Citrullinemia Type I

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
[updated ].


Clinical characteristics: Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form (the "non-classic" form), a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals.

Diagnosis/testing: The diagnosis of CTLN1 is established in a proband with elevated plasma ammonia concentration (>150 µmol/L; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) and/or by the identification of biallelic pathogenic variants in ASS1 on molecular genetic testing.

Management: Treatment of manifestations: Acute management of hyperammonemia involves rapidly lowering plasma ammonia concentration using pharmacologic nitrogen scavenger therapy (sodium benzoate, sodium phenylacetate, and arginine) or hemodialysis, if scavenger therapy fails; reversal of catabolism via intravenous glucose infusion and intralipids or protein-free enteral nutrition, if tolerated; and control of intracranial pressure. Chronic management involves lifelong dietary management to maintain plasma ammonia concentration lower than100 µmol/L and near-normal plasma glutamine concentration; oral administration of sodium phenylbutyrate or glycerol phenylbutyrate; L-carnitine to prevent systemic hypocarnitinemia. Liver transplantation, the only known cure for CTLN1, is best performed between age three months (and/or attainment of 5 kg body weight) and one year to decrease complications and improve survival; liver transplantation does not reverse any neurologic sequelae present at the time of transplant. Prevention of secondary complications: Medical attention during intercurrent infections to prevent hyperammonemia; routine vaccinations including annual influenza vaccine. Surveillance: Routine follow up in a metabolic clinic; monitoring for hyperammonemia and secondary deficiency of essential amino acids; monitoring older individuals for signs of impending hyperammonia (i.e., mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus) and elevated plasma glutamine concentration. Monitoring should be frequent in neonates and infants, based on disease severity, but may be extended to every six months to annually in older individuals, depending on clinical stability. Agents/circumstances to avoid: Excess protein intake; exposure to communicable diseases. Evaluation of relatives at risk: In utero diagnosis if the pathogenic variants in the family are known permits appropriate oral therapy beginning with the first feeds. Alternatively, sibs should be evaluated on day one of life by measurement of plasma concentrations of ammonia and citrulline; elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment.

Genetic counseling: Citrullinemia type I is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

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