Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

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.

The behavioral profile of 49,XXXXY and the potential impact of testosterone replacement therapy.

PURPOSE: 49,XXXXY (1:85,000-100,000) is a rare sex chromosome aneuploidy that often presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications. Hormonal replacement therapy, or testosterone replacement therapy, is associated with improved neurodevelopmental and behavioral outcomes in males with 49,XXXXY. Two forms of testosterone replacement therapy, early hormonal treatment (EHT) and hormonal booster therapy (HBT), are associated with improved neurodevelopmental and behavioral outcomes in these boys. This study investigates the impact of EHT and HBT on behavioral symptoms in males with 49,XXXXY. METHODS: A total of 59 individuals were divided into 4 groups: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT. An analysis of variance examined group differences on the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function ranging from 5 to 18 years. RESULTS: Although no differences were identified on the Behavior Rating Inventory of Executive Function, the 3 hormonal replacement therapy groups presented with decreased complications on numerous variables on the Child Behavior Checklist; these include somatic complaints (P = .0095), somatic problems (P = .041), internalizing problems (P = .034), externalizing problems (P = .0001), and withdrawn/depression (P = .025). CONCLUSION: This study presents evidence that HBT may be a beneficial treatment for individuals with 49,XXXXY.