We describe a woman in her 40s with acute myeloid leukemia (AML) who developed fulminant nonhepatic hyperammonemic encephalopathy while receiving intensive consolidation chemotherapy. The event occurred during high-dose cytarabine. Hyperammonemic encephalopathy is an uncommon but frequently lethal complication in patients undergoing intensive therapy for hematological malignancies; its causes are often unclear.
This case is notable because metabolic evaluation and subsequent genetic testing identified an underlying inherited predisposition: a heterozygous pathogenic variant in the ornithine transcarbamylase (OTC) gene consistent with partial OTC deficiency, which had not been recognized prior to the chemotherapy episode.
On day 5 of consolidation therapy the patient developed rapidly progressive alteration of consciousness. Marked elevation of serum ammonia accompanied this neurologic deterioration. At the time of presentation there was no evidence of hepatic or renal failure; hepatic and renal function tests were reported as preserved. There was also no active sepsis identified as a proximate trigger.
The rapid onset of neurocognitive decline on a background of intensive cytotoxic therapy prompted urgent neuroimaging and metabolic assessment.
Brain magnetic resonance imaging (MRI) showed cortical abnormalities judged more consistent with a metabolic encephalopathy than with alternative chemotherapy-related neurotoxicities. The imaging appearance was considered less compatible with classic cytarabine-associated neurotoxicity or with posterior reversible encephalopathy syndrome (PRES). The pattern supported a metabolic cause for the acute neurologic decline.
Serum ammonia was markedly elevated and increased further despite supportive measures. Hepatic and renal function remained preserved, and clinicians found no evidence of active systemic infection to explain the hyperammonemia. Given the clinical picture and imaging, a metabolic etiology—specifically a disorder of the urea cycle—was suspected and pursued.
The authors report that metabolic evaluation suggested a urea cycle disorder as the underlying mechanism for the hyperammonemia.
Genetic analysis identified a heterozygous pathogenic variant in the OTC gene. This finding established previously unrecognized partial ornithine transcarbamylase deficiency as an inherited metabolic predisposition in this patient. The report emphasizes that genetically confirmed urea cycle disorders remain rare among reported adult cases of severe nonhepatic hyperammonemia in patients with hematologic malignancies.
Despite supportive therapy, the patient’s serum ammonia continued to rise. Her condition progressed to clinical seizures, diffuse cerebral edema, and death. The reported course was fulminant, with rapid neurologic decline after the initial recognition of altered consciousness and hyperammonemia.
The report does not provide further detail on specific ammonia-lowering therapies used or their timing beyond the description that standard supportive measures were instituted.
Adult hyperammonemia in the setting of hematologic malignancy and intensive chemotherapy is frequently classified as idiopathic or attributed to infection, but this case highlights that occult inherited metabolic disorders, such as partial OTC deficiency, can present at this time and may contribute to pathogenesis. Intensive cytotoxic regimens may unmask a latent defect in nitrogen metabolism by increasing protein catabolism or otherwise overwhelming urea cycle capacity.
This report expands the recognized spectrum of chemotherapy-associated nonhepatic hyperammonemia by documenting a genetically confirmed urea cycle disorder in an adult patient whose metabolic predisposition had been clinically silent until provoked by chemotherapy.
Consider serum ammonia measurement in patients receiving intensive chemotherapy who develop unexplained altered mental status or encephalopathy, even when liver and kidney function appear normal.
Recognize that nonhepatic hyperammonemia in adults with hematologic malignancy may occasionally reflect an underlying inherited urea cycle disorder, including partial OTC deficiency.
Early identification of hyperammonemia should prompt metabolic evaluation and consideration of genetic testing when a urea cycle disorder is suspected; such testing may reveal previously unrecognized inherited predisposition.
The fatal outcome in this case underscores the potential severity and rapid progression of chemotherapy-associated hyperammonemia when an occult metabolic vulnerability exists.
The authors report that the institutional review board approved the study and that informed consent for publication was obtained from the patient’s family. The authors declared no conflicts of interest.