Argininosuccinate Lyase Deficiency 

  • Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 13, 2012
 

Background

Argininosuccinate (ASA) lyase deficiency results in defective cleavage of ASA. This leads to an accumulation of ASA in cells and an excessive excretion of ASA in urine. In virtually all respects, this disorder shares the characteristics of other urea cycle defects.[1] The most important characteristic of ASA lyase deficiency is its propensity to cause hyperammonemia in affected individuals. See the image below.

Compounds comprising the urea cycle are numbered sCompounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; 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 (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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Pathophysiology

The hepatic urea cycle is the major route for waste nitrogen disposal; nitrogen generation results 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. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, the cycle’s activity is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle.

The rate-limiting step is carbamoyl phosphate synthetase (CPS) disposal of waste nitrogen. However, in patients with a genetic deficiency in an additional enzyme in the cycle (other than CPS), the deficient enzyme becomes rate limiting. This occurs in patients with argininosuccinic aciduria, despite the fact that formation of this substance ensures incorporation of the 2 waste nitrogen molecules normally found in urea. Although failure to release the arginine limits the cycle rate and slows hepatic regeneration of the distal intermediates of the cycle, this is unlikely to entirely explain the clinical findings, because ASA is excreted by the kidney at a rate practically equivalent to the glomerular filtration rate (GFR).[2, 3, 4]

Whether ASA itself causes a degree of toxicity due to hepatocellular accumulation is unknown; such an effect could help explain hyperammonemia development in affected individuals. Regardless, the name of the disease is derived from the rapid clearance of ASA in urine, although elevated levels of ASA can be found in plasma. Hyperammonemia in this disease manifests with the typical findings and carries all of the attendant consequences associated with other urea cycle diseases.

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Epidemiology

Frequency

United States

ASA lyase deficiency is rare. As with other disorders in this category, this deficiency can manifest in neonates or later in life, and true incidence cannot be cited without population screening data.[5]

International

The Druze community in Israel has a carrier frequency of 1:41.[6] According a study of urea cycle diseases in Finland, 20 cases of ASA lyase deficiency had been reported by 2007.[7]

Mortality/Morbidity

ASA lyase deficiency is associated with high mortality and morbidity rates. Failure to suspect hyperammonemia and to obtain blood ammonia levels results in certain morbidity and, likely, death because routine laboratory test findings are unrevealing.

Sex

Inherited as an autosomal recessive trait, argininosuccinic aciduria affects both sexes equally.

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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.

Specialty Editor Board

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Leonard G Feld, MD, PhD, MMM, FAAP  Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

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 and Genetics, Director RSA, 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.

References

  1. Mitchell S, Ellingson C, Coyne T, et al. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. Jan 2009;30(1):56-60. [Medline].

  2. Nagamani SC, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. Jan 5 2012;[Medline].

  3. Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet. Feb 15 2011;157(1):45-53. [Medline]. [Full Text].

  4. Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. Nov 13 2011;17(12):1619-26. [Medline].

  5. Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, et al. Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab. May 2010;100(1):24-8. [Medline].

  6. Falik-Zaccai TC, Kfir N, Frenkel P, et al. Population screening in a Druze community: the challenge and the reward. Genet Med. Dec 2008;10(12):903-9. [Medline].

  7. Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. Oct 2008;97(10):1412-9. [Medline].

  8. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S56-60; discussion S60-1. [Medline].

  9. Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr. Jun 2007;137(6 Suppl 2):1656S-1661S. [Medline].

  10. Brusilow SW, Batshaw ML. Arginine therapy of argininosuccinase deficiency. Lancet. Jan 20 1979;1(8108):124-7. [Medline].

  11. Collins FS, Summer GK, Schwartz RP. Neonatal argininosuccinic aciduria-survival after early diagnosis and dietary management. J Pediatr. Mar 1980;96(3 Pt 1):429-31. [Medline].

  12. Glick NR, Snodgrass PJ, Schafer IA. Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity. Am J Hum Genet. Jan 1976;28(01):22-30. [Medline].

  13. Kleijer WJ, Garritsen VH, van der Sterre ML, et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenatal Diagnosis. Mar 2006;26(3):242-7. [Medline].

  14. Linnebank M, Tschiedel E, Haberle J, et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. Oct 2002;111(4-5):350-9. [Medline].

  15. Reid Sutton V, Pan Y, Davis EC, Craigen WJ. A mouse model of argininosuccinic aciduria: biochemical characterization. Mol Genet Metab. Jan 2003;78(1):11-6. [Medline].

  16. Saudubray JM, Rabier D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J Nutr. Jun 2007;137(6 Suppl 2):1669S-1672S. [Medline].

  17. Stadler S, Gempel K, Bieger I, et al. Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry. J Inherit Metab Dis. Jun 2001;24(3):370-8. [Medline].

  18. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].

  19. Stephenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology. Apr 2006;130(4):1317-23. [Medline].

  20. Trevisson E, Salviati L, Baldoin MC, et al. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat. Feb 26 2007;28(7):694-702. [Medline].

  21. Widhalm K, Koch S, Scheibenreiter S, et al. Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics. Jun 1992;89(6 Pt 2):1182-4. [Medline].

 
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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; 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 (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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