{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:36:04Z","timestamp":1772174164770,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Maple syrup urine disease (MSUD) is an intoxication\u2010type inherited metabolic disorder in which hyperleucinemia leads to brain swelling and death without treatment. MSUD is caused by branched\u2010chain alpha\u2010ketoacid dehydrogenase deficiency due to biallelic loss of the protein products from the genes <jats:italic>BCKDHA<\/jats:italic>, <jats:italic>BCKDHB<\/jats:italic>, or <jats:italic>DBT<\/jats:italic>, while a distinct but related condition is caused by loss of <jats:italic>DLD<\/jats:italic>. In this case series, eleven individuals with MSUD caused by two pathogenic variants in <jats:italic>DBT<\/jats:italic> are presented. All eleven individuals have a deletion of exon 2 (delEx2, NM_001918.3:c.48_171del); six individuals are homozygous and five individuals are compound heterozygous with a novel missense variant (NM_001918.5:c.916\u2009T\u2009&gt;\u2009C [p.Ser306Pro]) confirmed to be in trans. Western Blot indicates decreased amount of protein product in delEx2;c.916\u2009T\u2009&gt;\u2009C liver cells and absence of protein product in delEx2 homozygous hepatocytes. Ultrahigh performance liquid chromatography\u2013tandem mass spectrometry demonstrates an accumulation of branched\u2010chain amino acids and alpha\u2010ketoacids in explanted hepatocytes. Individuals with these variants have a neonatal\u2010onset, non\u2010thiamine\u2010responsive, classical form of MSUD. Strikingly, the entire cohort is derived from families who immigrated to the Washington, DC, metro area from Honduras or El Salvador suggesting the possibility of a founder effect.<\/jats:p>","DOI":"10.1002\/ajmg.a.62893","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T05:19:12Z","timestamp":1657257552000},"page":"2738-2749","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genomic and biochemical analysis of repeatedly observed variants in <scp><i>DBT<\/i><\/scp> in individuals with maple syrup urine disease of Central American ancestry"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-1860","authenticated-orcid":false,"suffix":"Jr","given":"Charles J.","family":"Billington","sequence":"first","affiliation":[{"name":"Children's National Rare Disease Institute  Washington District of Columbia USA"},{"name":"Department of Pediatrics University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5471-9083","authenticated-orcid":false,"given":"Kimberly A.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Children's National Rare Disease Institute  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eyby","family":"Leon","sequence":"additional","affiliation":[{"name":"Children's National Rare Disease Institute  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrix W.","family":"Meltzer","sequence":"additional","affiliation":[{"name":"Laboratory Medicine, Children's National Hospital  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth I.","family":"Berger","sequence":"additional","affiliation":[{"name":"Children's National Rare Disease Institute  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Olson","sequence":"additional","affiliation":[{"name":"HemoShear Therapeutics, Inc.  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Figler","sequence":"additional","affiliation":[{"name":"HemoShear Therapeutics, Inc.  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve A.","family":"Hoang","sequence":"additional","affiliation":[{"name":"HemoShear Therapeutics, Inc.  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cui","family":"Wanxing","sequence":"additional","affiliation":[{"name":"Georgetown University Hospital  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian R.","family":"Wamhoff","sequence":"additional","affiliation":[{"name":"HemoShear Therapeutics, Inc.  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Sol","family":"Collado","sequence":"additional","affiliation":[{"name":"HemoShear Therapeutics, Inc.  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Cusmano\u2010Ozog","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Medical Center  Stanford California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/11563"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2018.09.017"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.123463.111"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2015.07.001"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.24953\/turkjped.2019.01.017"},{"key":"e_1_2_10_7_1","unstructured":"Billington C. Jr. Ferreira C. R. MacLeod E. Ah Mew N. &Cusmano\u2010Ozog K.(2018).A tale of two variants: Salvadoran founder mutations in DBT cause classical MSUD. 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