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Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.
International Journal of Molecular Sciences 2024 January 24
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.
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