The International Journal of Biochemistry & Cell Biology ( IF 3.4 ) Pub Date : 2020-12-03 , DOI: 10.1016/j.biocel.2020.105899 Michelle Mereis 1 , Ronald J A Wanders 2 , Maryke Schoonen 3 , Marli Dercksen 1 , Izelle Smuts 4 , Francois H van der Westhuizen 1
Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), or glutaric aciduria type II (GAII), is a group of clinically heterogeneous disorders caused by mutations in electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) – the two enzymes responsible for the re-oxidation of enzyme-bound flavin adenine dinucleotide (FADH2) via electron transfer to the respiratory chain at the level of coenzyme Q10. Over the past decade, an increasing body of evidence has further coupled mutations in FAD metabolism (including intercellular riboflavin transport, FAD biosynthesis and FAD transport) to MADD-like phenotypes. In this review we provide a detailed description of the overarching and specific metabolic pathways involved in MADD. We examine the eight associated genes (ETFA, ETFB, ETFDH, FLAD1, SLC25A32 and SLC52A1−3) and clinical phenotypes, and report ∼436 causative mutations following a systematic literature review. Finally, we focus attention on the value and shortcomings of current diagnostic approaches, as well as current and future therapeutic options for MADD and its phenotypic disorders.
中文翻译:
黄素腺嘌呤二核苷酸代谢紊乱:MADD 和相关缺陷
多酰基辅酶 A 脱氢酶缺乏症 (MADD) 或 II 型戊二酸尿症 (GAII) 是一组由电子转移黄素蛋白 (ETF) 和 ETF-泛醌氧化还原酶 (ETFQO) 突变引起的临床异质性疾病,这两种酶负责通过电子转移到辅酶 Q10 水平的呼吸链,重新氧化酶结合的黄素腺嘌呤二核苷酸 (FADH 2 )。在过去的十年中,越来越多的证据进一步将 FAD 代谢(包括细胞间核黄素转运、FAD 生物合成和 FAD 转运)的突变与 MADD 样表型联系起来。在这篇综述中,我们详细描述了 MADD 涉及的总体和特定代谢途径。我们检查了八个相关基因( ETFA、ETFB、ETFDH、FLAD1、SLC25A32和SLC52A1−3 )和临床表型,并在系统文献综述后报告了~436 个致病突变。最后,我们重点关注当前诊断方法的价值和缺点,以及 MADD 及其表型疾病当前和未来的治疗选择。