Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, 2300 I Street N.W., Washington, DC 20037, USA.
Children's National Medical Center, Division of Neurogenetics and Neurodevelopmental Pediatrics, Washington, DC 20010, USA.
Int J Mol Sci. 2024 Jan 23;25(3):1386. doi: 10.3390/ijms25031386.
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.
我们报告了一例复杂病史的四岁男性患者，他因胎盘功能不全导致宫内生长受限而早产。他的临床表现包括严重的神经发育缺陷、全面发育迟缓、Pierre-Robin 序列和难以控制的癫痫，具有全面性和局灶性特征。受检者在给予 Depakoke 后出现柠檬酸和乳酸水平降低，提示可能存在线粒体病因。由于未检测到核和线粒体致病性变异，受检者的基因型-表型相关性在全基因组和线粒体基因组深度测序中仍未得到明确。然而，活细胞线粒体代谢研究提供了证据，表明氧化磷酸化途径（负责三磷酸腺苷 [ATP] 合成）存在缺陷，导致受检者慢性能量危机。此外，我们的代谢分析揭示了有利于糖酵解合成 ATP 的代谢可塑性。我们通过透射电子显微镜进行的线粒体形态计量分析证实了可疑的线粒体病因，因为受检者的线粒体表现出不成熟的形态，嵴发育不良且稀少。因此，我们的结果支持这样的概念，即宫内氧气和营养物质水平不足会改变胎儿线粒体代谢重编程，导致氧化磷酸化（OXPHOS）不足，从而导致出生后线粒体能量代谢不足。总之，我们的综合研究揭示了由特发性胎盘功能不全导致的宫内生长受限对胎儿和出生后脑能量需求发育的长期产后线粒体病理生理学的影响。
