Newborn screening · Amino acid disorder
Citrullinemia, Type I · CIT-I
Urea cycle disorder. Severe neonatal hyperammonemia in classic form; milder late-onset forms exist.
Description
Citrullinemia type I, CTLN1, is an autosomal recessive urea cycle disorder. Pathogenic variants in ASS1 reduce or abolish the activity of argininosuccinate synthetase, the cytosolic enzyme that condenses citrulline and aspartate to argininosuccinate in the third step of the urea cycle. Without functional enzyme, ammonia cannot be efficiently cleared, citrulline accumulates in plasma, and arginine becomes conditionally essential. The causative gene is ASS1 on chromosome 9q34.
Clinical presentation falls along a severity spectrum. The classic neonatal-onset form presents in the first days of life with progressive lethargy, poor feeding, vomiting, hyperventilation, and seizures, driven by severe hyperammonemia. Without rapid recognition and treatment, neonatal hyperammonemia produces cerebral edema, coma, and lasting neurologic injury or death. Late-onset forms present in childhood or adulthood with milder, episodic hyperammonemia triggered by infection, surgery, prolonged fasting, high-protein intake, or the postpartum period. Some adults remain effectively asymptomatic until a metabolic stressor unmasks the disease.
Detection is by newborn screening on the dried blood spot using tandem mass spectrometry. The primary marker is elevated citrulline. Confirmation uses plasma amino acids, urine orotic acid, plasma ammonia, and ASS1 sequencing. Reported live-birth incidence in general newborn screening populations is roughly 1 in 50,000 to 1 in 250,000, with classic neonatal-onset disease the rarer end of that range. Citrullinemia type I is on the US RUSP core panel and is biochemically and clinically distinct from citrullinemia type II, which is caused by SLC25A13 variants.
Treatments to date
Acute neonatal hyperammonemia is a metabolic emergency. Treatment combines protein restriction, intravenous dextrose and lipid to reverse catabolism, intravenous arginine, intravenous nitrogen scavengers, and hemodialysis or continuous renal replacement therapy when ammonia rises above accepted thresholds or fails to fall promptly. Speed to dialysis is the central determinant of neurologic outcome.
Long-term management combines a protein-restricted diet supervised by a metabolic dietitian, oral arginine or citrulline supplementation as appropriate, and oral nitrogen scavengers. Sodium phenylbutyrate, marketed as Buphenyl, was approved by the FDA in 1996 for chronic management of urea cycle disorders, including citrullinemia. Glycerol phenylbutyrate, marketed as Ravicti, was approved by the FDA in 2013 for chronic management of urea cycle disorders in adults and pediatric patients aged two months and older, and the lower age limit was later expanded to include all ages. Sodium benzoate and sodium phenylacetate, marketed as Ammonul, was approved by the FDA in 2005 for intravenous adjunctive treatment of acute hyperammonemia.
Liver transplantation is curative for the urea cycle defect and is offered to children with severe disease, recurrent hyperammonemic crises, or poor metabolic control on medical therapy. Outcomes after transplant are generally good, with normalization of ammonia handling and liberalization of diet, although neurologic deficits incurred before transplant do not reverse. No gene therapy is approved. Several investigational mRNA and gene therapy programs targeting urea cycle disorders, including citrullinemia type I, have entered early-phase clinical trials.