Citrullinemia

Citrullinemia is a rare inherited disorder of the urea cycle, the metabolic pathway responsible for removing ammonia (a toxic waste product of protein metabolism) from the body. There are two main forms: Citrullinemia type I (classic citrullinemia, also known as argininosuccinate synthetase deficiency or CTLN1) and Citrullinemia type II (also known as citrin deficiency or CTLN2). Both forms result in the accumulation of ammonia (hyperammonemia) and citrulline in the blood, which can cause serious damage to the nervous system. Citrullinemia type I is caused by mutations in the ASS1 gene, which encodes argininosuccinate synthetase, a key enzyme in the urea cycle. The severe neonatal form presents within the first few days of life with poor feeding, vomiting, lethargy, seizures, and potentially life-threatening hyperammonemic crises that can lead to cerebral edema, coma, and death if untreated. Milder forms may present later in infancy, childhood, or even adulthood with episodic hyperammonemia triggered by illness or high protein intake. Citrullinemia type II is caused by mutations in the SLC25A13 gene encoding citrin, a mitochondrial aspartate-glutamate carrier. In infants, citrin deficiency may present as neonatal intrahepatic cholestasis (NICCD), which often resolves spontaneously. However, some individuals develop adult-onset type II citrullinemia (CTLN2) characterized by recurrent hyperammonemia, neuropsychiatric symptoms, fatty liver, and a peculiar preference for protein-rich and lipid-rich foods with an aversion to carbohydrates. Treatment for citrullinemia type I includes dietary protein restriction, nitrogen-scavenging medications (such as sodium benzoate and sodium phenylbutyrate), and arginine supplementation to facilitate alternative pathways for nitrogen excretion. Acute hyperammonemic crises require emergency treatment, which may include hemodialysis. Liver transplantation can be curative for both types and is considered for patients with severe or recurrent disease. For citrullinemia type II, avoidance of excessive carbohydrate intake and medium-chain triglyceride supplementation may be beneficial, and liver transplantation is the definitive treatment for adult-onset CTLN2. Early diagnosis through newborn screening programs, which can detect elevated citrulline levels, has improved outcomes significantly.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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