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.

Pregnancy-related Type Citrullinemia Type 1: an Analysis of 14 Cases and Review of the Literature

Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder, without functional argininosuccinate synthase (ASS) enzyme, mostly occurring in newborns and infants, but it has been reported having an adult-onset in carriers of the pathogenic gene, and even more rarely, the onset of the disease is pregnancy related. The diagnosis and management process of pregnancy-related type citrullinemia 1 was found very challenging in the clinical practice. Citrullinemia type 1 was, often seen in newborns with a worldwide prevalence of 1:44,300-250,000, characterized by hyperammonemia and elevated citrulline levels in blood and urine as clinical features. Since 1980, only 14 cases with onset during pregnancy and puerperium have been reported. This review provides an overview of the relationship between Citrullinemia type 1 and pregnancy and discusses the mechanisms, clinical manifestations and genetic characteristics of pregnancy-related onset.

Non-coding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.-3065A>C and NM_153006.2:c-3098C>T reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Sequence variants NM_153006.2:c.426+326G>A and NM_153006.2:c.427-218A>C reside in the first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor α. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing non-coding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.

Brain-lung-thyroid syndrome in a neonate with argininosuccinate lyase deficiency

Argininosuccinate lyase (ASL) deficiency is a rare autosomal recessive urea cycle disorder. The severe neonatal-onset form is characterised by hyperammonaemia in the first days of life and manifests with a variety of severe symptoms. However, an index of suspicion for additional or alternative diagnoses must be maintained when the patient’s presentation is out of keeping with expected manifestations and course. We present a case of a neonate with ASL deficiency and concomitant hypotonia, severe respiratory distress, pulmonary hypertension, systemic hypotension and congenital hypothyroidism. The patient was investigated and subsequently diagnosed with brain-lung-thyroid syndrome, caused by a mutation in the NKX2-1 gene.

High Blood Pressure in a Urea Cycle Disorder: Case Report

Introduction Urea cycle disorders (UCDs) form a group of metabolic pathological conditions that might develop serious neurological consequences. Early diagnosis, before irreversible damage is established, is the most important prognostic and morbidity factor. Case Report We present the case of a 5-day newborn with high blood pressure and respiratory distress. Diagnosis was type I citrullinemia. With appropriate citrullinemia guided-treatment blood pressure returned to normal. Conclusion High blood pressure has been rarely described as a lead symptom for the debut of a UCD. We must take this into consideration as an early recognition and treatment of these disorders are of the utmost importance.