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Chapter 38 - Urea Cycle Disorders in Children

from Section IV - Metabolic Liver Disease

Published online by Cambridge University Press:  19 January 2021

By
Kimberly A. Kripps ,
Derek A. Wong  and
Shawn E. McCandless
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
Edited in association with
Jorge A. Bezerra ,
Cara L. Mack  and
Benjamin L. Shneider
Frederick J. Suchy
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Ronald J. Sokol
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
William F. Balistreri
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Jorge A. Bezerra
Affiliation:
Cincinnati Children’s Hospital Medical Center, Cincinnati
Cara L. Mack
Affiliation:
University of Colorado, Children’s Hospital Colorado, Aurora
Benjamin L. Shneider
Affiliation:
Texas Children’s Hospital, Houston
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Summary

The urea cycle, first described in 1932 by Krebs and Henseleit, is the only metabolic pathway responsible for converting nitrogenous waste, produced by the breakdown of protein and other nitrogen-containing molecules into urea, which can be easily excreted from the body (Figure 38.1). Urea cycle disorders (UCDs) result from defects in this pathway and lead to an inability to rid excess nitrogen from the body, resulting in accumulation of nitrogen species, namely ammonia and glutamine, which are toxic in high concentrations. The incidence of these disorders is estimated to be at least one in 35,000 births [1], but partial defects, which may not manifest until later in life, may make this number higher.

Type
Chapter
Information
Liver Disease in Children , pp. 698 - 709
Publisher: Cambridge University Press
Print publication year: 2021

