AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

Pathophysiology

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.

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 incorporated into the urea cycle by a reaction of citrulline to aspartic acid; however, this reaction is 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 disorder to a condition known as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) remains unclear because the same gene is implicated in both conditions and the mutations do not seem unique to each. 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

Frequency

United States

Incidence cannot be cited because of the lack of population-screening data. Recent developments in expanded metabolic screening may soon lead to a better understanding of the incidence of neonatal citrullinemia.

International

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. 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.

Mortality/Morbidity

Morbidity and mortality rates are high.

Sex

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

Age

• As with other urea cycle defects, the age of presentation can widely vary, 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• At least one half of genetically affected newborns 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. 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. 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.

Physical

• General
  
  
  • Signs of severe hyperammonemia may be present.
  • 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.
• Pulmonary
  
  
  • Tachypnea or hyperpnea may be present.
  • Apnea and respiratory failure may occur in later stages.
• Abdominal: Hepatomegaly may be present and is usually mild.
• Neurologic
  
  
  • Poor coordination
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy progressing to combativeness, obtundation, and coma
  • Decorticate or decerebrate posturing

Causes

• Citrullinemia is an autosomal recessive genetic condition. The gene has been mapped to chromosome 9 and has a locus at band 9q34. 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 20 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.
• 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).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency or dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In patients 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 ASA synthase in cultured skin fibroblasts can provide an unequivocal biochemical diagnosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Consultations

• Geneticist
• Metabolic disease specialist
• Dietitian

Diet

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Metabolic agents

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.

Drug Name	Sodium phenylbutyrate (Buphenyl)
Description	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.
Pediatric Dose	0.5 g/kg/d PO divided tid pc
Contraindications	Documented hypersensitivity; severe hypertension; heart failure; renal dysfunction; acute hyperammonemia
Interactions	Valproate and haloperidol may increase ammonia levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema

Drug Name	Arginine (R-Gene 10)
Description	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).
Pediatric Dose	Hyperammonemic crisis: Loading dose: 600 mg/kg IV (not to exceed 1 g/kg/h) IV maintenance dose: 600 mg/kg/d IV as a continuous infusion Dilute IV in 30 mL/kg of dextrose 10% Maintenance treatment in a stable child: 400-700 mg (as free base)/kg/d PO
Contraindications	Documented hypersensitivity; renal or hepatic failure
Interactions	Coadministration with amphotericin, triamterene, amiloride, or spironolactone may increase risk of hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal impairment; diagnostic aid not intended for therapeutic use: administer only in a large medical facility with close laboratory monitoring available; may cause nausea, vomiting, headache, hyperkalemia, hyperglycemia, or venous irritation during IV administration

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients 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.

Transfer

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

Deterrence/Prevention

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

Complications

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

Prognosis

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

Patient Education

• Both parents of an affected infant 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Suspect hyperammonemia in all infants and children with unexplained neurologically related symptoms and signs. Failure to do so may result in missed diagnosis of a treatable disorder.
• Failure to establish a diagnosis in a proband may result in subsequent infants in the family with the same disease.

Special Concerns

Adults with hepatic cirrhosis unassociated with most common causes, such as long-term alcohol consumption, should be evaluated for the adult-onset form of citrullinemia. This condition has been most frequently reported in Japan and was initially described in that country, probably leading to a heightened clinical awareness not shared in the United States. Thus, the disorder could be significantly more common than originally believed. 

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Prestes CC, Sgaravatti AM, Pederzolli CD, et al. Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro. Metab Brain Dis. Mar 2006;21(1):63-74. [Medline].
2. Saheki E, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the casue of adult-onset type II citrullinemia(CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002;47:333-341.
3. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S56-S62. [Medline].
4. Hayakawa M, Kato Y, Takahashi R, Tauchi N. Case of citrullinemia diagnosed by DNA analysis: including prenatal genetic diagnosis from amniocytes of next pregnancy. Pediatr Int. Apr 2003;45(2):196-8. [Medline].
5. Issa AR, Yadav G, Teebi AS. Intrafamilial phenotypic variability in citrullinaemia: report of a family. J Inherit Metab Dis. 1988;11(3):306-7. [Medline].
6. Kennaway NG, Harwood PJ, Ramberg DA, Koler RD, Buist NR. Citrullinemia: enzymatic evidence for genetic heterogeneity. Pediatr Res. Jun 1975;9(6):554-8. [Medline].
7. Kuhara H, Wakabayashi T, Kishimoto H, et al. Neonatal type of argininosuccinate synthetase deficiency. Report of two cases with autopsy findings. Acta Pathol Jpn. Jul 1985;35(4):995-1006. [Medline].
8. Matsuda I, Anakura M, Arashima S, Saito Y, Oka Y. A variant form of citrullinemia. J Pediatr. May 1976;88(5):824-6. [Medline].
9. Morrow G 3rd, Barness LA, Efron ML. Citrullinemia with defective urea production. Pediatrics. Oct 1967;40(4):565-74. [Medline].
10. Ohura T, Kobayashi K, Tazawa Y, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis. Apr 2007;30(2):139-44. [Medline].
11. Saheki T, Kobayashi K, Iijima M, et al. Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatol Res. Oct 2005;33(2):181-4. [Medline].
12. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].
13. Tamamori A, Fujimoto A, Okano Y, et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. Oct 2004;56(4):608-14. [Medline].
14. Tazawa Y, Kobayashi K, Abukawa D, et al. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab. Nov 2004;83(3):213-9. [Medline].
15. Walter JH, Allen JT, Holton JB. Arginosuccinate synthetase deficiency: good outcome despite severe neonatal hyperammonemia. J Inherit Metab Dis. 1992;15(2):282-3. [Medline].

Article Last Updated: Jul 12, 2007