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Arginase Deficiency Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Sep 08, 2015
 

History

A history of delayed development, protein intolerance, and spasticity is suggestive of arginase deficiency.[7]

Although a catastrophic neonatal presentation is uncommon in patients with arginase deficiency, surmising that onset is at birth and that progression is relatively slow compared with other urea cycle disorders is reasonable. Specifically, dietary protein intolerance is an early sign and should not be overlooked.

The typical presentation is that of an older infant whose development is delayed, who has occasional episodes of vomiting and somnolence without apparent cause, who is protein intolerant, and who shows evidence of long-tract neurological impairment.

A common clinical feature in this disorder is spasticity, and the disease is likely underdiagnosed because many affected children are diagnosed with cerebral palsy without effort to diagnose arginase deficiency.

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, disorders in the urea cycle defect family are individually considered in this article; however, hyperammonemia is a common denominator and can present with some or all of the following symptoms:

  • 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 individual urea cycle disorder relate to the constellation of symptoms of hyperammonemia and rough temporal sequence of events.

Arginase deficiency may have a somewhat different manifestation for reasons cited above.

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Physical

General

Signs of severe hyperammonemia may be present.

Poor growth may be observed.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.

Pulmonary

See the list below:

  • Tachypnea or hyperpnea may be present.
  • Apnea and respiratory failure may occur in latter stages.

Abdominal

Hepatomegaly may be present and is usually mild.

Neurologic

See the list below:

  • Poor coordination and spasticity
  • Hyperreflexia
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy progressing to combativeness to obtundation to coma; decorticate or decerebrate posturing if profound hyperammonemia present
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Causes

The gene for liver arginase has been cloned and is located on chromosome 6. It has been mapped to locus 6q23, consists of 11.5 kilobases, and comprises 8 exons. A mouse "knockout" model for arginase I deficiency has been produced. These animals die within 10-12 days of birth of severe hyperammonemia, whereas animals deficient in arginase II have no identifiable phenotype, except for impaired fertility in the male.

Approximately 20 mutational variants have been identified.

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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. Cederbaum SD, Yu H, Grody WW, et al. Arginases I and II: do their functions overlap?. Mol Genet Metab. 2004 Apr. 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. 2010 Jan. 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. 1998 Aug. 64(4):243-9. [Medline].

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

  5. Carvalho DR, Brum JM, Speck-Martins CE, et al. Clinical features and neurologic progression of hyperargininemia. Pediatr Neurol. 2012 Jun. 46(6):369-74. [Medline].

  6. Zhang Y, Landau YE, Miller DT, Marsden D, Berry GT, Kellogg MD. Recurrent unexplained hyperammonemia in an adolescent with arginase deficiency. Clin Biochem. 2012 Dec. 45(18):1583-6. [Medline].

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

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

  9. Carvalho DR, Farage L, Martins BJ, Brum JM, Speck-Martins CE, Pratesi R. Brain MRI and Magnetic Resonance Spectroscopy Findings in Patients with Hyperargininemia. J Neuroimaging. 2012 Aug 28. [Medline].

  10. Smith W, Diaz GA, Lichter-Konecki U, 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 Jun. 162(6):1228-34, 1234.e1. [Medline].

  11. Silva ES, Cardoso ML, Vilarinho L, Medina M, Barbot C, Martins E. Liver transplantation prevents progressive neurological impairment in argininemia. JIMD Rep. 2013. 11:25-30. [Medline]. [Full Text].

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

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

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

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

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

  17. 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].

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

  19. 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. 2004 Nov. 24(11):857-60. [Medline].

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

  21. 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].

  22. 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].

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

  24. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. 2001 Jan. 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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