AUTHOR INFORMATION

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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 Uri S Alon, MD, Director of Research and Education, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri at Kansas City; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; 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:	Uri S Alon, MD

eMedicine Journal, March 16 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: Normal enzyme function of N-acetylglutamate synthetase (NAGS) deficiency is confined to the hepatic mitochondria and mediates the reaction acetyl-coenzyme A (CoA) + glutamate ® N-acetylglutamate + CoA. As a mitochondrial reaction, each of the substrates normally is omnipresent. Acetyl-CoA is a cofactor in many mitochondrial reactions, and glutamate is the transamination product of a-ketoglutarate and alanine; a-ketoglutarate is produced by the Krebs cycle.

The normal function of N-acetylglutamate (NAG), the reaction product, is to act as an activator of carbamyl phosphate synthetase (CPS) (see Image 1), which is also a mitochondrial enzyme. The activation process requires physical binding of NAG to the CPS enzyme, in turn, causing the inactive form of CPS to convert to an active state. Thus, CPS activity is regulated by the relationship of available NAG to inactive CPS enzyme protein.

The biochemical effect of NAGS deficiency is an inability to form adequate NAG; this results in failure to activate the enzyme responsible for the reaction NH₄⁺ + CO₂ + ATP ® H₂N-CO-PO₃^2- + ADP, which is the entry step into the urea cycle (see Carbamyl Phosphate Synthetase Deficiency).

Clinical signs and symptoms of NAGS deficiency occur when ammonia fails to fix into carbamoyl phosphate (CP) effectively, thus disabling the urea cycle. This leads to accumulation of alanine and glutamine (transamination products of pyruvate and glutamate, respectively) and, finally, of ammonia. The condition is progressive without intervention.

Pathophysiology: Overall, 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 NAG, the enzyme activator that initiates incorporation of ammonia into the cycle.

Frequency:

• In the US: Too few cases have been reported to cite any incidence figures. However, there has been an increasing recognition of affected patients.

• Internationally: Only a handful of cases have been reported worldwide.

Mortality/Morbidity: NAGS deficiency is associated with significant morbidity and mortality. Patients who present with hyperammonemia are at risk for cerebral edema and death if treatment is not begun immediately. Survivors of hyperammonemic coma will likely suffer brain damage and resulting developmental delays, learning disabilities, and/or mental retardation.

Sex: Case reports of NAGS deficiency have shown the condition to occur in both sexes.

Age: NAGS deficiency can present at any age. As with many inherited metabolic diseases, the most likely time of presentation is in the newborn period.

CLINICAL

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History:

• 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 in this article; 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 urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.

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 to obtundation to coma
  
  
  
  • Decorticate or decerebrate posturing
  
  
  

Causes:

• The pedigree distribution of reported cases supports an autosomal recessive inheritance pattern, and the growing numbers of reported cases confirm that this is the case.



• Nothing is known of the genetic basis of this condition.



• 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
Citrullinemia
Hyperammonemia
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Ornithine Transcarbamylase Deficiency

Other Problems to be Considered:

Lysinuric protein intolerance
Reye syndrome

WORKUP

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Lab Studies:

• Ammonia level: Affected newborns may experience fulminant hyperammonemia, which will go undetected unless index of suspicion is high.



• No routine laboratory tests provide definitive clues.


• • The BUN level may be low, but this is an unreliable index of high blood ammonia.
  
  
  
  • A respiratory alkalosis may be present.
  
  
  
  • Urine orotic acid levels are within reference ranges.
  
  
  
• Blood amino acids: Plasma alanine and glutamine levels are elevated.



• Urine amino acids are nondiagnostic in NAGS but are important in order to help rule out hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) or lysinuric protein intolerance (LPI) (see Differentials).



• Urine organic acids are within reference ranges in NAGS deficiency. Ruling out organic acid disorders, which can present with similar signs and symptoms and hyperammonemia, is important.

Imaging Studies:

• Imaging studies generally are not helpful, with the exception of brain imaging when cerebral edema is suspected. Documenting a finding of cerebral edema is important.

Procedures:

• Liver biopsy


• • A liver biopsy, best performed when the patient is stable, is essential for definitive diagnosis.
  
  
  
  • As a mitochondrial enzyme, it is quite labile; therefore, handle the specimen with scrupulous care and identify a laboratory prior to scheduling the biopsy that is capable of performing the enzymatic testing.
  