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References

Summar, ML, Koelker, S, Freedenberg, D, et al. The incidence of urea cycle disorders. Mol Genet Metab 2013;110(1–2):179–80.Google Scholar
Adeva, MM, Souto, G, Blanco, N, Donapetry, C. Ammonium metabolism in humans. Metabolism 2012;61(11):1495–511.CrossRefGoogle ScholarPubMed
Braissant, O, McLin, VA, Cudalbu, C. Ammonia toxicity to the brain. J Inherit Metab Dis 2013;36(4):595–612.CrossRefGoogle ScholarPubMed
Batshaw, ML, Tuchman, M, Summar, M, Seminara, J, Members of the Urea Cycle Disorders C. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014;113(1–2):127–30.CrossRefGoogle ScholarPubMed
Fecarotta, S, Parenti, G, Vajro, P, et al. HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis-like presentation. J Inherit Metab Dis 2006;29(1):186–9.Google Scholar
Gallagher, RC, Lam, C, Wong, D, Cederbaum, S, Sokol, RJ. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr 2014;164(4):720–5 e726.CrossRefGoogle ScholarPubMed
Mori, T, Nagai, K, Mori, M, et al. Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency. Pediatr Dev Pathol 2002;5(6):597–601.Google Scholar
Mustafa, A, Clarke, JT. Ornithine transcarbamoylase deficiency presenting with acute liver failure. J Inherit Metab Dis 2006;29(4):586.Google Scholar
Tuchman, M, Mauer, SM, Holzknecht, RA, Summar, ML, Vnencak-Jones, CL. Prospective versus clinical diagnosis and therapy of acute neonatal hyperammonaemia in two sisters with carbamyl phosphate synthetase deficiency. J Inherit Metab Dis 1992;15(2):269–77.Google Scholar
Summar, ML, Barr, F, Dawling, S, et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005;21(4 Suppl.):S1–8.CrossRefGoogle ScholarPubMed
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(10):1420–5.Google Scholar
Batshaw, ML, Brusilow, SW. Valproate-induced hyperammonemia. Ann Neurol 1982;11(3):319–21.CrossRefGoogle ScholarPubMed
Castro-Gago, M, Rodrigo-Saez, E, Novo-Rodriguez, I, Camina, MF, Rodriguez-Segade, S. Hyperaminoacidemia in epileptic children treated with valproic acid. Childs Nerv Syst 1990;6(8):434–6.Google Scholar
Kugoh, T, Yamamoto, M, Hosokawa, K. Blood ammonia level during valproic acid therapy. Jpn J Psychiatry Neurol 1986;40(4):663–8.Google Scholar
Mitchell, RB, Wagner, JE, Karp, JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases. Am J Med 1988;85(5):662–7.Google Scholar
Vainstein, G, Korzets, Z, Pomeranz, A, Gadot, N. Deepening coma in an epileptic patient: the missing link to the urea cycle. Hyperammonaemic metabolic encephalopathy. Nephrol Dial Transplant 2002;17(7):1351–3.Google Scholar
Baddour, E, Tewksbury, A, Stauner, N. Valproic acid-induced hyperammonemia: incidence, clinical significance, and treatment management. Ment Health Clin 2018;8(2):73–7.Google Scholar
Haberle, J, Pauli, S, Schmidt, E, Schulze-Eilfing, B, Berning, C, Koch, HG. Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). Mol Genet Metab 2003;80(3):302–6.Google Scholar
Erez, A, Nagamani, SC, Lee, B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet 2011;157C(1):45–53.Google ScholarPubMed
Saheki, T, Song, YZ (1993). Citrin deficiency. In: Adam, MP, Ardinger, HH, Pagon, RA, et al., (Eds.), GeneReviews((R)). Seattle, WA: University of Washington.Google Scholar
Ohura, T, Kobayashi, K, Tazawa, Y, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 2007;30(2):139–44.CrossRefGoogle ScholarPubMed
Naito, E, Ito, M, Matsuura, S, et al. Type II citrullinaemia (citrin deficiency) in a neonate with hypergalactosaemia detected by mass screening. J Inherit Metab Dis 2002;25(1):71–6.Google Scholar
Saheki, T, Kobayashi, K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002;47(7):333–41.Google Scholar
Saheki, T, Kobayashi, K, Iijima, M, et al. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 2004;81(Suppl. 1):S20–26.CrossRefGoogle ScholarPubMed
Ben-Shalom, E, Kobayashi, K, Shaag, A, et al. Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids. Mol Genet Metab 2002;77(3):202–8.Google Scholar
Tamamori, A, Okano, Y, Ozaki, H, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr 2002;161(11):609–13.Google Scholar
Martinelli, D, Diodato, D, Ponzi, E, et al. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis 2015;10:29.Google Scholar
Hommes, FA, Eller, AG, Scott, DF, Carter, AL. Separation of ornithine and lysine activities of the ornithine-transcarbamylase-catalyzed reaction. Enzyme 1983;29(4):271–7.CrossRefGoogle ScholarPubMed
da Fonseca-Wollheim, F. Deamidation of glutamine by increased plasma gamma-glutamyltransferase is a source of rapid ammonia formation in blood and plasma specimens. Clin Chem 1990;36(8 Pt 1): 1479–82.Google Scholar
