EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND HINDRANCE OF UREA CYCLE ERROR OF METABOLISM
Keywords:Inborn errors of metabolism, Urea cycle disorders, Urea cycle disorders classification, Management of urea cycle disorders
Inborn errors of metabolism (IEMs) are a class of genetic disorders that are rare individually, but collectively they occur in common terms exhibiting an average prevalence of 1 in 1000 individuals. One of the most commonly occurring IEMs is the urea cycle disorders (UCDs), which are a group of unusual disorders that have an effect on the urea cycle, a sequence of metabolic processes through which nitrogen is transformed into urea and expelled from the body by the urine. These diseases are the primary cause of hereditary hyperammonemia, and they can result in developmental disabilities, epilepsy, loss of psychomotor control, and death. UCDs are most commonly diagnosed during infancy, although certain infants do not exhibit symptoms until they are in their early childhood. IEMs are precisely diagnosed and recorded through tandem mass spectroscopy-based newborn screening. Recent advances in IEMs include new therapies based on dietary modification, enzyme replacement therapy, development of novel compounds, and diagnosis involving untargeted metabolomics and whole-exome sequencing are also widely being used in new disease discovery. Modern improvements in diagnosis and care have increased the prognosis significantly for a lot of children with IEM. It has been suggested that expanded access to awareness of IEMs is the most significant change leading to better treatment. The purpose of this review is to provide an overview on IEM and present in-depth knowledge about the UCDs including their subtypes.
Arnold GL. Inborn errors of metabolism in the 21st century: Past to present. Ann Transl Med 2018;6:10-20.
Vernon HJ. Inborn errors of metabolism: advances in diagnosis and therapy. JAMA Pediatr 2015;169:778-82.
Garrod A. The incidence of alkaptonuria: A study in chemical individuality. Lancet 1902;160:1616-20.
Ferreira CR, van Karnebeek CD, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med 2019;21:102-6.
Morava E, Rahman S, Peters V, Baumgartner MR, Patterson, Zschocke J. Quo vadis: The re-definition of inborn metabolic diseases. J Inherit Metab Dis 2015;38:1003-6.
Leonard JV, Morris AA. Inborn errors of metabolism around time of birth. Lancet 2000;356:583-7.
Argmann CA, Houten SM, Zhu J, Schadt EE. A next generation multiscale view of inborn errors of metabolism. Cell Metab 2016;23:13-26.
Burton BK. Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics 1998;102:69.
Adam S, Champion H, Daly A, Dawson S, Dixon M, Dunlop C, et al. Dietary management of urea cycle disorders: UK practice. J Hum Nutr Dietetics 2012;25:398-404.
Ozturk K, McKinney AM, Nascene D. Urea cycle disorders: A neuroimaging pattern approach using diffusion and FLAIR MRI. J Neuroimag 2021;31:144-50.
Maestri, NE, McGowan KD, Brusilow SW. Plasma glutamine concentration: A guide in the management of urea cycle disorders. J Pediatr 1992;121:259-61.
Stojanovic VD, Doronjski AR, Barisic N, Kovacevic BB, Pavlovic VS. A case of transient hyperammonemia in the newborn transient neonatal hyperammonemia. J Matern Fetal Neonatal Med 2010;23:347-50.
Hwang MW, Yu ST, Oh YK. A case of severe transient hyperammonemia in a newborn. Korean J Pediatr 2010;53:598-602.
Rice GM, Steiner RD. Inborn errors of metabolism (metabolic disorders). Pediatr Rev 2016;37:3-15.
Gropman AL, Batshaw ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab 2004;81:58-62.
Burton BK. Urea cycle disorders. Clin Liver Dis 2000;4:815-30.
Therrell BL Jr. US newborn screening policy dilemmas for the twenty-first century. Mol Genet Metab 2000;74:64-74.
El-Hattab AW. Inborn errors of metabolism. Clin Perinatol 2015;42:413-39.
Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, et al. Current status of newborn screening worldwide: 2015. In: Seminars in Perinatology. Vol. 39. WB Saunders 2015. p. 171-87.
Feuchtbaum L, Carter J, Dowray S, Currier RJ, Lorey F. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet Med 2012;14:937-45.
Mak CM, Lee HC, Chan AY, Lam CW. Inborn errors of metabolism and expanded newborn screening: Review and update. Crit Rev Clin Lab Sci 2013;50:142-62.
Mew NA, Simpson KL, Gropman AL, Lanpher BC, Chapman, KA, Summar ML. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, editors. Urea Cycle Disorders Overview. Seattle, WA: GeneReviews®; 2003.
