Discussion

Ornithine transcarbamylase deficiency is an X-linked urea cycle defect which results in the accumulation of ammonia and glutamine and subsequent irreversible brain damage. ^{Reference Summar1} The estimated frequency of ornithine transcarbamylase deficiency is 1/80000 in Japan. ^{Reference Nagata, Matsuda and Oyanagi2} Protein overtake, decreased energy intake, infection, and surgery are known to be triggering factors. ^{Reference Häberle, Burlina and Chakrapani3,Reference Brassier, Gobin and Arnoux4} Chiong et al. reported late-onset ornithine transcarbamylase deficiency in adult after coronary bypass surgery. ^{Reference Chiong, Bennetts, Strasser and Wilcken5} They concluded that surgery stress and inadequate calorie intake uncover latent-ornithine transcarbamylase deficiency. In our case, cardiac surgery using cardiopulmonary bypass and post-operative catabolism were thought to be the triggers.

Ornithine transcarbamylase deficiency is suspected in neonates with an undiagnosed lethargy, irritability, and vomiting. However, there are several factors that delayed suspicion of underlying urea cycle disorder in this case. First, those non-specific symptoms are often observed in peri-operative cardiac surgery. In fact, 33.2–82% of children experience post-operative nausea and vomiting. ^{Reference Urits, Orhurhu and Jones6} Second, even though there were signs of concealed metabolic disorder such as tachypnea and metabolic acidosis, his high serum digoxin concentration and symptoms misled to focus on only digoxin toxicity. As digoxin toxicity and ornithine transcarbamylase deficiency share common clinical features such as gastrointestinal and neurological symptoms, ornithine transcarbamylase deficiency was underdiagnosed in this case. ^{Reference Cummings and Swoboda7} Moreover, no prior case of acute-onset ornithine transcarbamylase deficiency after cardiac surgery in neonates has been reported. Furthermore, his no remarkable family history excluded congenital metabolism disorder. Subsequently, his mutation analysis confirmed de novo mutation since the analysis showed c. 472C>T (p.P158S) mutation in ornithine transcarbamylase Exon 5 which was not identified in his mother and brother.

Management of ornithine transcarbamylase deficiency in neonate is difficult; mortality rate is 74%. ^{Reference Brassier, Gobin and Arnoux4} Recommended treatments of ornithine transcarbamylase deficiency are early diagnosis and rapid treatment with glucose injection, protein restriction, intravenous arginine and citrulline, and administration of sodium phenylbutyrate and/or sodium benzoate. Mattke et al. reported successful treatment of a neonatal case with deteriorating cardiac function using extracorporeal membrane oxygenation and continuous hemodiafiltration. ^{Reference Mattke, Shikata, McGill, Justo and Venugopal8} Likewise, continuous hemodiafiltration and extracorporeal membrane oxygenation were used in our case; however, underdiagnosis of ornithine transcarbamylase deficiency and deteriorating condition resulted in poor response to intensive care. Routine measurement of plasma ammonia level and examination of organic acid in urine in neonates before and after emergency cardiac surgery may prevent underdiagnosis of ornithine transcarbamylase deficiency.

Severe cardiac dysfunction is thought to be rare in ornithine transcarbamylase deficiency. However, Mattke et al. reported that our case also presented severe left ventricular dysfunction. Mattke et al. proposed that NH3, metabolic acidosis, and oxidative stress might be the cause of severely dilated left ventricular dysfunction. In addition to Mattke’s hypothesis, since ornithine transcarbamylase deficiency is known to cause carnitine deficiency, carnitine may have also played an important role in cardiac function and arrythmia in this case. ^{Reference Mayatepek, Kurczynski, Hoppel and Gunning9,Reference Fu, Huang and Chen10} Carnitine transfers long-chain fatty acids to mitochondria for β-oxidation. Since long-chain fatty acids are an essential energy source for myocardium, deficiency of carnitine is expected to affect cardiac muscle and results in cardiac dysfunction. Although factors that lead to the development of heart failure are unknown, echocardiogram may be recommended in neonates with ornithine transcarbamylase deficiency.