{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:23:26Z","timestamp":1790875406650,"version":"4.1.0"},"reference-count":18,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including <jats:italic>MT\u2010ATP6<\/jats:italic> mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3\u20135\u00a0\u03bcM; screening cutoff &gt;5) and ultimately diagnosed with <jats:italic>MT\u2010ATP6<\/jats:italic> mitochondrial disease. Follow\u2010up testing revealed a pattern of hypocitrullinemia together with elevated propionyl\u2010(C3) and 3\u2010hydroxyisovaleryl\u2010(C5\u2010OH) acylcarnitines, and a homoplasmic pathogenic variant in <jats:italic>MT\u2010ATP6<\/jats:italic> in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clir.mayo.edu\">https:\/\/clir.mayo.edu<\/jats:ext-link>) demonstrated citrulline &lt;1st percentile, C3\u2009&gt;\u200950th percentile, and C5\u2010OH &gt;90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false\u2010positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in <jats:italic>MT\u2010ATP6,<\/jats:italic> low citrulline, elevated C3, and\/or elevated C5\u2010OH. All molecularly confirmed individuals (<jats:italic>n<\/jats:italic>\u00a0=\u00a017) with either no symptoms (<jats:italic>n<\/jats:italic>\u00a0=\u00a012), migraines (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (<jats:italic>n<\/jats:italic>\u00a0=\u00a03) were found to have an A or U mitochondrial haplogroup, while one child with infantile\u2010lethal Leigh syndrome had a B haplogroup.<\/jats:p>","DOI":"10.1002\/ajmg.a.63159","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T08:10:41Z","timestamp":1678263041000},"page":"1492-1501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp><i>MT\u2010ATP6<\/i><\/scp> mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6227-7895","authenticated-orcid":false,"given":"Christina G.","family":"Tise","sequence":"first","affiliation":[{"name":"Division of Medical Genetics Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney P.","family":"Verscaj","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce A.","family":"Mendelsohn","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Kaiser Permanente Northern California  Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Woods","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University  Stanford California USA"},{"name":"Department of Medical Genetics and Metabolism Valley Children's Healthcare  Madera California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung U.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Enns","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zinandr\u00e9","family":"Stander","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia L.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina M.","family":"Cowan","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina P.","family":"Cusmano\u2010Ozog","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"ACT Sheets and Algorithms.2022.https:\/\/www.acmg.net\/ACMG\/Medical-Genetics-Practice-Resources\/ACT_Sheets_and_Algorithms.aspx"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813409106"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.194"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2016_559"},{"key":"e_1_2_9_6_1","unstructured":"Conditions by State.2022.https:\/\/babysfirsttest.org\/newborn-screening\/rusp-conditions"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23723"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2018.01.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2012.2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2021.06.011"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2014_332"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/ane.13566"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2021.06.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijns7020023"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000393"},{"key":"e_1_2_9_16_1","volume-title":"Mitochondrial DNA\u2010associated Leigh syndrome and NARP","author":"Thorburn D. 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