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)
- 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.
- 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