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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
Uittenbogaard, M.; Gropman, A.L.; Whitehead, M.T.; Brantner, C.A.; Gropman, E.; Chiaramello, A. Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency. Int. J. Mol. Sci.2024, 25, 1386.
Uittenbogaard, M.; Gropman, A.L.; Whitehead, M.T.; Brantner, C.A.; Gropman, E.; Chiaramello, A. Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency. Int. J. Mol. Sci. 2024, 25, 1386.
Uittenbogaard, M.; Gropman, A.L.; Whitehead, M.T.; Brantner, C.A.; Gropman, E.; Chiaramello, A. Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency. Int. J. Mol. Sci.2024, 25, 1386.
Uittenbogaard, M.; Gropman, A.L.; Whitehead, M.T.; Brantner, C.A.; Gropman, E.; Chiaramello, A. Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency. Int. J. Mol. Sci. 2024, 25, 1386.
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 include 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 are evocative of a mitochondrial etiology. However, the genotype-phenotype correlation remains undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provide evidence of a deficient oxidative phosphorylation pathway responsible for ATP synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis reveals metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirms the suspected mitochondrial etiology, as the proband’s mitochondria exhibit an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that sub-optimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward 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 fetal and postnatal brain.
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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