AUTHOR INFORMATION

Section 1 of 11

Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, July 22 2005, VOLUME 6, Number 7

INTRODUCTION

Section 2 of 11

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. Deficiency of ASA synthase leads to accumulation of citrulline, or citrullinemia.

Pathophysiology: The hepatic urea cycle is the major route for waste nitrogen disposal, generation of which is chiefly from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal as well. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in 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 of 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, by reaction of citrulline with aspartic acid, a second waste nitrogen molecule is incorporated into the urea cycle; however, this reaction is impaired and results in reduction of the overall capacity of the urea cycle to dispose of ammonia by 50%. Accordingly, affected individuals have a propensity for developing hyperammonemia.

Frequency:

• In the US: 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.

• Internationally: Cases have been reported in Japan that show, among adults, a particular form of citrullinemia that previously had been undiscovered and untreated, one case was discovered as late as age 48 years. Some of the patients were developmentally delayed from childhood, but 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 causing both neonatal intrahepatic cholestasis and adult-onset citrullinemia has been accomplished in East Asia.

Mortality/Morbidity: Morbidity and mortality are high.

Sex:

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

Age:

• As with other urea cycle defects, the age of presentation can be widely variable, though the most common presentation is in the neonatal period. Reports exist of older children who have survived the neonatal period untreated to be diagnosed later as part of an evaluation for the etiology of their mental retardation.

CLINICAL

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History:

• At least 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, are somewhat variable in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually; however, the common denominator, hyperammonemia, can be manifested clinically by 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)
  
  
  
• As a consequence, 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 will lead the physician to obtain a blood ammonia level. 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 that is based on a good history will 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 impairing function of the mitochondrial malate-aspartate shuttle. The abnormal protein which affects this impairment is called citrin and is encoded by the SLC25A13 gene at locus 7q21.3. It is noteworthy that a specific form of neonatal intrahepatic cholestasis is also due to a mutation in the same gene. It is unclear at this time whether such infants will be affected by the adult form of citrullinemia later in life.

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 latter stages.
  
  
  
• Abdominal: Hepatomegaly may be present and is usually mild if present.



• Neurologic


• • Poor coordination
  
  
  
  • Dysdiadochokinesia
  
  
  
  • Hypotonia or hypertonia
  
  
  
  • Ataxia
  
  
  
  • Tremor
  
  
  
  • Seizures and hypothermia
  
  
  
  • Lethargy progressing to combativeness to obtundation to coma
  
  
  
  • Decorticate or decerebrate posturing
  
  
  

Causes:

• This 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 neonatal intrahepatic cholestasis. The etiologic connection between the two latter 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.

DIFFERENTIALS

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Arginase Deficiency
Argininosuccinate Lyase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Hyperammonemia
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Hyperinsulinemia
Methylmalonic Acidemia
N-Acetylglutamate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

Other Problems to be Considered:

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

WORKUP

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Lab Studies:

• In a symptomatic patient, the measurement of blood ammonia is the primary laboratory test in diagnosis. No other routinely obtained study provides diagnostically useful information.



• Quantitative measurement of blood amino acids is the next immediate step. In the affected patient, citrulline is unmistakably elevated. In such cases, analyzing urine amino acids, urine organic acids, and urine orotic acid is important. Orotic acid in urine is abnormally elevated in citrullinemia.



• Measurement of ASA synthase in cultured skin fibroblasts can provide the unequivocal biochemical diagnosis.

TREATMENT

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Medical Care:

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



• Intravenous sodium benzoate, sodium phenylacetate, and arginine are important therapeutic avenues for reduction of blood ammonia. IV benzoate/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 dosage of sodium phenylbutyrate and arginine.



• In every case, a biochemical geneticist should administer definitive acute and long-range treatment with sufficient laboratory backup to obtain rapid ammonia and amino acid measurements.

Consultations:

• Medical genetics/metabolic disease



• Dietitian

MEDICATION

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Drug Category: Metabolic agents -- The use of benzoate and phenylacetate is based on the need to provide alternate routes for disposition of waste nitrogen. 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 2 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 benzoate (Ucephan) -- Combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes l mol of nitrogen. The oral product Ucephan is a combination of sodium benzoate 10 g and sodium phenylacetate 10 g per 100 mL (100 mg of each/mL).
Pediatric Dose	Loading dose: 250 mg/kg IV infused over 90 min Maintenance dose: 250 mg/kg IV infused over 24 h Dilute IV dose in 30 mL/kg of dextrose 10% Oral maintenance dose: 375 mg/kg/d PO divided tid/qid in conjunction with a low-protein diet
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); because of sodium content, exercise caution when administering to patients with CHF, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbances

Drug Name	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.
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) -- 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 subjects with intact pituitary function.
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: only perform administration 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

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Further Outpatient Care:

• Patients must be under the ongoing care of a biochemical geneticist/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 acids 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 follow a case of 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 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 will predictably recur with any intercurrent infection. With appropriate treatment, survival into adulthood is possible and has been documented.

