eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

N-Acetylglutamate Synthetase Deficiency

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Contributor Information and Disclosures

Updated: Aug 4, 2008

Introduction

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 is normally 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 Media file 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 ® H2 N-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

United States

Too few cases have been reported to cite any incidence figures. However, recognition of affected patients is increasing. Because the clinical presentation is indistinguishable from that of CPS deficiency and because the diagnosis is difficult, requiring an open liver biopsy, the true incidence may be underestimated. This is further emphasized by the fact that genetically affected individuals may remain asymptomatic for many years.

International

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 immediately begun. Survivors of hyperammonemic coma are likely to 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; because the mutation is inherited as an autosomal recessive trait, this is to be expected.

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

History

  • The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, somewhat vary 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.
  • The NAGS gene was the last one of the urea cycle to be cloned. The gene locus is 17q21.31, spans 4.5 kb, and contains 6 introns and 7 exons. The 534 amino acid residues contained in the ribosomal protein are reduced to 486 by cleavage at the N -terminus upon import to the mitochondrion. A total of 21 mutations have been reported, 10 of which were associated with acute neonatal presentation.1 Interestingly, no mutations were found in exon 1, which is believed to code for the 50 amino acid mitochondrial-targeting segment that is cleaved.
  • 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.

More on N-Acetylglutamate Synthetase Deficiency

Overview: N-Acetylglutamate Synthetase Deficiency
Differential Diagnoses & Workup: N-Acetylglutamate Synthetase Deficiency
Treatment & Medication: N-Acetylglutamate Synthetase Deficiency
Follow-up: N-Acetylglutamate Synthetase Deficiency
Multimedia: N-Acetylglutamate Synthetase Deficiency
References
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References

  1. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. Aug 2007;28(8):754-9. [Medline].

  2. Bachmann C, Colombo JP, Jaggi K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol. 1982;153:39-45. [Medline].

  3. Caldovic L, Morizono H, Panglao MG, et al. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat. Mar 2005;25(3):293-8. [Medline].

  4. 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. Apr 2003;112(4):364-8. [Medline].

  5. Elpeleg O, Shaag A, Ben-Shalom E, Schmid T, Bachmann C. N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol. Dec 2002;52(6):845-9. [Medline].

  6. Elpeleg ON, Colombo JP, Amir N, et al. Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr. Jun 1990;149(9):634-6. [Medline].

  7. Guffon N, Schiff M, Cheillan D, et al. Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr. Aug 2005;147(2):260-2. [Medline].

  8. 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].

  9. Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. May 2004;24(5):378-83. [Medline].

  10. 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. Dec 1998;157(12):996-8. [Medline].

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Further Reading

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Keywords

N -acetylglutamate synthetase deficiency, NAGS, NAGS deficiency, acetyl-coenzyme A, acetyl-CoA, carbamyl phosphate synthetase, CPS, hyperammonemia, urea cycle defect, anorexia, coma, apnea, respiratory failure, seizures, dysdiadochokinesia, hypothermia, respiratory alkalosis, arginase deficiency, hyperammonemia-hyperornithinemia-homocitrullinemia syndrome

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Contributor Information and Disclosures

Author

Karl S Roth, MD, Professor and Chair, 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 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
Disclosure: Nothing to disclose.

Medical Editor

Uri S Alon, MD, Director of Research and Education, Department of Pediatrics, Division of Pediatric Nephrology, Children's Mercy Hospital of Kansas City; Professor, University of Missouri at Kansas City
Uri S Alon, MD is a member of the following medical societies: American Federation for Medical Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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