Arginase Deficiency Workup

  • Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 5, 2012
 

Laboratory Studies

Beyond the inherent problems in diagnosis of any urea cycle disorder, arginase deficiency is somewhat difficult to diagnose.

The typical crisis associated with hyperammonemia is rare, and random measurement of blood ammonia levels during periods of clinical stability is not helpful.

Arginine excretion in urine is not usually massively increased because of isozyme induction; however, a urinary amino acid excretion pattern can be observed. The excretion pattern is similar to that found in cystinuria, with increased arginine, ornithine, lysine, and, possibly, cystine. It can be observed because of competitive inhibition of dibasic amino acid reabsorption by elevated arginine in the renal proximal tubule.

Plasma arginine levels may not be greatly increased in cases of self-restriction of protein intake; therefore, even experienced clinicians may fail to diagnose the disease. Urine orotic acid is usually mildly increased.[6] Plasma ammonia levels may be mildly increased or normal.

When mild-to-moderate elevated plasma arginine levels are observed in association with developmental delay and spasticity, a red cell arginase assay is indicated for definitive biochemical diagnosis.

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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.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

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. Cederbaum SD, Yu H, Grody WW, et al. Arginases I and II: do their functions overlap?. Mol Genet Metab. Apr 2004;81 Suppl 1:S38-44. [Medline].

  2. Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. Jan 2010;42(1):49-52. [Medline].

  3. Ash DE, Scolnick LR, Kanyo ZF, et al. Molecular basis of hyperargininemia: structure-function consequences of mutations in human liver arginase. Mol Genet Metab. Aug 1998;64(4):243-9. [Medline].

  4. Scheuerle AE, McVie R, Beaudet AL, Shapira SK. Arginase deficiency presenting as cerebral palsy. Pediatrics. May 1993;91(5):995-6. [Medline].

  5. Morris SM Jr. Arginases and arginine deficiency syndromes. Curr Opin Clin Nutr Metab Care. Jan 2012;15(1):64-70. [Medline]. [Full Text].

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

  7. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S56-S62. [Medline].

  8. Cederbaum SD, Shaw KN, Valente M. Hyperargininemia. J Pediatr. Apr 1977;90(4):569-73. [Medline].

  9. Cowley DM, Bowling FG, McGill JJ, et al. Adult-onset arginase deficiency. J Inherit Metab Dis. Aug 1998;21(6):677-8. [Medline].

  10. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. Mar 2005;84(3):243-51. [Medline].

  11. Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. May 2004;24(5):378-383. [Medline].

  12. Iyer R, Jenkinson CP, Vockley JG, et al. The human arginases and arginase deficiency. J Inherit Metab Dis. 1998;21 Suppl 1:86-100. [Medline].

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

  14. Korman SH, Gutman A, Stemmer E, Kay BS, Ben-Neriah Z, Zeigler M. Prenatal diagnosis fro arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis. Prenat Diagn. Nov 2004;24(11):857-60. [Medline].

  15. Picker JD, Puga AC, Levy HL, et al. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr. Mar 2003;142(3):349-52. [Medline].

  16. Qureshi IA, Letarte J, Ouellet R, Batshaw ML, et al. Treatment of hyperargininemia with sodium benzoate and arginine- restricted diet. J Pediatr. Mar 1984;104(3):473-6. [Medline].

  17. 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].

  18. Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet. May 15 2006;142(2):113-20. [Medline].

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

 
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Compounds that comprise the urea cycle are sequentially numbered, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS), in this step. 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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