Matsumoto S, Häberle J, Kido J, Mitsubuchi H, Endo F, Nakamura K. Urea cycle disorders update. J Hum Genet 2019;64:833-47.
Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 2004;134:2775-82.
Machado MC, da Silva FP. Hyperammonemia due to urea cycle disorders: A potentially fatal condition in the intensive care setting. J Intens Care 2014;2:1-5.
Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med 2015;17:561-8.
Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 1998;21:101-11.
Ezgu F. Inborn errors of metabolism. Adv Clin Chem 2016;73:195-250.
Saudubray JM, Garcia-Cazorla À. Inborn errors of metabolism overview: Pathophysiology, manifestations, evaluation, and management. Pediatr Clin North Am 2018;65:179-208.
Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, et al. Genetic variation in the urea cycle: A model resource for investigating key candidate genes for common diseases. Hum Mutat 2009;30:56-60.
Aoshima T, Kajita M, Sekido Y, Mimura S, Itakura A, Yasuda I, et al. Carbamoyl phosphate synthetase I deficiency: Molecular genetic findings and prenatal diagnosis. Prenat Diagn 2001;21:634-7.
Martínez AI, Pérez-Arellano I, Pekkala S, Barcelona B, Cervera J. Genetic, structural and biochemical basis of carbamoyl phosphate synthetase 1 deficiency. Mol Genet Metab 2010;101:311-23.
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;10:1-4.
Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, LeMons C, et al. Establishing a consortium for the study of rare diseases: The urea cycle disorders consortium. Mol Genet Metab 2010;100:97-105.
Gordon N. Ornithine transcarbamylase deficiency: A urea cycle defect. Eur J Paediatr Neurol 2003;7:115-21.
Lichter-Konecki U, Caldovic L, Morizono H, Simpson K. Ornithine Transcarbamylase Deficiency. Seattle, WA: University of Washington, Seattle; 2016.
Campbell AG, Rosenberg LE, Snodgrass PJ, Nuzum CT. Ornithine transcarbamylase deficiency: A cause of lethal neonatal hyperammonemia in males. N Engl J Med 1973;288:1-6.
Torkzaban M, Haddad A, Baxter JK, Berghella V, Gahl WA, Al‐ Kouatly HB. Maternal ornithine transcarbamylase deficiency, a genetic condition associated with high maternal and neonatal mortality every clinician should know: A systematic review. Am J Med Genet Part A 2019;179:2091-100.
Batshaw ML, Berry GT. Use of citrulline as a diagnostic marker in the prospective treatment of urea cycle disorders. J Pediatr 1991;118:914-7.
Faghfoury H, Baruteau J, de Baulny HO, Häberle J, Schulze A. Transient fulminant liver failure as an initial presentation in citrullinemia Type I. Mol Genet Metab 2011;102:413-7.
Maestri NE, Clissold DB, Brusilow SW. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 1995;127:929-35.
Woo HI, Park HD, Lee YW. Molecular genetics of citrullinemia Types I and II. Clin Chim Acta 2014;431:1-8.
Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, et al. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: Prenatal and postnatal diagnosis in five unrelated families. J Inherit Metab Dis 2002;25:399-410.
Baruteau J, Diez‐Fernandez C, Lerner S, Ranucci G, Gissen P, Dionisi‐Vici C, et al. Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects. J Inherit Metab Dis 2019;42:1147-61.
Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency argininosuccinic aciduria and beyond. In: American Journal of Medical Genetics Part C: Seminars in Medical Genetics. Hoboken: Wiley Subscription Services, Inc., A Wiley Company; 2011;157:45-53.
Therrell BL, Currier R, Lapidus D, Grimm M, Cederbaum SD. Newborn screening for hyperargininemia due to arginase 1 deficiency. Mol Genet Metab 2017;121:308-13.
Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: The original patients and their natural history, and a review of the literature. Amino Acids 2015;47:1751-62.
Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab 2005;84:243-51.
Christopher R, Rajivnath V, Shetty KT. Arginase deficiency. Indian J Pediatr 1997;64:266-9.
Olgac A, Kasapkara ÇS, Kilic M, Derinkuyu BE, Azapagasi E, Kesici S, et al. A rare urea cycle disorder in a neonate: N-acetylglutamate synthetase deficiency. Arch Argen Pediatr 2020;118:545-8.
Caldovic L, Tuchman M. N-acetylglutamate and its changing role through evolution. Biochem J 2003;372:279-90.
Kenneson A, Singh RH. Presentation and management of N-acetylglutamate synthase deficiency: A review of the literature. Orphanet J Rare Dis 2020;15:1-10.
