S. T.","year":"2022","journal-title":"JIMD Reports"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82101-9"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13256-018-1666-3"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.64.5.680"},{"issue":"5","key":"e_1_2_11_18_1","article-title":"Valproate\u2010Induced Fatal Acute Hyperammonaemia\u2010Related Encephalopathy in Late\u2010Onset Ornithine Transcarbamylase Deficiency","volume":"14","author":"Kazmierski D.","year":"2021","journal-title":"BMJ"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(97)00026-X"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.15419\/jmri.108"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.3.666"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/106002809302700510"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.11.031"}],"container-title":["JIMD Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmd2.70064","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jmd2.70064","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmd2.70064","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:00:55Z","timestamp":1769601655000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmd2.70064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/jmd2.70064"],"URL":"https:\/\/doi.org\/10.1002\/jmd2.70064","archive":["Portico"],"relation":{},"ISSN":["2192-8312","2192-8312"],"issn-type":[{"value":"2192-8312","type":"print"},{"value":"2192-8312","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-08-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70064"}}