Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset 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 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.
Citrullinemia type I results from deficiency of the enzyme argininosuccinate synthase (ASS), the third step in the urea cycle, in which citrulline is condensed with aspartate to form argininosuccinic acid. Untreated individuals with the severe form of citrullinemia type I have hyperammonemia (plasma ammonia concentration 1000-3000 micromol/L). Plasma quantitative amino acid analysis shows absence of argininosuccinic acid and concentration of citrulline usually greater than 1000 micromol/L (normal: <50 micromol/L). Argininosuccinate synthase enzyme activity, measured in fibroblasts, liver, and in all tissues in which ASS is expressed, is decreased. Molecular genetic testing of ASS1, the only gene in which mutation is known to cause citrullinemia type I, is clinically available.
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 disease-causing mutations in the family are known.