Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype. JIMD Rep 2024 May;65(3):144-155
Date
05/13/2024Pubmed ID
38736638Pubmed Central ID
PMC11078707DOI
10.1002/jmd2.12419Scopus ID
2-s2.0-85193389190 (requires institutional sign-in at Scopus site)Abstract
Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism caused by a defect in the branched-chain α-ketoacid 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-chain 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-defined disease associations. We report on two families with the same BCKDK variant (c.1115C>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-based (2D), structural-based (3D), and dynamic-based (4D) analyses. The BCKDK variant modeling indicated a gain-of-function 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-of-function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course.
Author List
Singh E, Chi YI, Kopesky J, Zimmerman M, Urrutia R, Basel D, Schwoerer JSAuthors
Donald Basel MD Chief, Professor in the Pediatrics department at Medical College of WisconsinYoung-In Chi PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
