Sections

Ornithine Transcarbamylase (OTC) Deficiency

Sections Ornithine Transcarbamylase (OTC) Deficiency
Overview
Presentation
- History
- Physical
- Causes
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DDx
Workup
Treatment
Medication
References

Medication

Medication Summary

As noted above, intravenous sodium benzoate, arginine, and sodium phenylacetate should only be administered in a large medical facility setting with close laboratory monitoring available.

Class Summary

These agents assist in the excretion of nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.

Arginine (R-Gene 10)

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Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol arginine when cleaved by arginase. Pituitary stimulant for the release of human growth hormone (HGH). Often induces pronounced HGH levels in patients with intact pituitary function.

Sodium phenylacetate and sodium benzoate (Ammonul)

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Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for CPS, OTC, ASS, or ASL deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.

Glycerol phenylbutyrate (Ravicti)

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Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.

Brooks M. FDA Clears Drug for Urea Cycle Disorders. Medscape Medical News. February 1, 2013. Available at http://www.medscape.com/viewarticle/778646. Accessed: February 9, 2013.
Crosbie DC, Sugumar H, Simpson MA, Walker SP, Dewey HM, Reade MC. Late-onset ornithine transcarbamylase deficiency: a potentially fatal yet treatable cause of coma. Crit Care Resusc. 2009 Sep. 11(3):222-7. [QxMD MEDLINE Link].
[Guideline] Pearlman E, National Headache Foundation. Special treatment situations: pediatric migraine. Standards of care for headache diagnosis and treatment. 2004. 98-107. [Full Text].
Wang L, Morizono H, Lin J, Bell P, Jones D, McMenamin D, et al. Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Mol Genet Metab. 2012 Feb. 105(2):203-11. [QxMD MEDLINE Link]. [Full Text].
Caldovic L, Abdikarim I, Narain S, et al. Genotype-phenotype correlations in ornithine transcarbamylase deficiency: a mutation update. J Genet Genomics. May 2015. 42:181-194. [QxMD MEDLINE Link].
Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab. 2009 Sep. 11(9):823-35. [QxMD MEDLINE Link].
Kim HJ, Park SJ, Park KI, Lee JS, Eun HS, Kim JH, et al. Acute treatment of hyperammonemia by continuous renal replacement therapy in a newborn patient with ornithine transcarbamylase deficiency. Korean J Pediatr. 2011 Oct. 54(10):425-8. [QxMD MEDLINE Link]. [Full Text].
Gascon-Bayarri J, Campdelacreu J, Estela J, Reñé R. Severe hyperammonemia in late-onset ornithine transcarbamylase deficiency triggered by steroid administration. Case Rep Neurol Med. 2015. 2015:453752. [QxMD MEDLINE Link].
Bergmann KR, McCabe J, Smith TR, et al. Late-onset ornithine transcarbamylase deficiency: treatment and outcome of hyperammonemic crisis. Pediatrics. April 2014. 133:e1072-1076. [QxMD MEDLINE Link].
Arranz JA, Riudor E, Marco-Marin C, et al. Estimation of the total number of disease-causing mutations in ornitine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. J Inherit Metab Dis. 2007 Apr. 30(2):217-26. [QxMD MEDLINE Link].
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].
Brassier A, Gobin S, Arnoux JB, Valayannopoulos V, Habarou F, Kossorotoff M, et al. Long-term outcomes in Ornithine Transcarbamylase deficiency: a series of 90 patients. Orphanet J Rare Dis. 2015 May 10. 10:58. [QxMD MEDLINE Link].
Arn PH, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyl transferase locus. A cause of postpartum coma. N Engl J Med. 1990 Jun 7. 322(23):1652-5. [QxMD MEDLINE Link].
Batshaw ML, Roan Y, Jung AL, et al. Cerebral dysfunction in asymptomatic carriers of ornithine transcarbamylase deficiency. N Engl J Med. 1980 Feb 28. 302(9):482-5. [QxMD MEDLINE Link].
Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Pt 2):S56-S62. [QxMD MEDLINE Link].
Campbell AG, Rosenberg LE, Snodgrass PJ, Nuzum CT. Ornithine transcarbamylase deficiency: a cause of lethal neonatal hyperammonemia in males. N Engl J Med. 1973 Jan 4. 288(1):1-6. [QxMD MEDLINE Link].
Cordero DR, Baker J, Dorinzi D, Toffle R. Ornithine transcarbamylase deficiency in pregnancy. J Inherit Metab Dis. 2005. 28(2):237-40. [QxMD MEDLINE Link].
Drogari E, Leonard JV. Late onset ornithine carbamoyl transferase deficiency in males. Arch Dis Child. 1988 Nov. 63(11):1363-7. [QxMD MEDLINE Link].
Finkelstein JE, Hauser ER, Leonard CO, Brusilow SW. Late-onset ornithine transcarbamylase deficiency in male patients. J Pediatr. 1990 Dec. 117(6):897-902. [QxMD MEDLINE Link].
Fox J, Hack AM, Fenton WA, et al. Prenatal diagnosis of ornithine transcarbamylase deficiency with use of DNA polymorphisms. N Engl J Med. 1986 Nov 6. 315(19):1205-8. [QxMD MEDLINE Link].
Galloway PJ, MacPhee GB, Galea P, Robinson PH. Severe hyperammonaemia in a previously healthy teenager. Ann Clin Biochem. 2000 Sep. 37 (Pt 5):727-8. [QxMD MEDLINE Link].
Gilchrist JM, Coleman RA. Ornithine transcarbamylase deficiency: adult onset of severe symptoms. Ann Intern Med. 1987 Apr. 106(4):556-8. [QxMD MEDLINE Link].
Gyato K, Wray J, Huang ZJ, et al. Metabolic and neuropsychological phenotype in women heterozygous for ornithinetranscarbamylase deficiency. Ann Neurol. 2004 Jan. 55(1):80-6. [QxMD MEDLINE Link].
Hauser ER, Finkelstein JE, Valle D, Brusilow SW. Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med. 1990 Jun 7. 322(23):1641-5. [QxMD MEDLINE Link].
Lee B, Yu H, Jahoor F, et al. In vivo urea cycle flux distinguishes and correlates with phenotypic severityin disorders of the urea cycle. Proc Natl Acad Sci U S A. 2000 Jul 5. 97(14):8021-6. [QxMD MEDLINE Link]. [Full Text].
Legras A, Labarthe F, Maillot F, et al. Late diagnosis of ornithine transcarbamylase defect in three related femalepatients: polymorphic presentations. Crit Care Med. 2002 Jan. 30(1):241-4. [QxMD MEDLINE Link].
Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med. 1996 Sep 19. 335(12):855-9. [QxMD MEDLINE Link]. [Full Text].
McCullough BA, Yudkoff M, Batshaw ML, et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000 Aug 14. 93(4):313-9. [QxMD MEDLINE Link].
Morioka D, Kasahara M, Takada Y, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. 2005 Nov. 11(11):1332-42. [QxMD MEDLINE Link].
Nicolaides P, Liebsch D, Dale N, et al. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002 Jan. 86(1):54-6. [QxMD MEDLINE Link].
Riudor E, Arranz JA, Rodes M. Partial ornithine transcarbamylase deficiency. Pediatrics. 2003 May. 111(5 Pt 1):1123-4; author reply 1123-4. [QxMD MEDLINE Link]. [Full Text].
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Pt 2):S21-S29. [QxMD MEDLINE Link].
Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximalurea cycle disorders. AJNR Am J Neuroradiol. 2003 Jun-Jul. 24(6):1184-7. [QxMD MEDLINE Link]. [Full Text].
Takanashi J, Kurihara A, Tomita M, et al. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylasedeficiency. Neurology. 2002 Jul 23. 59(2):210-4. [QxMD MEDLINE Link].
Tuchman M, Matsuda I, Munnich A, et al. Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency. Am J Med Genet. 1995 Jan 2. 55(1):67-70. [QxMD MEDLINE Link].
Tuchman M, McCullough BA, Yudkoff M. The molecular basis of ornithine transcarbamylase deficiency. Eur J Pediatr. 2000 Dec. 159 Suppl 3:S196-8. [QxMD MEDLINE Link].
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency. Mol Genet Metab. 2012 Mar. 105(3):404-7. [QxMD MEDLINE Link].
Wilcken B. Problems in the management of urea cycle disorders. Mol Genet Metab. 2004 Apr. 81 Suppl 1:S86-91. [QxMD MEDLINE Link].
Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006 Jul. 27(7):626-32. [QxMD MEDLINE Link].
Prasun P, Altinok D, Misra VK. Ornithine transcarbamylase deficiency presenting with acute reversible cortical blindness. J Child Neurol. May 2015. 30:782-785. [QxMD MEDLINE Link].

