Citrullinemia type I

Citrullinemia type I (also known as classic citrullinemia, argininosuccinate synthetase deficiency, or CTLN1) is a rare inherited disorder of the urea cycle caused by deficiency of the enzyme argininosuccinate synthetase 1 (ASS1). The urea cycle is the metabolic pathway responsible for converting toxic ammonia into urea for excretion by the kidneys. When this enzyme is deficient, ammonia and citrulline accumulate in the blood, leading to hyperammonemia, which is particularly toxic to the brain and central nervous system. The classic neonatal form typically presents within the first few days of life with poor feeding, vomiting, lethargy, seizures, and progressive encephalopathy that can rapidly progress to coma and death if untreated. Some individuals have milder or later-onset forms with episodic hyperammonemia triggered by illness, stress, or high-protein intake. Intellectual disability and developmental delays may occur, particularly if hyperammonemic episodes are severe or recurrent. The liver is the primary organ affected metabolically, though the brain bears the greatest burden of damage from ammonia toxicity. Treatment involves a combination of dietary protein restriction, nitrogen-scavenging medications (such as sodium benzoate and sodium phenylbutyrate), and arginine supplementation to promote alternative pathways for nitrogen excretion. Acute hyperammonemic crises require emergency management, which may include hemodialysis. Liver transplantation can be curative, as it restores urea cycle function, and is considered for patients with severe or recurrent episodes. Newborn screening programs in many countries now include citrullinemia type I, enabling earlier diagnosis and intervention, which has improved outcomes significantly.

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