Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid

Objectives: The aims of this report are to 1) present a rare case of fatal cerebral edema associated with late-onset ornithine transcarbamylase (OTC) deficiency in a juvenile male patient receiving valproic acid and 2) review the neuropathologic changes associated with the hyperammonemia. Design: Case report. Setting. A community hospital and a tertiary pediatric critical care unit. Interventions. Carbohydrate administration, intravenous nitrogen excretion cocktail, and high-flux hemodialysis. Measurements and Main Results., Despite aggressive therapy for presumed late-onset OTC deficiency, the patient rapidly developed fatal cerebral edema with tonsillar herniation. A liver biopsy confirmed OTC deficiency with similar to 3% of residual hepatic enzyme activity. Chromosomal analysis showed a normal male karyotype. A thorough molecular analysis of the coding region in the OTC gene Xp21.1 was completed, but mutations were not identified, suggesting an upstream or downstream abnormality. Severe brain swelling was evident on neuropathology, and histopathology showed Alzheimer type II astrocytes, neuronal cytoplasmic changes, and hypertrophy and eosinophilia of the small arterial walls. Conclusions. OTC deficiency is the most common urea cycle defect causing hyperammonemia. Late-onset presentations of OTC are infrequent, primarily affecting female patients. We present a rare case of a late-onset OTC deficiency in a juvenile male patient receiving valproic acid therapy who developed fatal cerebral edema. Valproic acid exacerbates acute elevations in ammonia and may contribute synergistically with ammonia to cerebral mitochondrial dysfunction.