Fatal hyperammonemic encephalopathy triggered by valproic acid in adult-onset type II citrullinemia: A diagnostic pitfall

Abstract

Adult-onset type II citrullinemia (CTLN2) is a rare urea cycle disorder caused by SLC25A13 mutations, often misdiagnosed due to fluctuating neuropsychiatric and metabolic symptoms. Hyperammonemia is its defining feature and can be fatal if unrecognized. A 30-year-old woman with intellectual disability presented with recurrent seizure-like episodes and behavioral changes. Brain MRI showed bilateral temporal lobe abnormalities suggestive of encephalitis or metabolic encephalopathy. Despite antiviral and antiseizure therapy, her consciousness deteriorated. On the sixth hospital day, valproic acid (VPA) was administered for seizure control, after which she rapidly progressed to coma and respiratory failure. Serum ammonia levels were markedly elevated (>615 µmol/L), and metabolic studies revealed increased citrulline and arginine levels. Genetic testing confirmed compound heterozygous SLC25A13 mutations consistent with CTLN2. Despite aggressive management, the patient died 23 days after admission. This case underscores the diagnostic difficulty of CTLN2 and highlights the fatal risk of VPA-induced hyperammonemia in patients with unrecognized urea cycle disorders. Early metabolic screening should be considered in unexplained encephalopathy, especially when imaging and EEG findings are nonspecific, and VPA should be avoided to prevent catastrophic outcomes.