{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:26:42Z","timestamp":1715300802422},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008980","name":"Medical College of Wisconsin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008980","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Maple syrup urine disease (MSUD) is a disorder of branched\u2010chain amino acid metabolism caused by a defect in the branched\u2010chain \u03b1\u2010ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched\u2010chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well\u2010defined disease associations. We report on two families with the same <jats:italic>BCKDK<\/jats:italic> variant (c.1115C&gt;G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence\u2010based (2D), structural\u2010based (3D), and dynamic\u2010based (4D) analyses. The <jats:italic>BCKDK<\/jats:italic> variant modeling indicated a gain\u2010of\u2010function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain\u2010of\u2010function variants in <jats:italic>BCKDK<\/jats:italic> may represent a novel biochemical phenotype of MSUD with a benign clinical course.<\/jats:p>","DOI":"10.1002\/jmd2.12419","type":"journal-article","created":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T05:42:20Z","timestamp":1712641340000},"page":"144-155","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational structural genomics and clinical evidence suggest <scp>BCKDK<\/scp> gain\u2010of\u2010function may cause a potentially asymptomatic maple syrup urine disease phenotype"],"prefix":"10.1002","volume":"65","author":[{"given":"Emily","family":"Singh","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Pediatrics Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young\u2010In","family":"Chi","sequence":"additional","affiliation":[{"name":"Mellowes Center for Genomic Sciences and Precision Medicine Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Kopesky","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition Children's Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Mellowes Center for Genomic Sciences and Precision Medicine Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raul","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Mellowes Center for Genomic Sciences and Precision Medicine Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"Basel","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica Scott","family":"Schwoerer","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207490"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20103\u2010662\u201049771\u20105"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00107-6"},{"key":"e_1_2_13_5_1","unstructured":"OMIM\u00ae.Online Mendelian Inheritance in Man. 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