Acute Fatal Presentation of Adult-onset Ornithine Transcarbamylase (OTC) Deficiency

Abstract

Purpose: A 19-year-old soldier was admitted to ICU from an outside hospital with seizures. He was admitted there with altered mental status three days prior. An extensive work-up for infectious and toxic etiologies was negative at the time. He improved on empiric antibiotics and was discharged with a diagnosis of encephalopathy of unknown etiology. He was readmitted and transferred to our hospital with status epilepticus. History was negative for preceding viral prodrome, aspirin, recreational drug use, travel history, or insect bites. His developmental and family history was unremarkable, and he was only taking multivitamins. At admission, he was found to have a fever of 38.3 with tachycardia and normal blood pressure. Examination was significant for mild hepatomegaly with no signs of advanced liver disease. Neurological examination was non-focal with bilateral down-going planters and negative meningism. He was started on propofol, fosphenytoin, and levetiracetam with control of seizures. His comprehensive metabolic profile was significant for elevated creatinine at 1.88, elevated AST, ALT at 88, and 189 IU/ml with normal bilirubin, alkaline phosphatase, and synthetic functions. Ammonia level was significantly elevated at 1,248 mmol/L. Other work-up including acute hepatitis panel, iron studies, ANA, and serum ceruloplasmin were normal. CT head showed bilateral diffuse sulcal effacement. USG abdomen showed decreased parenchymal echogenicity. Lumbar puncture and a metabolic drug screen were normal. Patient was started on hemodialysis, along with IV infusions of ammonul, arginine and empiric levocarnitine, with improvement of NH3 down to 112 by the next day. Acylcarnitine profile, urine amino acids, urine orotic acid levels, and OTC comprehensive sequence and deletion duplication analysis were sent out. However, despite being off sedation, he displayed no signs of spontaneous neurological activity, and was declared brain dead after two formal assessments. His urine orotic acid level came back elevated at 225.9 mmol/mol, and his DNA analysis revealed R277W mutation at exon eight for OTC gene. OTC deficiency is the most common enzyme deficiency for urea cycle disorder. Being an X-linked pattern of inheritance, it most commonly affects males in infancy, with a wide range of clinical presentations. With more than 40 point mutations and nucleotide deletions described for the OTC gene, it has variable phenotypical presentations with variable severity and outcomes. Our case is a unique presentation at a later age, which is rare, and emphasizes the importance of considering as differential in any patient with altered mental status, irrespective of age, as prompt and early diagnosis has the potential to prevent lethal outcomes.