Knowledge on rare diseases and orphan drugs

The worldwide prevalence ranges between 1/526,000-1,300,000 live births.

In the neonatal-onset form of carbamoyl-phosphate synthetase 1 deficiency (CPS1D), patients are usually healthy at birth but after few days they begin to manifest with lethargy and unwillingness to feed. Severe hyperammonemia continues and manifests with vomiting, hypothermia, hypotonia, seizures, coma, and can lead to death. Outside the newborn period, patients can present at any time in life. Risk factors for manifestation include catabolic stressors such as fasting and intercurrent illness. Manifestations include hyperammonemia with irritability, lethargy, headache, seizures, confusion, avoidance of high-protein meals, axial hypotonia and cognitive disability.

CPS1D is due to mutations in the CPS1 gene (2p) that encodes carbamoyl-phosphate synthetase I (CPS1), an enzyme located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa that controls the first step of the urea cycle where ammonia is converted into carbamoyl-phosphate. Mutations in this gene lead to an interruption in the urea cycle and excess nitrogen is not converted to urea for excretion by the kidneys, leading to hyperammonemia.

Diagnosis is based mainly on clinical findings and laboratory test results. Biochemical findings include severe hyperammonemia with very low plasma levels of citrulline and arginine, high plasma levels of glutamine, increased transaminases and low or normal levels of orotic acid in the urine. Molecular genetic testing confirms the diagnosis.

Differential diagnoses mainly include other urea cycle disorders and organic acidurias. Amino acid profiles will distinguish CPS1D from argininosuccinic aciduria, citrullinemia type I and arginase deficiency while orotic acid in urine should help to distinguish from ornithine transcarbamylase deficiency. Another more recent differential diagnosis is hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.

CPS1D is inherited in an autosomal recessive manner; there is a 25% risk of inheriting the disease where both parents are unaffected carriers.

Patients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (EEG surveillance and treatment of seizures, if necessary). A life-long diet low in natural protein, supplements of essential amino acids, citrulline and arginine as needed, nitrogen scavenger therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) and appropriate nutritional support to avoid catabolic stress are recommended. Early liver transplantation for those with neonatal-onset CPS1D can correct metabolic abnormalities but does not reverse any neurological complications. Valproic acid should be avoided.

Prognosis depends on disease severity but is considered bleak in patients with early neonatal disease. With early diagnosis and optimal treatment started without any delay, the prognosis improves. Episodes of hyperammonemic coma of long duration are associated with a poor neurological outlook.

Last update: October 2019 - Expert reviewer(s): Pr Johannes HÄBERLE