Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Argininosuccinate Lyase Deficiency Follow-up

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Sep 10, 2015
 

Further Outpatient Care

Under no circumstances should a patient with a urea cycle defect be cared for exclusively by a primary care provider.

Consult with a biochemical geneticist/metabolic disease specialist who is skilled in treating urea cycle diseases when treating patients with argininosuccinate (ASA) lyase deficiency.

Frequent dietary and medication adjustments are essential, especially in growing infants, and should be made only with quantitative monitoring of plasma amino acid levels.

Close attention to dietary intake and adjustments is a critical part of management and should involve the help of a highly trained nutritionist.

Next

Deterrence/Prevention

Using chorionic villus sampling, prenatal diagnosis is possible as early as 11-12 weeks’ gestation. It is essential to establish the nature of the mutation in the parents first, given the large number of private mutations known to occur. This should be discussed with any family with one or more affected first-degree relatives.

Previous
Next

Complications

Untreated patients may develop cerebral edema and die, and some patients die despite treatment.

Mental retardation is a common sequela.

Previous
Next

Prognosis

Prognosis is guarded.

Although intellectual impairment is the rule, even among patients who receive excellent and timely treatment, some patients with ASA lyase deficiency reportedly develop normally.

Previous
Next

Patient Education

Advise parents of an affected infant that they are obligate heterozygotes because the disease is inherited as an autosomal recessive trait. This trait leads to a recurrence risk of 1:4 (25%) with each subsequent pregnancy.

Prenatal diagnosis is available for ASA lyase deficiency, although the involved diagnostic procedures are not trivial. Even in cases in which elective abortion is not an option, parents should be prepared for an affected infant in order to avoid early hyperammonemia.

Advise parents to scrupulously follow the dietary and medication instructions and to seek early medical attention for all intercurrent illnesses.

Previous
 
Contributor Information and Disclosures
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, 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 Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

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 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: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

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. 2009 Jan. 30(1):56-60. [Medline].

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

  3. 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. [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. 2011 Nov 13. 17(12):1619-26. [Medline].

  5. Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. September-October 2013. 110:179-180. [Medline].

  6. 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. 2010 May. 100(1):24-8. [Medline].

  7. 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. [Medline].

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

  9. Zimmermann A, Bachmann C, Baumgartner R. Severe liver fibrosis in argininosuccinic aciduria. Arch Pathol Lab Med. 1986. 110:136-140. [Medline].

  10. Ficicioglu C, Mandell R, Shih VE. Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. Mol Genet Med. Novemeber 2009. 98:273-277. [Medline].

  11. 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. [Medline]. [Full Text].

  12. 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. [Medline].

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

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

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

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

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

  18. 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. 2006 Mar. 26(3):242-7. [Medline].

  19. 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. 2002 Oct. 111(4-5):350-9. [Medline].

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

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

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

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

  24. 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. 2006 Apr. 130(4):1317-23. [Medline].

  25. 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. 2007 Feb 26. 28(7):694-702. [Medline].

  26. 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. [Medline].

  27. Hu L, Pandey AV, Balmer C, et al. Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria. J Inherit Metab Dis. March 17 2015. Epub ahead of print:[Medline].

  28. 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. [Medline].

  29. Balmer C, Pandey AV, Ruefenacht V, et al. Mutations and polymorphisms in the human argininosuccinate lyase(ASL) gene. Hum Mutat. January 2014. 35:27-35. [Medline].

Previous
Next
 
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.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.