Chronic and Variable Manifestations of Ornithine Transcarbamylase Deficiency in Heterozygous Carriers: A Case Series of Three Colombian Patients

Abstract Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder with an estimated prevalence ranging from 1 in 56,500 to 1 in 113,000 live births. While hemizygous males typically present with early-onset hyperammonemic encephalopathy, females carrying pathogenic variants in OTC exhibit highly variable phenotypes due to random X-chromosome inactivation, ranging from asymptomatic states to severe metabolic and neuropsychiatric manifestations. In many cases, diagnosis in females is delayed, especially when symptoms are misinterpreted as behavioral or psychiatric disorders, increasing the risk of irreversible neurological sequelae. This case series describes three Colombian females with genetically confirmed OTCD: two pediatric patients and one adult. In pediatric cases, metabolic decompensations were triggered by febrile viral illnesses and infections. In the adult patient, initial symptoms occurred during pregnancy and were misattributed to a primary psychiatric disorder. In all three cases, diagnosis was established only after multiple episodes of illness. All patients presented early on with protein aversion, which we consider a significant red flag to suspect metabolic disorders. This series underscores the diagnostic challenges in females heterozygous for OTC, the importance of recognizing catabolic stressors as triggers for clinical deterioration, and the need for early biochemical and molecular evaluation to prevent complications and reduce diagnostic delays.