  
  

TREATMENT

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Medical Care:

• Immediate cessation of protein intake is mandatory in the face of high blood ammonia levels with provision of supplementary nonprotein energy to close the caloric gap. In most cases of severe hyperammonemia, the patient is given nothing enterally until the hyperammonemia is well controlled.



• Treatment of severe hyperammonemia is a true emergency.


• • Reduction of blood ammonia can usually be achieved with intravenous sodium benzoate and phenylacetate. Intravenous sodium benzoate and phenylacetate (Ammonul) was approved in the United States in February, 2005.
  
  
  
  • Alternatively, hemodialysis is usually effective in bringing down the ammonia level, especially with the initial presentation.
  
  
  
  • Exchange transfusion is ineffective and not generally recommended.

  • Intravenous fluids with glucose and sometimes arginine hydrochloride (HCl) added may be indicated.

  • Maintaining as high of an energy intake as possible is important.
  
  
  
• Specific therapy of NAGS following diagnosis rests upon dietary protein restriction and provision of arginine to enhance availability of ornithine and administration of carbamylglutamate (which is not widely available), a functional analogue of NAG. Some patients have done well using this regimen. Whether or not PO sodium phenylbutyrate is helpful in this condition is unclear.

Consultations: NAGS deficiency is an extremely rare disorder with complex treatment. Consultation with a metabolic disease/medical genetic specialist is usually necessary for assistance with laboratory diagnosis and clinical care. Contact these consultants by telephone if they are not available locally.

Diet: A low-protein diet is generally recommended with dietary supervision under the direction of a dietitian experienced in the care of patients with metabolic disease.

MEDICATION

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Drug Category: Metabolic analogue -- In the absence of any ability to fix nitrogen generated from endogenous catabolism of protein, the urea cycle is of no use whatsoever to the homeostasis of nitrogen metabolism. In order to stimulate urea cycle action, investigators have used N-carbamoyl-L-glutamate as an analogue of N-acetyl-L-glutamate to activate CPS.

Drug Name	Carbamylglutamic acid (Carbaglu) -- Also called N-carbamoyl-L-glutamate, carglumic acid, or carglutamic acid. Structural analogue of N-acetylglutamate, which enters cells and enables activation of CPS I in vitro. The compound is also resistant to enzymatic degradation. Orphan drug available as a 200-mg dispersible tab. The tab is scored and can be split to provide accurate dose.
Pediatric Dose	80-100 mg/kg/d PO divided tid/qid initially; disperse tab in at least 5-10 mL of water and administer on an empty stomach Alternatively, 2.2 g/m2/d PO divided qid May increase dose if needed, not to exceed 250 mg/kg/d; over time, some individuals require only a small dose (as low as 10 mg/kg/d)
Contraindications	Documented hypersensitivity
Interactions	Limited data exist; none reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Limited data exist, monitor ammonia and amino acids, plasma levels, blood parameters, and hepatic, renal, and cardiovascular function; clinical experience of 90 patient-years showed increased sweating (2 patients) and increased transaminases (1 patient)

Drug Category: Metabolic agents -- These agents assist in the excretion of nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.

Drug Name	Arginine (R-Gene 10) -- Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol 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.
Pediatric Dose	Hyperammonemic crisis: 0.66 g/kg/dose IV infused over 24 h; dilute in 25-35 mL dextrose 10% Maintenance treatment in a stable child: (administer as the free base) 0.4-0.7 g/kg/d PO
Contraindications	Documented hypersensitivity
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; may cause nausea, vomiting, headache, hyperkalemia, hyperglycemia, or venous irritation during IV administration

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul) -- Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Adult Dose	Loading dose: 55 mL (5.5 g)/m2 IV over 90-120 min via central line Maintenance dose: 55 mL (5.5 g)/m2/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration
Pediatric Dose	<20 kg: Loading dose: 2.5 mL (250 mg)/kg IV over 90-120 min via central line Maintenance dose: 2.5 mL (250 mg)/kg/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration >20 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects of sodium benzoate/sodium phenylacetate; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate; corticosteroids may increase body protein metabolism, thereby increasing plasma ammonia levels; do not use concomitantly with oral sodium phenylbutyrate (Buphenyl) because of additive effects
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 giving to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance; IV must be diluted with dextrose 10% and administered via central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe congestive heart failure or severe renal insufficiency since it contains large amount of sodium (30.5 mg/mL in undiluted IV product)

FOLLOW-UP

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Further Outpatient Care:

• The patient should be under the care of a biochemical geneticist (metabolic disease specialist) who is an expert in the care of patients with urea cycle defects.



