A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet.
A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet.
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DOI：
10.1073/pnas.0307074101
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发表时间：
2004-03
影响因子：
11.1
通讯作者：
Michael R. Taylor;J. Hurley;H. V. Van Epps;Susan E. Brockerhoff
中科院分区：
文献类型：
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作者：
Michael R. Taylor;J. Hurley;H. V. Van Epps;Susan E. Brockerhoff
丙酮酸脱氢酶(PDH)复合体的缺陷会导致严重的神经功能障碍、先天性乳酸酸中毒、生长迟缓和过早死亡。目前治疗PDH缺乏症的方法是在出生后给药，通常都不成功。由于许多患有这种疾病的患者出生时就有不可逆转的缺陷，开发有效的产前和产后治疗的模式系统将具有重要价值。在旨在识别具有视觉功能缺陷的斑马鱼的行为遗传学筛查中，我们先前分离到了隐性致死突变体NOA(NOA)的两个等位基因。在此，我们报告NOA缺乏PDH E2亚基二氢硫胺S乙酰转移酶(DLAT)，并表现出与人类PDH缺乏症患者相似的表型。为了弥补这一缺陷，我们在胚胎发育的水中添加了生酮底物。这种治疗方法成功地恢复了视力，促进了进食行为，减少了乳酸酸中毒，提高了存活率。我们的研究证明了一种建立有效治疗PDH缺乏症和其他影响早期胚胎发育的先天性疾病的方法。
Defects in the pyruvate dehydrogenase (PDH) complex result in severe neurological dysfunction, congenital lactic acidosis, growth retardation, and early death. Current treatments for PDH deficiency are administered postnatally and are generally unsuccessful. Because many patients with this disease are born with irreversible defects, a model system for the development of effective pre- and postnatal therapies would be of great value. In a behavioral genetic screen aimed to identify zebrafish with visual function defects, we previously isolated two alleles of the recessive lethal mutant no optokinetic response a (noa). Here we report that noa is deficient for dihydrolipoamide S-acetyltransferase (Dlat), the PDH E2 subunit, and exhibits phenotypes similar to human patients with PDH deficiency. To rescue the deficiency, we added ketogenic substrates to the water in which the embryos develop. This treatment successfully restored vision, promoted feeding behavior, reduced lactic acidosis, and increased survival. Our study demonstrates an approach for establishing effective therapies for PDH deficiency and other congenital diseases that affect early embryonic development.