Citrullinemia is inherited in an autosomal recessive pattern. Normally a person has two functional ASS1 genes. In people with citrullinemia, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with citrullinemia typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.
Carriers of citrullinemia do not typically have symptoms.
The symptoms of citrullinemia are variable and there are three different types (classic neonatal-onset, mild later-onset, asymptomatic). The classic neonatal form is very serious. Infants appear healthy at birth, but can quickly become lethargic, begin vomiting and having seizures, and develop increased intracranial pressure. Untreated, infants can progress to coma and death. Infants with the milder form are at risk for similar symptoms to the neonatal form, but they are less severe.
- Incidence: The overall incidence is approximately 1 in 57,000 births.
- New York State Method of Screening (first tier): Screening for citrullinemia is accomplished by measuring citrulline by tandem mass spectrometry (MS/MS).
- Confirmatory testing (second tier): None
- Testing can be affected by: Screening for this disorder is not reliable in newborns receiving total parenteral nutrition.
- Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
- Referral to Specialty Care Center: Patients with an abnormal newborn screen for citrullinemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of citrullinemia.
Diagnostic testing may include quantification of plasma amino acids, ammonia, argininosuccinate synthase enzyme activity and molecular genetic testing of the ASS1 gene.
Treatment is usually a protein restricted diet and medication to remove nitrogen from the body (sodium benzoate and phenylacetate). If ammonia is very elevated from high protein meals, fasting or illness, in-patient treatment including intravenous fluids, sodium benzoate, phenylacetate and dietary management may be required. If these treatments fail, hemodialysis may be needed. There have been reports of liver transplants as a treatment for citrullinemia.
Prognosis is poor for the neonatal onset form. Infants that receive prompt treatment may survive, but often have remaining neurological symptoms. Prognosis for the milder form is variable, and dependent on response to treatment.
Citrullinemia is a urea cycle disorder (inherited metabolic disorder).
Type 1 citrullinemia is caused by mutations in the ASS1 gene. Individuals with mutations in ASS1 have low or absent argininosuccinate synthase enzyme activity, which is needed for the third step of the urea cycle. The urea cycle is a process in the liver to remove nitrogen from the body. Nitrogen (in the form of ammonia) accumulates in the body. The accumulation of ammonia is highly toxic.