Acute neonatal citrullinemia type I

Acute neonatal citrullinemia type I (also known as classic or severe neonatal citrullinemia, or argininosuccinate synthetase deficiency) is a severe form of citrullinemia type I, a urea cycle disorder caused by deficiency of the enzyme argininosuccinate synthetase 1 (ASS1). This enzyme plays a critical role in the urea cycle, which is the metabolic pathway responsible for converting toxic ammonia into urea for excretion by the kidneys. When ASS1 is deficient, ammonia and citrulline accumulate to dangerously high levels in the blood, leading to hyperammonemia and its devastating consequences on the central nervous system. The acute neonatal form is the most severe presentation of citrullinemia type I and typically manifests within the first few days of life, often 24 to 72 hours after birth. Affected newborns initially appear normal but rapidly develop poor feeding, vomiting, lethargy, hypothermia, and progressive encephalopathy due to hyperammonemia. Without prompt treatment, the condition can progress to seizures, cerebral edema, coma, and death. Neurological damage may occur even with treatment if ammonia levels remain elevated for prolonged periods. Laboratory findings include markedly elevated plasma citrulline levels and hyperammonemia. Treatment of acute neonatal citrullinemia type I requires emergency management of hyperammonemia, which may include hemodialysis or hemofiltration, intravenous sodium benzoate and sodium phenylacetate (nitrogen-scavenging agents), and intravenous arginine supplementation to promote alternative pathways for nitrogen excretion. Long-term management involves dietary protein restriction, oral nitrogen-scavenging medications, and arginine supplementation. Liver transplantation is considered a curative treatment, as it provides a functional source of ASS1 enzyme, and is often recommended for patients with the severe neonatal form to prevent recurrent hyperammonemic crises and progressive neurological deterioration. Newborn screening programs in many regions can detect elevated citrulline levels, enabling earlier diagnosis and intervention.

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