Citrullinemia

Citrullinemia is a rare inherited disorder of the urea cycle characterized by elevated plasma citrulline, often with hyperammonemia. It results from impaired conversion of citrulline to argininosuccinate, most commonly due to defects in argininosuccinate synthetase (ASS1) or related transporters. The condition is usually autosomal recessive and can present in infancy or adulthood depending on the form.

Type I citrullinemia (ASS1 deficiency) typically presents in the neonatal period with poor feeding, vomiting, lethargy, hypotonia, and seizures. Untreated hyperammonemia can cause encephalopathy and death. Diagnosis shows high citrulline and ammonia; genetic testing confirms ASS1 mutations. Management includes a protein-restricted diet, essential amino acid supplementation, arginine to support residual urea-cycle activity, and ammonia-scavenging therapies during crises; liver transplantation may be considered in severe cases.

Type II citrullinemia, or citrin deficiency, results from SLC25A13 mutations and usually presents later in life with intermittent hyperammonemia, often triggered by fasting or illness, and sometimes with hepatocellular disease. It is more common in certain populations. Treatment emphasizes preventing catabolism with regular, carbohydrate-rich meals, avoiding prolonged fasting, and strategies to reduce ammonia and citrulline levels; liver disease influences prognosis.

Diagnosis relies on plasma amino acid profiling showing elevated citrulline and ammonia, with confirmation by genetic testing. Newborn screening can detect elevations of citrulline in some programs. The prognosis varies by age of onset, severity, and response to treatment, but early recognition and management improve outcomes. Regular follow-up with metabolic specialists is recommended.