Carbamoyl-phosphate synthetase 1 deficiency

Carbamoyl-phosphate synthetase 1 (CPS1) deficiency is a rare inherited disorder of the urea cycle, caused by mutations in the CPS1 gene located on chromosome 2q34. CPS1 is a mitochondrial enzyme that catalyzes the first committed step of the urea cycle, which is the primary pathway for removing excess nitrogen (in the form of ammonia) from the body. When this enzyme is deficient or absent, ammonia accumulates in the blood (hyperammonemia), leading to severe and potentially life-threatening toxicity, particularly to the brain and central nervous system. The disease most commonly presents in the neonatal period, typically within the first few days of life, with symptoms including poor feeding, vomiting, lethargy, hypothermia, hyperventilation, and rapidly progressive encephalopathy that can lead to coma and death if untreated. A late-onset (partial deficiency) form also exists, which may present in infancy, childhood, or even adulthood, often triggered by physiological stress such as illness, surgery, or high-protein intake. Symptoms in late-onset cases can include episodic vomiting, developmental delay, intellectual disability, behavioral abnormalities, and recurrent episodes of hyperammonemia. Treatment involves acute management of hyperammonemic crises with intravenous sodium benzoate and sodium phenylacetate (or phenylbutyrate) to provide alternative pathways for nitrogen excretion, along with hemodialysis in severe cases. Long-term management includes dietary protein restriction, supplementation with citrulline or arginine, and nitrogen-scavenging medications such as sodium phenylbutyrate or glycerol phenylbutyrate. Liver transplantation is considered a curative treatment and may be recommended for patients with severe, recurrent hyperammonemia or poor metabolic control despite medical management. Despite treatment, neurological outcomes depend heavily on the severity and duration of hyperammonemic episodes, particularly in the neonatal period.

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