Updated: Aug 06, 2019
Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD 



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.




At least one half of newborns with citrullinemia present in the first several days of life.

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, urea cycle defects are considered individually; however, the common denominator, hyperammonemia, can manifest clinically as some or all of the following:

  • Anorexia

  • Irritability

  • Heavy or rapid breathing

  • Lethargy

  • Vomiting

  • Disorientation

  • Somnolence

  • Asterixis (rare)

  • Combativeness

  • Obtundation

  • Coma

  • Cerebral edema

  • Death (if treatment is not forthcoming or effective)

The most striking clinical findings of each individual urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.

No routine laboratory studies provide a diagnostic clue, and only a high index of suspicion can prompt the physician to obtain a blood ammonia measurement. The need for a high index of suspicion cannot be sufficiently emphasized.

In the face of intercurrent illness, other affected children experience delayed development from infancy with exaggerated lethargy and vomiting. Again, only a high index of suspicion based on a thorough history can lead to proper diagnosis.

The adult form of citrullinemia has been reported almost exclusively in Japan, and these cases are associated with unusual self-selection of diet.[8] {ref628-INVALID REFERENCE} These individuals have been shown by DNA studies to be affected by a mutation that impairs function of the mitochondrial malate-aspartate shuttle. The abnormal protein that affects this impairment is called citrin and is encoded by the SLC25A13 gene at locus 7q21.3. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is also due to a mutation in the same gene. Whether such infants will be affected by the adult form of citrullinemia later in life is unclear.



Signs of severe hyperammonemia may be present in citrullinemia (see History).

Poor growth may be evident.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.


Tachypnea or hyperpnea may be present.

Apnea and respiratory failure may occur in later stages.


Hepatomegaly may be present and is usually mild.


See the list below:

  • Poor coordination

  • Dysdiadochokinesia

  • Hypotonia or hypertonia

  • Ataxia

  • Tremor

  • Seizures and hypothermia

  • Lethargy progressing to combativeness, obtundation, and coma

  • Decorticate or decerebrate posturing


Citrullinemia is an autosomal recessive genetic condition. The gene has been mapped to chromosome 9 and has a locus at band 9q34.[9, 10, 6] The adult-onset type is caused by mutation at locus 7q21.3 and, therefore, must be considered a separate disorder; the same mutation also causes NICCD. The etiologic connection between the 2 clinical entities remains problematic.

At least 137 distinct mutations have been reported. Most of them are single-base substitutions that cause missense mutations that result in an enzyme protein with abnormal kinetic properties.[11]

Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms (see Arginase Deficiency).


Complications of citrullinemia are chiefly neurological, including mental retardation, acute hyperammonemic coma, and death.





Laboratory Studies

In patients with citrullinemia who are symptomatic, the measurement of blood ammonia levels is the primary laboratory test in diagnosis. No other routinely obtained study provides diagnostically useful information.

Quantitative measurement of blood amino acid levels is the next immediate step. Citrulline levels are unmistakably elevated in patients with citrullinemia. In such patients, urine amino acid, urine organic acid, and urine orotic acid levels should be analyzed. Orotic acid levels in urine are abnormally elevated in citrullinemia.

Measurement of argininosuccinic acid (ASA) synthase in cultured skin fibroblasts can provide an unequivocal biochemical diagnosis.

Molecular analysis of the gene should be pursued to establish the nature of the mutation, which can be used for prenatal diagnostic studies.

In neonates who are jaundiced and have normal or mildly elevated ammonia levels, hypercholesterolemia suggests citrin deficiency.[12, 3]

Imaging Studies

MRI of the brain in affected infants shows several associated abnormalities, the extent of which are helpful in predicting neurological outcomes.[13, 14, 15]

Other Tests

New experimental data in a mouse model have suggested that T-cell function may be impaired in individuals with citrullinemia.[16]



Medical Care

As in all hyperammonemic states, immediately restrict dietary protein in patients with citrullinemia. Emphasize other nonprotein caloric sources to compensate.

Intravenous sodium benzoate, sodium phenylacetate, and arginine are important therapeutic avenues for reduction of blood ammonia levels. Intravenous benzoate and phenylacetate are investigational new drugs. In severe cases, hemodialysis may be indicated to rapidly reduce the blood ammonia level.

Long-term management requires close dietary monitoring and oral administration of sodium phenylbutyrate and arginine.

In every case, a biochemical geneticist should administer definitive short- and long-term treatment with sufficient laboratory backup to obtain rapid ammonia and amino acid levels.

Surgical Care

As is the case for the other members of the family of urea cycle disorders, liver transplantation can be performed. The procedure has been used in several cases with excellent results,[17] the most successful report being that of a partial orthoptic transplant from a sibling in an adult (type II) patient.[18]


See the list below:

  • Geneticist

  • Metabolic disease specialist

  • Dietitian


As in all hyperammonemic states, immediately restrict dietary protein in patients with citrullinemia.

Emphasize other nonprotein caloric sources to compensate.


Prenatal diagnosis of citrullinemia is possible and is available at academic centers. Molecular diagnosis is possible, using amniocytes or chorionic villi.

Further Outpatient Care

Patients with citrullinemia must be under the ongoing care of a biochemical geneticist or metabolic disease specialist with expertise in the care of urea cycle disorders.

A trained nutritionist should monitor the low-protein diet, which is essential in treatment.

Frequent monitoring of growth and blood amino acid levels is imperative in order to make adjustments before essential amino acid levels fall below normal and the child becomes catabolic.

Under no circumstances should a primary care provider provide follow-up for a patient with citrullinemia without the frequent input of a specialist.


Any infant or child noted to have hyperammonemia should be considered for transfer to a medical center for further evaluation.



Medication Summary

Intravenous sodium benzoate, sodium phenylacetate, and arginine are important therapeutic avenues for reduction of blood ammonia levels.

Metabolic agents

Class Summary

The use of benzoate and phenylacetate is based on the need to provide alternate routes for waste nitrogen disposal. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl CoA and then conjugated with glutamine to form phenylacetylglutamine. Each of these pathways results in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)

Combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. The oral product (Ucephan) and IV product (Ammonul) contain a combination of sodium benzoate (10 g) and sodium phenylacetate (10 g per 100 mL; 100 mg of each/mL).

Sodium phenylbutyrate (Buphenyl)

Prodrug rapidly converted orally to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine, carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste.

Arginine (R-Gene 10)

Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase. Pituitary stimulant for the release of human growth hormone (HGH). Often induces pronounced HGH levels in patients with intact pituitary function. Available as 10% injection (100 mg/mL).