Late-onset citrullinemia type I

Late-onset citrullinemia type I (also known as late-onset or mild form of classical citrullinemia, or late-onset argininosuccinate synthetase deficiency) is a rare inherited metabolic disorder caused by deficiency of the enzyme argininosuccinate synthetase 1 (ASS1), which plays a critical role in the urea cycle. The urea cycle is the metabolic pathway in the liver responsible for converting toxic ammonia into urea for excretion. Unlike the severe neonatal form of citrullinemia type I, this late-onset variant presents later in life — from childhood through adulthood — and typically follows a milder clinical course, though episodes of hyperammonemia can still be life-threatening. The condition primarily affects the liver and the central nervous system. Patients may remain asymptomatic for years until a metabolic crisis is triggered by physiological stress such as illness, surgery, fasting, high-protein meals, or pregnancy. During hyperammonemic episodes, patients can experience confusion, lethargy, behavioral changes, headaches, vomiting, seizures, ataxia, and in severe cases, coma. Chronic or recurrent hyperammonemia can lead to cognitive impairment and neurological damage. Laboratory findings characteristically show elevated plasma citrulline levels and elevated blood ammonia during crises. Management focuses on preventing hyperammonemic crises and includes dietary protein restriction, nitrogen-scavenging medications such as sodium benzoate and sodium phenylbutyrate, and arginine supplementation to support residual urea cycle function. Acute hyperammonemic episodes require emergency treatment with intravenous nitrogen scavengers and, in some cases, hemodialysis. Liver transplantation may be considered in patients with recurrent severe crises refractory to medical management. Genetic counseling is recommended for affected families, as the condition is inherited in an autosomal recessive manner, caused by pathogenic variants in the ASS1 gene located on chromosome 9q34.11.

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