Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Urea cycle disorders: Management

Brendan Lee, MD, PhD
Section Editor
Sihoun Hahn, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). The UCDs are:

Carbamoyl phosphate synthetase I (CPSI) deficiency (MIM #237300)

Ornithine transcarbamylase (OTC) deficiency (MIM #311250)

Argininosuccinate synthetase (ASS) deficiency (also known as classic citrullinemia or type I citrullinemia, CTLN1, MIM #215700)

Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria, MIM #207900)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Feb 08, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999; 134:268.
  2. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984; 310:1500.
  3. Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr 2011; 170:21.
  4. Lilliu F. Treatment of organic acidurias and urea cycle disorders. J Matern Fetal Neonatal Med 2010; 23 Suppl 3:73.
  5. Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009; 11:823.
  6. Enns GM. Nitrogen sparing therapy revisited 2009. Mol Genet Metab 2010; 100 Suppl 1:S65.
  7. Kamoun PP, Rabier D. Valproate-induced inhibition of urea synthesis. Lancet 1987; 1:48.
  8. Schaefer F, Straube E, Oh J, et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant 1999; 14:910.
  9. Donn SM, Swartz RD, Thoene JG. Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant. J Pediatr 1979; 95:67.
  10. GeneReviews: Arginase Deficiency. http://www.ncbi.nlm.nih.gov/books/NBK1159/ (Accessed on September 21, 2011).
  11. Summar M, Pietsch J, Deshpande J, Schulman G. Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr 1996; 128:379.
  12. Wong KY, Wong SN, Lam SY, et al. Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration. Pediatr Nephrol 1998; 12:589.
  13. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138:S30.
  14. Darmaun D, Welch S, Rini A, et al. Phenylbutyrate-induced glutamine depletion in humans: effect on leucine metabolism. Am J Physiol 1998; 274:E801.
  15. Green TP, Marchessault RP, Freese DK. Disposition of sodium benzoate in newborn infants with hyperammonemia. J Pediatr 1983; 102:785.
  16. Brusilow SW, Valle DL, Batshaw M. New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 1979; 2:452.
  17. Praphanphoj V, Boyadjiev SA, Waber LJ, et al. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia. J Inherit Metab Dis 2000; 23:129.
  18. Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007; 356:2282.
  19. Nassogne MC, Héron B, Touati G, et al. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005; 28:407.
  20. Kline JJ, Hug G, Schubert WK, Berry H. Arginine deficiency syndrome. Its occurrence in carbamyl phosphate synthetase deficiency. Am J Dis Child 1981; 135:437.
  21. Brusilow SW, Batshaw ML. Arginine therapy of argininosuccinase deficiency. Lancet 1979; 1:124.
  22. Batshaw ML, Brusilow S, Waber L, et al. Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Med 1982; 306:1387.
  23. Lee B, Yu H, Jahoor F, et al. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc Natl Acad Sci U S A 2000; 97:8021.
  24. Thompson CA. Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm 2010; 67:690.
  25. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. Int J Gen Med 2011; 4:21.
  26. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 2007; 30:880.
  27. FDA news release. FDA approves new drug for the chronic management of some urea cycle disorders. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337639.htm (Accessed on February 19, 2013).
  28. Ravicti (glycerol phenylbutyrate) prescribing information. https://www.ravicti.com//files/RAVICTI_Prescribing_Information.pdf (Accessed on February 19, 2013).
  29. Diaz GA, Krivitzky LS, Mokhtarani M, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology 2013; 57:2171.
  30. 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; 162:1228.
  31. Mokhtarani M, Diaz GA, Rhead W, et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab 2012; 107:308.
  32. Thibault A, Cooper MR, Figg WD, et al. A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer. Cancer Res 1994; 54:1690.
  33. Thibault A, Samid D, Cooper MR, et al. Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer 1995; 75:2932.
  34. Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 2001; 7:2292.
  35. Scaglia F, Carter S, O'Brien WE, Lee B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab 2004; 81 Suppl 1:S79.
  36. Burrage LC, Jain M, Gandolfo L, et al. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab 2014; 113:131.
  37. Lee B, Diaz GA, Rhead W, et al. Glutamine and hyperammonemic crises in patients with urea cycle disorders. Mol Genet Metab 2016; 117:27.
  38. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med 2015; 17:561.
  39. Mokhtarani M, Diaz GA, Rhead W, et al. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab 2013; 110:446.
  40. Morgan TM, Schlegel C, Edwards KM, et al. Vaccines are not associated with metabolic events in children with urea cycle disorders. Pediatrics 2011; 127:e1147.
  41. Klein NP, Aukes L, Lee J, et al. Evaluation of immunization rates and safety among children with inborn errors of metabolism. Pediatrics 2011; 127:e1139.
  42. Mendez-Figueroa H, Lamance K, Sutton VR, et al. Management of ornithine transcarbamylase deficiency in pregnancy. Am J Perinatol 2010; 27:775.
  43. Dutoit AP, Flick RR, Sprung J, et al. Anesthetic implications of ornithine transcarbamylase deficiency. Paediatr Anaesth 2010; 20:666.
  44. Nagamani SC, Campeau PM, Shchelochkov OA, et al. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet 2012; 90:836.
  45. Saudubray JM, Touati G, Delonlay P, et al. Liver transplantation in urea cycle disorders. Eur J Pediatr 1999; 158 Suppl 2:S55.
  46. Whitington PF, Alonso EM, Boyle JT, et al. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis 1998; 21 Suppl 1:112.
  47. Moini M, Mistry P, Schilsky ML. Liver transplantation for inherited metabolic disorders of the liver. Curr Opin Organ Transplant 2010; 15:269.
  48. Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010; 100 Suppl 1:S77.
  49. Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014; 60:362.
  50. Sundaram SS, Alonso EM, Whitington PF. Liver transplantation in neonates. Liver Transpl 2003; 9:783.
  51. McBride KL, Miller G, Carter S, et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 2004; 114:e523.
  52. 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; 11:1332.
  53. Yu L, Rayhill SC, Hsu EK, Landis CS. Liver Transplantation for Urea Cycle Disorders: Analysis of the United Network for Organ Sharing Database. Transplant Proc 2015; 47:2413.
  54. Meyburg J, Das AM, Hoerster F, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009; 87:636.
  55. Batshaw ML, Robinson MB, Ye X, et al. Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency. Pediatr Res 1999; 46:588.
  56. Batshaw ML, Wilson JM, Raper S, et al. Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD). Hum Gene Ther 1999; 10:2419.
  57. Raper SE, Yudkoff M, Chirmule N, et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 2002; 13:163.
  58. Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab 2009; 96:151.
  59. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003; 80:148.
  60. Lehrman S. Virus treatment questioned after gene therapy death. Nature 1999; 401:517.
  61. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 1998; 21 Suppl 1:151.
  62. Maestri NE, Clissold DB, Brusilow SW. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 1995; 127:929.
  63. Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis 2012; 35:777.
  64. Krivitzky L, Babikian T, Lee HS, et al. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009; 66:96.
  65. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001; 138:S56.
  66. Brunetti-Pierri N, Erez A, Shchelochkov O, et al. Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency? Mol Genet Metab 2009; 98:195.
  67. Nagasaka H, Tsukahara H, Yorifuji T, et al. Evaluation of endogenous nitric oxide synthesis in congenital urea cycle enzyme defects. Metabolism 2009; 58:278.
  68. Seminara J, Tuchman M, Krivitzky L, et al. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab 2010; 100 Suppl 1:S97.