Updated: Aug 06, 2019
  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
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Citrulline is the resultant product of the condensation reaction that occurs during normal function of the ornithine transcarbamylase reaction. Under normal circumstances, citrulline is condensed with aspartic acid to form argininosuccinic acid (ASA), which is a reaction mediated by the argininosuccinic acid synthase enzyme. Participation of aspartate in the reaction fixes a second waste nitrogen atom into the reaction product, ASA; the first waste nitrogen molecule derives from free ammonia in the carbamyl phosphate synthetase (CPS) reaction. ASA synthase deficiency leads to accumulation of citrulline, a condition known as citrullinemia.



The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in hyperammonemia (see Hyperammonemia). Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle. See the image below.

Urea cycle. Compounds that comprise the urea cycle Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.

Citrulline can be metabolized outside the liver, and ASA synthase is normally expressed in the brain, kidney, and skin fibroblasts. In citrullinemia, the genetic defect is expressed in all of these tissues. The body is unable to circumvent the defect by conversion of citrulline to arginine, as it can under normal circumstances. As mentioned above, a second waste nitrogen molecule is normally incorporated into the urea cycle by a reaction of citrulline to aspartic acid; however, this reaction is secondarily impaired and results in a 50% reduction of the overall capacity of the urea cycle to dispose of ammonia. Accordingly, affected individuals have a propensity for developing hyperammonemia.

In vitro evidence in rat brains suggests that accumulated citrulline and ammonia impair the organ's antioxidant capacity. L-citrulline added to the cerebral cortex reduced the 30-day-old rat brains’ total radical-trapping antioxidant potential, the total antioxidant reactivity, and specific activities of catalase, superoxide dismutase, and glutathione peroxidase. [1] Therefore, oxidative stress may contribute to the neuropathologic events observed in citrullinemia.

The relationship of the classic disorder citrullinemia to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the adult-onset form of citrin deficiency (both of which manifest citrullinemia) remains unclear because the same gene is implicated in both the latter conditions and the mutations do not seem unique to each. The gene loci for classic citrullinemia and for citrin deficiency reside on separate chromosomes. The citrin gene (SLC25A13) codes for a mitochondrial aspartate-glutamate carrier. NICCD is usually a transient condition, whereas adult-onset citrullinemia is not benign. The pathophysiologic relationship between the mutation and the form of clinical disease has yet to be elucidated. [2, 3]




United States

The incidence of citrullinemia has been inferred from data obtained from several large-scale newborn screening programs. One recent report has set the overall US incidence of all urea cycle disorders as 1 in 35,000 and, of citrullinemia, as 1 in 250,000. [4]


Citrullinemia cases have been reported in Japan that show a particular form of citrullinemia in adults that had been previously undiscovered and untreated; one case was discovered as late as age 48 years. [5, 6] Some patients were developmentally delayed from childhood, whereas others were asymptomatic until onset. Thus, age of onset is as unpredictable in citrullinemia as in ornithine transcarbamylase (OTC) deficiency. Mass screening for the citrin mutation that causes both NICCD and adult-onset citrullinemia has occurred in East Asia.


Morbidity and mortality rates associated with citrullinemia are high.


Citrullinemia is inherited as an autosomal recessive trait; thus, both genders are equally affected.


As with other urea cycle defects, the age of presentation can widely vary among individuals with citrullinemia, although the most common presentation is in the neonatal period. Older children who were not treated in the neonatal period and were diagnosed later as part of an evaluation for the etiology of their mental retardation have been reported.



Consistent with the course of most urea cycle disorders, the degree of intellectual impairment is roughly parallel to the severity of initial presentation and frequency of subsequent hyperammonemic episodes. Subsequent hyperammonemic episodes predictably recur with any intercurrent infection. [7]

With appropriate treatment, survival into adulthood is possible and has been documented.


Patient Education

Both parents of an infant with citrullinemia are assumed to be obligate heterozygotes because citrullinemia is an autosomal recessive trait; therefore, the recurrence rate in every subsequent pregnancy is 1 in 4, or 25%.

Genetic counseling is indicated.

Advise the parents to seek early medical care for the affected child at the earliest signs of infection.

Counsel the parents regarding strict adherence to the prescribed medical regimen.

Prenatal diagnosis is theoretically available, although it is not trivial.