Nikolac, N, Omazic, J, Simundic, AM. The evidence-based practice for optimal sample quality for ammonia measurement. Clin Biochem 2014;47(12):991–5.Google Scholar
Steiner, RD, Cederbaum, SD. Laboratory evaluation of urea cycle disorders. J Pediatr 2001;138(1 Suppl.):S21–9.Google Scholar
Summar, M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001;138(1 Suppl.):S30–9.Google Scholar
Usmani, SS, Cavaliere, T, Casatelli, J, Harper, RG. Plasma ammonia levels in very low birth weight preterm infants. J Pediatr 1993;123(5):797–800.Google Scholar
Tuchman, M, Georgieff, MK. Transient hyperammonemia of the newborn: a vascular complication of prematurity? J Perinatol 1992;12(3):234–6.Google Scholar
Hanudel, M, Avasare, S, Tsai, E, Yadin, O, Zaritsky, J. A biphasic dialytic strategy for the treatment of neonatal hyperammonemia. Pediatr Nephrol 2014;29(2):315–20.Google Scholar
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(3):379–82.Google Scholar
Batshaw, ML. Sodium benzoate and arginine: alternative pathway therapy in inborn errors of urea synthesis. Prog Clin Biol Res 1983;127:69–83.Google ScholarPubMed
Batshaw, ML, Brusilow, SW. Evidence of lack of toxicity of sodium phenylacetate and sodium benzoate in treating urea cycle enzymopathies. J Inherit Metab Dis 1981;4(4):231.Google Scholar
Butterworth, RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis 1998;21(Suppl. 1):6–20.Google Scholar
Willard-Mack, CL, Koehler, RC, Hirata, T, et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 1996;71(2):589–99.Google Scholar
Caldovic, L, Morizono, H, Daikhin, Y, et al. Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr 2004;145(4):552–4.Google Scholar
Kuchler, G, Rabier, D, Poggi-Travert, F, et al. Therapeutic use of carbamylglutamate in the case of carbamoyl-phosphate synthetase deficiency. J Inherit Metab Dis 1996;19(2):220–2.Google Scholar
Shi, D, Zhao, G, Ah Mew, N, Tuchman, M. Precision medicine in rare disease: mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes. Mol Genet Metab 2017;120(3):198–206.Google Scholar
Ah Mew, N, McCarter, R, Daikhin, Y, et al. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate. J Pediatr 2014;165(2):401–3 e403.Google Scholar
Ah Mew, N, Cnaan, A, McCarter, R, et al. Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: lessons from the N-Carbamylglutamate Consortium. Transl Sci Rare Dis 2018;3(3–4):157–70.Google Scholar
Fujiwara, M. Role of ammonia in the pathogenesis of brain edema. Acta Med Okayama 1986;40(6):313–20.Google Scholar
Fujiwara, M, Watanabe, A, Shiota, T, et al. Hyperammonemia-induced cytotoxic brain edema under osmotic opening of blood-brain barrier in dogs. Res Exp Med 1985;185(6):425–7.Google Scholar
Wiwattanadittakul, N, Prust, M, Gaillard, WD, et al. The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism. Mol Genet Metab 2018;125(3):235–40.Google Scholar
Msall, M, Batshaw, ML, Suss, R, Brusilow, SW, Mellits, ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984;310(23):1500–5.Google Scholar
Rabier, D, Narcy, C, Bardet, J, Parvy, P, Saudubray, JM, Kamoun, P. Arginine remains an essential amino acid after liver transplantation in urea cycle enzyme deficiencies. J Inherit Metab Dis 1991;14(3):277–80.Google Scholar
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(8):2413–18.Google Scholar
Crowe, L, Anderson, V, Hardikar, W, Boneh, A. Cognitive and behavioural outcomes of paediatric liver transplantation for ornithine transcarbamylase deficiency. JIMD Rep 2019;43:19–25.Google Scholar
Campeau, PM, Pivalizza, PJ, Miller, G, et al. Early orthotopic liver transplantation in urea cycle defects: follow up of a developmental outcome study. Mol Genet Metab 2010;100(Suppl. 1):S84–7.CrossRefGoogle ScholarPubMed
Wilnai, Y, Blumenfeld, YJ, Cusmano, K, et al. Prenatal treatment of ornithine transcarbamylase deficiency. Mol Genet Metab 2018;123(3):297–300.Google Scholar
Gropman, AL, Fricke, ST, Seltzer, RR, et al. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab 2008;95(1–2):21–30.Google Scholar
Waisbren, SE, Gropman, AL, Members of the Urea Cycle Disorders C, Batshaw, ML. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis 2016;39(4):573–84.CrossRefGoogle ScholarPubMed
Bireley, WR, Van Hove, JL, Gallagher, RC, Fenton, LZ. Urea cycle disorders: brain MRI and neurological outcome. Pediatr Radiol 2012;42(4):455–62.Google Scholar
Posset, R, Garbade, SF, Boy, N, et al. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders: a successful strategy for clinical research of rare diseases. J Inherit Metab Dis 2019;42(1):93–106.Google Scholar

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