Laboratory Studies

No routine laboratory data assist diagnosis of argininosuccinate (ASA) lyase deficiency.

BUN testing is subject to numerous factors aside from the rate of production via the urea cycle. Among the most obvious is the state of hydration, which frequently causes an artifactual increase to a normal concentration in a very sick infant. A very low BUN level is suggestive but must never be relied on as a diagnostic indicator.

As with all other urea cycle disorders, clinical suspicion is essential and should prompt the clinician to obtain blood ammonia levels, which are significantly elevated in symptomatic patients. This finding should lead to an immediate blood and urine amino acid quantitation, which confirms the presence of argininosuccinic acid in both fluids. In addition, levels of blood citrulline, glutamine, alanine, and lysine may be increased. Argininosuccinic acid lyase may be assayed in cultured fibroblasts, providing the definitive biochemical diagnosis. Urine orotic acid levels are elevated.

All 50 states in the United States include argininosuccinate (ASA) lyase deficiency in their newborn screening programs.

Other Tests

Molecular diagnosis is available for diagnostic confirmation. Prenatal diagnosis is possible, but the nature of the mutation must be known, given the wide variety of private mutations reported.

Treatment & Management

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. 2009 Jan. 30(1):56-60. [QxMD MEDLINE Link].
Nagamani SC, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. 2012 Jan 5. [QxMD MEDLINE Link].
Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet. 2011 Feb 15. 157(1):45-53. [QxMD MEDLINE Link]. [Full Text].
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. 2011 Nov 13. 17(12):1619-26. [QxMD MEDLINE Link].
Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. September-October 2013. 110:179-180. [QxMD MEDLINE Link].
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Falik-Zaccai TC, Kfir N, Frenkel P, et al. Population screening in a Druze community: the challenge and the reward. Genet Med. 2008 Dec. 10(12):903-9. [QxMD MEDLINE Link].
Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008 Oct. 97(10):1412-9. [QxMD MEDLINE Link].
Zimmermann A, Bachmann C, Baumgartner R. Severe liver fibrosis in argininosuccinic aciduria. Arch Pathol Lab Med. 1986. 110:136-140. [QxMD MEDLINE Link].
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Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2012 Sep 7. [QxMD MEDLINE Link]. [Full Text].
Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, et al. Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate. J Pediatr. 2013 Jan 13. [QxMD MEDLINE Link].
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Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr. 2007 Jun. 137(6 Suppl 2):1656S-1661S. [QxMD MEDLINE Link].
Brusilow SW, Batshaw ML. Arginine therapy of argininosuccinase deficiency. Lancet. 1979 Jan 20. 1(8108):124-7. [QxMD MEDLINE Link].
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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. 1992 Jun. 89(6 Pt 2):1182-4. [QxMD MEDLINE Link].
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Premkumar MH, Sule G, Nagamani SC, et al. Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. August 2014. 307:G347-G354. [QxMD MEDLINE Link].
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Media Gallery

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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Author

Karl S Roth, MD Retired 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 Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, The Scientific Research Honor Society, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD, FAAP, FACMG Professor (Clinical), Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Editor-in-Chief, Genetics in Medicine; Chief Medical Officer, PreventionGenetics

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

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: PreventionGenetics, ACMG, Acer Therapeutics, Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, CTX Alliance, Aeglea, Eton, Leadiant<br/>Serve(d) as a speaker or a member of a speakers bureau for: France Foundation, Medscape<br/>Received research grant from: Alexion<br/>Received income in an amount equal to or greater than $250 from: Marshfield Clinic, France Foundation, Medscape, PreventionGenetics, ACMG, Acer Therapeutics; Raptor, Retrophin/Travere, Censa; Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, Aeglea, Leadiant<br/>Travel Support for: CTX Alliance.

Sections Argininosuccinate Lyase (ASL) Deficiency
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Argininosuccinate Lyase (ASL) Deficiency Workup

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