Placental Pathology in Maternal Ornithine Transcarbamylase Deficiency

Introduction Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, inherited in an X-linked manner. Males are severely affected. Female phenotypes vary from asymptomatic to severe, and symptoms may be triggered by high metabolic states like childbirth. Literature on OTC deficiency in pregnancy and placental pathology is limited. Methods Pathology records were searched at a single referral center from 2000–2020 and identified three placental cases from two mothers heterozygous for OTC deficiency. Placental pathology and maternal and neonatal history were reviewed in detail. Results The placenta from one symptomatic mother carrying an affected male fetus showed widespread high-grade fetal vascular malperfusion (FVM) lesions of varying age. These lesions were not seen in the two placentas from the asymptomatic mother. Discussion In cases of symptomatic maternal OTC deficiency, our findings highlight the need for placental examination. Since thrombotic events in the placenta have the potential to associate with fetal and neonatal endothelial damage, a high index of suspicion for neonatal thrombosis may be warranted.

The Mechanism of Hyperammonemia Triggered by Corticosteroid Administration in Late-Onset Ornithine Transcarbamylase Deficiency

Background: Ornithine transcarbamylase deficiency (OTCD) is most popular among urea cycle disorders (UCDs), defined by the loss of function in any of the enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is well known to induce life-threatening hyperammonemia. The mechanism has been considered nitrogen overload due to the catabolic effect of corticosteroids; however, the pathophysiological process is unclear. We evaluated the effects of corticosteroids on urea cycle enzyme expressions and urea cycle-associated metabolites in OTC-deficient mice.Methods: The clinical courses of two adult-onset OTCD patients were presented. To elucidate the mechanism of hyperammonemia induced by corticosteroid administration in OTCD patients, we developed a mouse model by administering corticosteroids to OTCspf-ash mice deficient in the OTC gene. Dexamethasone (DEX; 20 mg/kg) was administered to the OTCspf-ash and wild-type (WT) mice at 0 and 24 h, and the serum ammonia concentrations, the levels of the hepatic metabolites, and the gene expressions of urea-cycle-related genes were analyzed.Results: Two adult-onset OTCD patients received multimodal treatment, including dialysis, and recovered completely from severe hyperammonemia. The ammonia levels in Otcspf-ash mice that were administered DEX tended to increase at 24 h and increased significantly at 48 h. The metabolomic analysis showed that the levels of citrulline, arginine, and ornithine did not differ significantly between Otcspf-ash mice that were administered DEX and normal saline; however, the level of aspartate was increased drastically in Otcspf-ash mice owing to DEX administration (P < 0.01). Among the enzymes associated with the urea cycle, mRNA expressions of carbamoyl-phosphate synthase 1, ornithine transcarbamylase, arginosuccinate synthase 1, and arginosuccinate lyase were significantly downregulated by DEX administration in both the Otcspf-ash and WT mice (P < 0.01).Conclusions: We elucidated that corticosteroid administration induced hyperammonemia in Otcspf-ash mice by suppressing urea-cycle-related gene expressions as early as 24 h. Since the urea cycle intermediate amino acids, such as arginine, might not be effective because of the suppressed expression of urea-cycle-related genes by corticosteroid administration, we should consider an early intervention by renal replacement therapy in cases of UCD patients induced by corticosteroids to avoid brain injuries or fatal outcomes.

Ornithine Transcarbamylase – From Structure to Metabolism: An Update

Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms, including vertebrates, microorganisms, and plants. Anabolic, mostly trimeric OTCs catalyze the production of L-citrulline from L-ornithine which is a part of the urea cycle. In eukaryotes, such OTC localizes to the mitochondrial matrix, partially bound to the mitochondrial inner membrane and part of channeling multi-enzyme assemblies. In mammals, mainly two organs express OTC: the liver, where it is an integral part of the urea cycle, and the intestine, where it synthesizes citrulline for export and plays a major role in amino acid homeostasis, particularly of L-glutamine and L-arginine. Here, we give an overview on OTC genes and proteins, their tissue distribution, regulation, and physiological function, emphasizing the importance of OTC and urea cycle enzymes for metabolic regulation in human health and disease. Finally, we summarize the current knowledge of OTC deficiency, a rare X-linked human genetic disorder, and its emerging role in various chronic pathologies.