To heighten clinical vigilance for adult-onset hyperammonemia due to previously unrecognized Ornithine Transcarbamylase Deficiency (OTCD), a treatable but often missed cause of acute neurologic decline and death and to increase awareness among neurologists regarding the variable and often subtle prodromal symptoms, and  importance of early recognition and metabolic testing to enable timely intervention and prevent fatal outcomes.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder that leads to toxic ammonia accumulation. While classically associated with catastrophic neonatal presentations in males, partial enzyme deficiency in both sexes can remain silent until triggered—often in adolescence or adulthood. In adults, OTCD masquerades as psychiatric illness, intoxication, or hepatic dysfunction. The earliest symptoms, headache, fatigue, confusion, or subtle behavior change are easily dismissed. As ammonia levels rise, lethargy, agitation, delirium, or psychosis can rapidly progress to seizures, cerebral edema, coma, and death. Too often, the diagnosis is made postmortem.

Common triggers include infection, surgery, fasting, postpartum catabolism, or medications such as corticosteroids or valproic acid. Recognition within hours, not days, is critical.

We present a case series from our clinical experience and the recent literature in which delayed recognition of hyperammonemia led to preventable brain injury or death in adults later confirmed to have OTCD.

Across cases, failure to measure ammonia at initial presentation delayed diagnosis until irreversible CNS injury occurred.