Pregnancy and labor were uneventful, and birth was by spontaneous vaginal delivery. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The infant's nursery course was unremarkable. On the evening after discharge, his parents noted he became sleepy and lost interest in feeding over the next 12 hours. The following morning, they noted his breathing was rapid, so they brought him to the emergency room. His general examination at presentation revealed suprasternal retractions, a flat anterior fontanelle, and an enlarged liver. Neurologic examination was notable for marked encephalopathy; he did not open his eyes or react to stimulation. His suck was weak and poorly coordinated and his gag reflex was absent. He lay in a frog-legged position; however, passive tone was increased in all 4 extremities. There were no spontaneous movements or motor response to noxious stimulation. Deep tendon reflexes were symmetrically brisk without ankle clonus.

A careful review of the history can help identify infectious risk factors, such as a maternal history of group B streptococcus colonization, prolonged rupture of membranes, or labor complicated by chorioamnionitis. Absence of herpetic lesions does not exclude the diagnosis of herpes simplex virus infection. A bulging fontanelle would suggest elevated intracranial pressure from either infection or intracranial hemorrhage.

Initial laboratory investigations to consider include serum electrolytes, complete blood count, arterial blood gas, lactate, pyruvate, ammonia, transaminases, total and direct bilirubin, coagulation studies, quantitative amino acids, carnitine levels, and acylcarnitine profile. Urine should be sent for routine urinalysis, urine organic acids, and orotic acid. A sepsis workup, including blood cultures, urine cultures, and CSF analysis, should be pursued. An urgent bedside head ultrasound can evaluate for cerebral hemorrhage. If there is concern for impending herniation or other neurosurgical emergencies, CT can be performed; however, MRI is preferred in children if available and if the patient is stable.

This infant had a noncontrast head CT in the emergency room, which was notable for cerebral edema. Ammonia (venous sample) was markedly elevated at 770 μmol/L (reference <49 μmol/L). Arterial blood gas showed a mild respiratory alkalosis. Serum glucose and anion gap were normal.

In a neonate, the differential diagnosis for hyperammonemia includes both inherited (e.g., urea cycle defects) and acquired (e.g., valproate usage) etiologies (table 1). In this infant, the combination of a highly elevated serum ammonia level, respiratory alkalosis, normal serum glucose, and normal anion gap suggested a urea cycle defect.

The acute management of hyperammonemic crisis involves 1) preventing further ammonia production by discontinuing protein intake and 2) urgent removal of accumulated ammonia via dialysis and administration of sodium benzoate and sodium phenylacetate.¹ These medications may improve survival by providing an alternative pathway for ammonia precursors to be excreted in the urine.² Generous fluid intake can also support urinary ammonia excretion. Encephalopathy makes seizures difficult to detect clinically and therefore continuous EEG is helpful. Consultation with a metabolic expert should be sought urgently to assist with management.

When this infant arrived at our tertiary care facility, EEG showed intermittent multifocal seizures. He was treated with phenobarbital. His ammonia peaked at >1,000 μmol/L. He was treated urgently with sodium benzoate, sodium phenylacetate, and hemodialysis. His metabolic labs revealed a low citrulline, high orotic acid, high glutamine and alanine, and normal arginine. This biochemical profile was diagnostic for ornithine transcarbamylase (OTC) deficiency, a urea cycle defect (table 2). There was no maternal history of protein intolerance, nor was there a family history of recurrent miscarriages, sudden unexplained death, or parental consanguinity.

Presentation in the neonatal period suggests a complete enzyme deficiency, while patients with partial deficiencies may only come to attention in adulthood. Neonates present with encephalopathy, seizures, hypotonia, and poor feeding after protein intake in the form of milk or formula.

To diagnose the specific urea cycle defect, plasma amino acids, urine organic acids, and urine orotic acid should be ordered (table 2).

The survival rate for acute neonatal hyperammonemia due to a urea cycle defect is 73%, significantly lower than the 98% survival rate of older patients.² Coma at admission is a negative prognostic indicator for survival, as is having a peak ammonia level >1,000 μmol/L.²

In one study, neurodevelopmental deficit after the initial hyperammonemic crisis related to the peak ammonia concentration; those neonates with ammonia levels greater than 350 μmol/L had severe deficits or died.³ Only those whose peak ammonia level was <180 μmol/L did not develop neurocognitive impairment.³ In another study, long-term neurologic sequelae related to the duration of hyperammonemia but not the peak level.⁴

OTC deficiency is the most common urea cycle defect, with an incidence of 1 in 14,000.⁵ It accounts for almost half of all neonatal onset cases.³ Males typically present in the neonatal period and have a higher mortality.² Female heterozygotes can become symptomatic, with severity and timing dependent on the pattern of hepatic lyonization. Neonatal presentation is associated with poor neurologic outcome.¹ Orthotopic liver transplant can be curative, but will not reverse neurologic injury already sustained.¹

Newborn screening results can take several weeks to be reported. Because newborns are typically discharged from the hospital on the first or second day of life, symptoms usually do not develop until the infant is home. Thus, newborn screening may not detect a urea cycle defect early enough to prevent all neonatal hyperammonemic crises and, instead, clinicians must remain astute to the nonspecific symptoms of hyperammonemia in a newborn.⁷

If there is a known family history of a urea cycle disorder, prenatal testing is available.⁸ Infants with OTC deficiency may have a more favorable neurologic outcome if hyperammonemic crisis is prevented by early detection.⁷

In infants with acute hyperammonemia, immediate cessation of protein intake and implementation of ammonia-lowering therapy are critical, while further diagnostic testing is ongoing, as peak ammonia level and duration of hyperammonemia are correlated with neurologic outcome.