PDF(Pubmed)
Abstract：
We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband\'s low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband\'s genotype-phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband\'s mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain.
摘要：
我们报告了一名四岁男性患者的病例，该患者具有复杂的病史，由于胎盘功能不全导致宫内生长受限而过早出生。他的临床表现包括严重的神经发育缺陷，全球发育迟缓，皮埃尔-罗宾序列,和具有全身性和局灶性特征的难治性癫痫。先证者的低水平瓜氨酸和因服用Depakoke引起的乳酸性酸中毒令人回想起线粒体病因。在通过两个基因组的深度测序检测到核和线粒体致病变异的情况下，先证者的基因型-表型相关性仍然不确定。然而,活细胞线粒体代谢研究提供了负责三磷酸腺苷（ATP）合成的氧化磷酸化途径缺陷的证据，导致先证者长期的能源危机。此外,我们的代谢分析显示代谢可塑性有利于糖酵解合成ATP。我们通过透射电子显微镜进行的线粒体形态分析证实了可疑的线粒体病因，因为先证者的线粒体表现出不成熟的形态，发育不良和罕见的cr。因此，我们的结果支持以下观点:宫内氧和营养物质的次优水平改变胎儿线粒体代谢重编程向氧化磷酸化(OXPHOS),导致出生后线粒体能量代谢不足.总之,我们的集体研究揭示了特发性胎盘功能不全导致宫内生长受限引起的长期产后线粒体病理生理学及其对胎儿和产后大脑能量需求发育的负面影响.
