The carbamoyl phosphate synthetase 1 (CPS1, CPS-I) gene is located on chromosome 2q35 composed of 43 exons that generate three alternatively spliced mRNAs. CPS-1 isoform a is a protein of 1506 amino acids. CPS-1 isoform b is a protein of 1500 amino acids. CPS-1 isoform c is a protein of 1049 amino acids which, unlike the larger isoforms, may not reside within the mitochondria. The functional enzyme exists as a homodimer. The CPS-1 enzyme of the urea cycle is distinct from the CPS-2 enzyme activity of pyrimidine nucleotide biosynthesis, although both the CPS-1 and CPS-2 catalyzed reactions yield carbamoyl phosphate. The CPS-2 activity of nucleotide synthesis is one of three enzymatic activities of the tri-functional enzyme encoded by the CAD gene.
There are at least 25 known mutations in the CPS1 gene that result in carbamoyl phosphate synthetase deficiency (CPSD). CPSD is inherited as an autosomal recessive disorder. Mutations in the CPS1 gene that cause CPSD include missense, nonsense and exon deletions. The frequency of CPSD is approximately 1 per 62,000 live births. Because CPS-1 is responsible for the first reaction of the urea cycle, defects in this gene manifest with the most severe symptoms of all UCDs.
CPSD is, like the other neonatal onset forms of UCDs, most severe when presenting in newborn infants. As with each of the four neonatal onset UCDs, CPSD is characterized by the accumulation of ammonia and glutamine with clinical manifestations appearing in full-term infants with no prior obstetric risk factors. The classic symptoms appear between 24hrs and 48hrs after birth (but not prior to 24hrs) and include convulsions, hyperventilation, ataxia, hypothermia, lethargy, vomiting and poor feeding. If left untreated the hyperammonemia with result in coma and death. The severe effects of hyperammonemia are described in the Nitrogen Metabolism page. Even though sepsis is a rare event in a normal term infant with no prior obstetric complications, this disorder is misdiagnosed in almost half of neonatal UCD cases. Initial laboratory findings will include respiratory alkalosis which is the earliest objective indication of encephalopathy. The encephalopathy will progress to the point where mechanical ventilation is required. Another routine laboratory finding is reduced serum (blood) urea nitrogen (BUN) which may be as low as 1mg/dl (normal for newborns is 3–12mg/dl). If plasma ammonia levels are not measured the infants' death will be attributed to sepsis, intracranial hemorrhage, or some other disorder that would normally be associated with a pre-term delivery.
CPSD patients are treated in much the same ways as for other neonatal UCDs in that protein intake must me highly regulated and the hyperammonemia must be controlled. Hemodialysis is the only effective means to rapidly lower serum ammonia levels in these patients. Acute episodes of hyperammonemia can be treated with intravenous administration of Ammunol® and with oral Buphenyl® for chronic adjunctive therapy of hyperammonemia. Additionally, CPSD patients are treated with a strict dietary regimen that includes 0.7g/kg/day of protein and 0.7g/kg/day of an essential amino acid mixture. The diet is also supplemented with citrulline to serve as a source of arginine. As development proceeds and the need for protein declines it is necessary to adjust the dietary intake of protein accordingly.