Patient Education:

• As citrullinemia is an autosomal recessive trait, both parents of an affected infant are assumed to be obligate heterozygotes; 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 with the earliest signs of infection.



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



• Prenatal diagnosis is theoretically available, though not trivial.

MISCELLANEOUS

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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.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Why is the reaction leading to further metabolism of citrulline of vital importance?

A: Citrulline is toxic.
B: The reaction product, argininosuccinic acid (ASA), is an essential amino acid.
C: It prevents formation of glutamine.
D: It is the place where aspartic acid enters the urea cycle.
E: None of the above

The correct answer is D: Incorporation of aspartic acid into the formation of ASA results in a second waste nitrogen, which is eliminated as a source of free ammonia.

CME Question 2: Which of the following is true of citrullinemia?

A: It occurs only in females.
B: It must be a part of the differential diagnosis of developmental delay.
C: It can be diagnosed only by liver biopsy.
D: It never occurs in adults.
E: All of the above

The correct answer is B: Citrullinemia may escape notice in the early period of infancy, as do other urea cycle disorders. Although the patient may have absent hyperammonemic crises in the history, subclinical episodes, which have a cumulative effect on the CNS and cause developmental delay, may still be frequent. Thus, amino acid quantitation of blood and urine should always be part of an evaluation of this clinical state.

Pearl Question 1 (T/F): The liver is the only tissue in which citrulline can be metabolized.

The correct answer is False: The brain, kidney, and skin also express the argininosuccinic acid (ASA) synthase enzyme, which normally leads to formation of ASA. It is this fact that allows relatively easy confirmation of the diagnosis by enzyme assay in cultured skin fibroblasts.

Pearl Question 2 (T/F): The rationale for withdrawal of dietary protein is to prevent citrulline intoxication.

The correct answer is False: The difficulty lies not with citrulline intoxication from dietary sources but a failure to incorporate waste nitrogen, which is derived from all amino acid constituents of dietary protein.

Pearl Question 3 (T/F): Sodium benzoate is used in the treatment of citrullinemia because of its role in the reduction of blood ammonia.

The correct answer is True: Benzoate, which is often used as a food preservative, is metabolized in the liver to hippuric acid by conjugation with glycine. Hippurate is excreted rapidly through the kidneys. Thus, a mol-for-mol relationship exists between the amount of benzoate conjugated and the excretion of a potential source of free ammonia. Moreover, because glycine is not an essential amino acid, each mol excreted as a benzoate conjugate is resynthesized, leading to additional incorporation of ammonia.

Pearl Question 4 (T/F): Intercurrent infections in a patient on chronic treatment of citrullinemia should be a concern.

The correct answer is True: Intercurrent infections are a source of metabolic stress, often accompanied by diminished oral intake. Thus, the body is vulnerable to a catabolic state, in which endogenous protein is broken down into constituent amino acids for use as gluconeogenic substrate. This leads to release of additional free ammonia, thereby imposing additional stress on the impaired urea cycle.

BIBLIOGRAPHY

Section 11 of 11

• Berry GT, Steiner RD: Long-term management of patients with urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S56-S62.
• 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 2003 Apr; 45(2): 196-8[Medline].
• Issa AR, Yadav G, Teebi AS: Intrafamilial phenotypic variability in citrullinemia: report of a family. J Inherit Metab Dis 1988; 11(3): 306-7[Medline].
• Kennaway NG, Harwood PJ, Ramberg DA: Citrullinemia: enzymatic evidence for genetic heterogeneity. Pediatr Res 1975 Jun; 9(6): 554-8[Medline].
• Kuhara H, Wakabayashi T, Kishimoto H: Neonatal type of argininosuccinate synthetase deficiency. Report of two cases with autopsy findings. Acta Pathol Jpn 1985 Jul; 35(4): 995-1006[Medline].
• Matsuda I, Anakura M, Arashima S: A variant form of citrullinemia. J Pediatr 1976 May; 88(5): 824-6[Medline].
• Morrow G 3d, Barness LA, Efron ML: Citrullinemia with defective urea production. Pediatrics 1967 Oct; 40(4): 565-74[Medline].
• 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.
• Steiner RD, Cederbaum SD: Laboratory evaluation of urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S21-S29.
• Tamamori A, Fujimoto A, Okana Y: Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res 2004; 56: 608-614.
• Tazawa Y, Kobayashi K, Abukawa D: Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: cawse reports from 16 patients. Mol Genet Metab 2004; 83: 213-219.
• 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].

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