• Make medication adjustments on the basis of continued growth and frequently measured plasma amino acids; include the input of a highly trained nutritionist.

Transfer:

• Consider transferring the patient to a facility equipped for emergent hemodialysis (if the patient is a neonate) and where the appropriate consultants (see Consultations) are immediately available.

Complications:

• Possible complications include cerebral edema with resulting brain damage or death.

Prognosis:

• Long-term prognosis is unclear; most likely, the future IQ depends upon the severity of the initial presentation and the subsequent hyperammonemic episodes suffered.

Patient Education:

• Family counseling


• • Inform parents of their obligate heterozygote status given the likelihood that this is an autosomal recessive trait.
  
  
  
  • Parents must understand that the chance of recurrence is 1:4 (25%) with each subsequent pregnancy.
  
  
  
  • Advise parents to seek early medical attention for the patient in the event of intercurrent illness.
  
  
  

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Always measure an ammonia level immediately in a patient of any age with unexplained lethargy or coma.



• Treat new onset hyperammonemia aggressively and immediately with advice from experts.



• Usual treatments for hyperammonemia, such as lactulose, are totally ineffective in patients with urea cycle disorders.

TEST QUESTIONS

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CME Question 1: Which of the following is not true of N-acetylglutamate synthetase (NAGS) deficiency?

A: Reaction product regulates entry of ammonia into the urea cycle.
B: Hyperammonemia may develop in a fulminant fashion.
C: Protein intake should be immediately discontinued.
D: Enzyme defect is common among all urea cycle defects.
E: All of the above

The correct answer is D: The enzyme defect is common among all urea cycle defects is an incorrect statement. NAGS deficiency has an enzyme defect distinct from other urea cycle defects.

CME Question 2: Which of the following is not related to treatment of N-acetylglutamate synthetase (NAGS) deficiency?

A: Hemodialysis
B: High carbohydrate intake
C: Sodium benzoate
D: Carbamylglutamate
E: None of the above

The correct answer is E: All of the above are relevant to treatment of NAGS deficiency.

Pearl Question 1 (T/F): The normal enzyme exhausts its substrate supply in N-acetylglutamate synthetase (NAGS) deficiency.

The correct answer is False: Because the substrate is supplied by glucose oxidation (acetyl-coenzyme A [CoA]) and the Krebs cycle (glutamate from alpha-ketoglutarate), substrate is supplied as long as the cell is alive.

Pearl Question 2 (T/F): N-acetylglutamate synthetase (NAGS) deficiency can be distinguished clinically from carbamyl phosphate synthetase (CPS) deficiency.

The correct answer is False: Both NAGS deficiency and CPS deficiency result in potentially fulminant and lethal hyperammonemia with few, if any, changes in any parameter that is measurable by the clinical laboratory.

Pearl Question 3 (T/F): Carbamylglutamate works by noncompetitively inhibiting the carbamyl phosphate synthetase (CPS) enzyme.

The correct answer is False: The normal function of N-acetylglutamate (NAG) is to activate CPS. Carbamylglutamate is a structural analogue of NAG. Carbamylglutamate has the capacity to bind to the CPS molecule, as normally occurs with NAG, thus activating the CPS molecule and bypassing the N-acetylglutamate synthetase (NAGS) deficiency.

Pearl Question 4 (T/F): N-acetylglutamate synthetase (NAGS) deficiency normally can account for all of the activation of carbamyl phosphate synthetase (CPS).

The correct answer is False: CPS can normally be partially activated by N-acetylglutamate (NAG), depending upon the relative quantities of each molecule present in the mitochondrion.

PICTURES

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Caption: Picture 1. Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; it is also at this step that 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 (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
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BIBLIOGRAPHY

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• Bachmann C: N-acetylglutamate synthetase deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol 1981; 153: 39-46.
• Caldovic L, Morizono H, Panglao MG, et al: Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 2003 Apr; 112(4): 364-8[Medline].
• Elpeleg O, Shaag A, Ben-Shalom E: N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol 2002; 52: 845-849.
• Elpeleg ON, Colombo JP, Amir N, et al: Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr 1990 Jun; 149(9): 634-6[Medline].
• Guffon N, Vianey-Saban C, Bourgeois J, et al: A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis 1995; 18(1): 61-5[Medline].
• Guffon N, Schiff M, Cheillan D: Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr 2005; 147: 260-262.
• Haberle J, Koch HG: Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn 2004; 24: 378-383.
• Plecko B, Erwa W, Wermuth B: Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr 1998 Dec; 157(12): 996-8[Medline].

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