W1869 Discrepancy in Neurologic Status and Liver Dysfunction in Fulminant Hepatic Failure, Leading to the Discovery of a Missense Mutation Causing Ornithine Transcarbamylase Deficiency in An Adult

Abstract

A 20-year-old male football player with 2 months of persistent nausea and emesis developed progressive mental status changes. Upon evaluation in an emergency room the patient became unresponsive requiring intubation. He was found to have hyperammonemia, elevated transaminases, and a mild coagulopathy. He was flown to our liver transplant center with a presumed diagnosis of fulminant liver failure. His history was also significant for the intake of multiple supplements, steroidal hormones, and a high protein diet. Exam noted an anicteric, muscular male with grade 4 encephalopathy and no stigmata of chronic liver disease. Ammonia level after transfer was 398 umol/L and INR was 2.0. ALT was 15X normal. Within 24 hours the patient developed seizures and was found to have cerebral edema on CT scan. A urea cycle disorder was considered given the discrepancy in his severe hyperammonemia, mental status changes and only mild biochemical evidence of liver dysfunction. After diagnostic studies were obtained, intravenous sodium phenylacetate, sodium benzoate, and arginine were administered. Within 8 hours of the infusion his arterial ammonia level had fallen to 18 umol/L. The urine organic acids revealed an elevated orotic acid and uracil, while his serum amino acid panel showed elevated arginine and low normal citrulline levels. Given the concern for an ornithine transcarbamylase deficiency, gene sequencing was performed and revealed a hemizygous unclassified missense variant (c.563G>C). The amino acid glycine at position 188 of the OTC gene is evolutionarily conserved and therefore this variant is likely pathogenic, particularly given the clinical context. The patient's hospital course was complicated by cerebral edema, requiring the use of an epidural pressure monitor, mannitol, cooling, paralytics, and hypertonic saline. Ammonia levels remained consistently normal through the hospitalization. Three months after the event he has returned to school and is functioning without apparent difficulties. Discussion: Urea cycle disorders are generally considered a pediatric condition. As illustrated by this case, presentation can occur in adulthood and if not identified quickly the initial presentation can be disabling or lethal. The clinical clues to this diagnosis are severe elevation of ammonia, normal anion gap, and normal serum glucose. Although the initial impression was that of drug-induced fulminant liver failure, a successful diagnosis was made only after noting a discrepancy between his neurologic status and mild liver dysfunction.