Media Gallery

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; during this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS). Compound 2 is citrulline, which is 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

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

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-part of Exact Sciences; Acer Therapeutics; DNARx; Best Doctors; PTC Therapeutics; CTX Alliance; Leadiant' Travere<br/>Received income in an amount equal to or greater than $250 from: Marshfield Clinic; PreventionGenetics-part of Exact Sciences; Acer Therapeutics; PTC Therapeutics; DNARx; Leadiant; Travere.

Sections Ornithine Transcarbamylase (OTC) Deficiency
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
References

Ornithine Transcarbamylase (OTC) Deficiency Medication

Medication Summary

Urea Cycle Disorder Treatment Agents

Class Summary

Arginine (R-Gene 10)

Arginine (R-Gene 10)

Sodium phenylacetate and sodium benzoate (Ammonul)

Sodium phenylacetate and sodium benzoate (Ammonul)

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate (Ravicti)

Ornithine Transcarbamylase (OTC) Deficiency Medication

Medication Summary

Urea Cycle Disorder Treatment Agents

Class Summary

Arginine (R-Gene 10)

Arginine (R-Gene 10)

Sodium phenylacetate and sodium benzoate (Ammonul)

Sodium phenylacetate and sodium benzoate (Ammonul)

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate (Ravicti)

References

Tables

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