Ohl Laura, Kuhs Amanda, Pluck Ryan, Durham Emily, Noji Michael, Philip Nathan D, Arany Zoltan, Ahrens-Nicklas Rebecca C
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
College of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Genet Metab Rep. 2024 May 10;39:101091. doi: 10.1016/j.ymgmr.2024.101091. eCollection 2024 Jun.
Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.
支链酮酸脱氢酶激酶（BCKDK）缺乏症是一种最近被描述的遗传性支链氨基酸（BCAA）代谢神经代谢紊乱疾病，意味着BCAA分解代谢增加。据推测，全身性BCAA水平的严重降低是该疾病病理生理学的基础，补充BCAA可能会改善疾病表型。为了验证这一假设，我们对最近建立的BCKDK缺乏症小鼠模型进行了表征，并评估了在该模型中肠内补充BCAA的效果。令人惊讶的是，尽管全身BCAA水平升高，但补充BCAA却加剧了神经发育缺陷，且未纠正生化异常。这些数据表明，通过BCAA分解代谢途径的异常通量，而不仅仅是BCAA不足，可能导致疾病病理。支持这一结论的是，通过单倍剂量不足对BCAA分解代谢进行基因重新调节，部分挽救了BCKDK缺乏症小鼠的生化和行为表型。总体而言，这些数据对关于BCKDK不足病理生理学的广泛假设提出了质疑，并提出了一种开发该疾病潜在疗法的新方法。
