Urea cycle disorders: Clinical features and diagnosis
- Brendan Lee, MD, PhD
Brendan Lee, MD, PhD
- Baylor College of Medicine
- Texas Children's Hospital
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:
●Carbamyl 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:
- Gene Reviews: Urea Cycle Disorders Overview. http://www.ncbi.nlm.nih.gov/books/NBK1217/ (Accessed on June 14, 2011).
- Gene Reviews: Citrullinemia type 1. http://www.ncbi.nlm.nih.gov/books/NBK1458/ (Accessed on June 14, 2011).
- Gene Reviews: Argininosuccinate lyase deficiency. http://www.ncbi.nlm.nih.gov/books/NBK51784/ (Accessed on June 14, 2011).
- Gene Reviews: Arginase deficiency. http://www.ncbi.nlm.nih.gov/books/NBK1159/ (Accessed on June 14, 2011).
- Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996; 43:127.
- Moammar H, Cheriyan G, Mathew R, Al-Sannaa N. Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008. Ann Saudi Med 2010; 30:271.
- Batshaw ML, Tuchman M, Summar M, et al. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014; 113:127.
- Braissant O. Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1:S3.
- GeneReviews: Arginase Deficiency. http://www.ncbi.nlm.nih.gov/books/NBK1159/ (Accessed on September 21, 2011).
- Brusilow SW, Horwich AL. Urea cycle enzymes. In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1909.
- Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol 2002; 7:27.
- Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 1996; 335:855.
- Gardeitchik T, Humphrey M, Nation J, Boneh A. Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr 2012; 161:328.
- Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr 2008; 97:1420.
- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102:E69.
- Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138:S30.
- Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999; 134:268.
- Butterworth RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis 1998; 21 Suppl 1:6.
- Maestri NE, Lord C, Glynn M, et al. The phenotype of ostensibly healthy women who are carriers for ornithine transcarbamylase deficiency. Medicine (Baltimore) 1998; 77:389.
- Serrano M, Martins C, Pérez-Dueñas B, et al. Neuropsychiatric manifestations in late-onset urea cycle disorder patients. J Child Neurol 2010; 25:352.
- Sedel F, Baumann N, Turpin JC, et al. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis 2007; 30:631.
- Houston B, Reiss KA, Merlo C. Healthy, but comatose. Am J Med 2011; 124:303.
- Iorio R, Sepe A, Giannattasio A, et al. Hypertransaminasemia in childhood as a marker of genetic liver disorders. J Gastroenterol 2005; 40:820.
- Miles L, Heubi JE, Bove KE. Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease. J Pediatr Gastroenterol Nutr 2005; 40:471.
- 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.
- Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet 2011; 157C:45.
- Erez A, Nagamani SC, Shchelochkov OA, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 2011; 17:1619.
- Arn PH, Hauser ER, Thomas GH, et al. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. N Engl J Med 1990; 322:1652.
- Tuchman M, Yudkoff M. Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. Mol Genet Metab 1999; 66:10.
- Usmani SS, Cavaliere T, Casatelli J, Harper RG. Plasma ammonia levels in very low birth weight preterm infants. J Pediatr 1993; 123:797.
- Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1:S20.
- 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; 322:1641.
- Burlina AB, Ferrari V, Dionisi-Vici C, et al. Allopurinol challenge test in children. J Inherit Metab Dis 1992; 15:707.
- Bonham JR, Guthrie P, Downing M, et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis 1999; 22:174.
- Ahrens MJ, Berry SA, Whitley CB, et al. Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation. Am J Med Genet 1996; 66:311.
- Scaglia F, Zheng Q, O'Brien WE, et al. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics 2002; 109:150.
- 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.
- 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; 93:313.
- Shchelochkov OA, Li FY, Geraghty MT, et al. High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH. Mol Genet Metab 2009; 96:97.
- Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12:745.
- Scaglia F, Brunetti-Pierri N, Kleppe S, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 2004; 134:2775S.
- Wilcken B. Expanded newborn screening: reducing harm, assessing benefit. J Inherit Metab Dis 2010; 33:S205.
- Cavicchi C, Malvagia S, la Marca G, et al. Hypocitrullinemia in expanded newborn screening by LC-MS/MS is not a reliable marker for ornithine transcarbamylase deficiency. J Pharm Biomed Anal 2009; 49:1292.
- Huang HP, Chu KL, Chien YH, et al. Tandem mass neonatal screening in Taiwan--report from one center. J Formos Med Assoc 2006; 105:882.
- Walser M, Stewart PM. Organic acidaemia and Hyperammonaemia: review. J Inherit Metab Dis 1981; 4:177.
- Salvi S, Santorelli FM, Bertini E, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 2001; 57:911.
- Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 1999; 22:151.
- Lemay JF, Lambert MA, Mitchell GA, et al. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr 1992; 121:725.
- Gene Reviews: Citrin deficiency. http://www.ncbi.nlm.nih.gov/books/NBK1181/ (Accessed on June 14, 2011).
- Tonini MC, Bignamini V, Mattioli M. Headache and neuropsychic disorders in the puerperium: a case report with suspected deficiency of urea cycle enzymes. Neurol Sci 2011; 32 Suppl 1:S157.
- Ko JM, Kim GH, Kim JH, et al. Six cases of citrin deficiency in Korea. Int J Mol Med 2007; 20:809.
- Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab 2012; 106:12.
- van Karnebeek CD, Sly WS, Ross CJ, et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 2014; 94:453.
- Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998; 338:1352.
- Hudak ML, Jones MD Jr, Brusilow SW. Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation. J Pediatr 1985; 107:712.
- Barnes PM, Wheldon DB, Eggerding C, et al. Hyperammonaemia and disseminated herpes simplex infection in the neonatal period. Lancet 1982; 1:1362.
- CLINICAL FEATURES
- Typical presentation
- Atypical presentation
- LABORATORY FINDINGS
- Plasma amino acid/urine orotic acid analyses
- Enzyme analysis
- Specialized testing
- DNA mutation analysis
- Prenatal testing
- Newborn screening
- DIFFERENTIAL DIAGNOSIS