Batshaw ML, Tuchman M, Summar M, Seminara J, Urea cycle disorders consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab 2014;113:127-30.
Camacho JA, Rioseco-Camacho N, Andrade D, Porter J, Kong J. Cloning and characterization of human ORNT2: A second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Mol Genet Metab 2003;79:257-71.
Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009;66:96-101.
Kleppe S, Mian A, Lee B. Urea cycle disorders. Curr Treat Options Neurol 2003;5:309-19.
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 2: Homocystinuria, organic acidurias, and urea cycle disorders. Arch Neurol 2010;67:148-53.
Ferreira CR, van Karnebeek CD. Inborn errors of metabolism. Handb Clin Neurol 2019;162:449-81.
Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30:865-79.
Nassogne MC, Heron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: Management and outcome. J Inherit Metab Dis 2005;28:407-14.
Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005;21:1-8.
Deignan JL, Cederbaum SD, Grody WW. Contrasting features of urea cycle disorders in human patients and knockout mouse models. Mol Genet Metab 2008;93:7-14.
Liu F, Bao LS, Liang RJ, Zhao XY, Li Z, Du ZF, et al. Identification of rare variants causing urea cycle disorders: A clinical, genetic, and biophysical study. J Cell Mol Med 2021;25:4099-109.
Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: Role of the nephrologist. Am J Kidney Dis 2001;37:1069-80.
Gropman AL, Prust M, Breeden A, Fricke S, VanMeter J. Urea cycle defects and hyperammonemia: Effects on functional imaging. Metab Brain Dis 2013;28:269-75.
Helman G, Pacheco-Colón I, Gropman AL. The urea cycle disorders. Semin Neurol 2014;34:341-9.
Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Smith M, et al. Urea cycle disorders: Clinical presentation outside the newborn period. Crit Care Clin 2005;21 Suppl 4:9-17.
Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr 2003;162:29-33.
Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, et al. The incidence of urea cycle disorders. Mol Genet Metab 2013;110:179-80.
Tarini BA. The current revolution in newborn screening: New technology, old controversies. Arch Pediatr Adolesc Med 2007;161:767-72.
Marsden D, Larson C, Levy HL. Newborn screening for metabolic disorders. J Pediatr 2006;148:577-84.
Rüfenacht, V, Häberle J. Mini-review: Challenges in newborn screening for urea cycle disorders. Int J Neonat Screen 2015;1:27-35.
Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012;7:1-30.
Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol 2002;7:27-35.
Urv TK, Parisi MA. Newborn screening: Beyond the spot. In: de la Paz MP, Taruscio D, Groft S, editors. Rare Diseases Epidemiology: Update and Overview. Advances in Experimental Medicine and Biology. Cham: Springer; 2017. p. 323-46.
Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis 2019;42:1192-230.
Singh RH, Rhead WJ, Smith W, Lee B, Summar ML. Genetic counseling issues in urea cycle disorders. Crit Care Clin 2005;21 Suppl 4:37-44.
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr 2001;138:21-9.
Ali R, Nagalli S. Urea Cycle Enzyme Defects. Treasure Island, FL: StatPearls Publishing; 2021.
Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 2007;30:880-7.
Leonard JV. The nutritional management of urea cycle disorders. J Pediatr 2001;138:40-5.
Singh RH, Rhead WJ, Smith W, Lee B, Summar M. Nutritional management of urea cycle disorders. Crit Care Clin 2005;21 Suppl 4:27-35.
Leonard JV, Platt MP, Morris AA. Hypothesis: Proposals for the management of a neonate at risk of hyperammonaemia due to a urea cycle disorder. Eur J Pediatr 2008;167:305-9.
Gardeitchik T, Humphrey M, Nation J, Boneh A. Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr 2012;161:328-32.
Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007;3562282-92.
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;81:79-85.
Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: Twenty years later. J Pediatr 2001;138:46-55.
Nakamura K, Kido J, Mitsubuchi H, Endo F. Diagnosis and treatment of urea cycle disorder in Japan. Pediatr Int 2014;56:506-9.
Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001;138:56-61.
Saudubray JM, Touati G, Delonlay P, Jouvet P, Narcy C, Laurent J, et al. Liver transplantation in urea cycle disorders. Eur J Pediatr 1999;158:55-9.
Lee B, Goss J. Long-term correction of urea cycle disorders. J Pediatr 2001;138:62-71.
Horslen SP, McCowan TC, Goertzen TC, Warkentin PI, Cai HB, Strom SC, et al. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder. Pediatrics 2003;111:1262-7.
Whitington PF, Alonso EM, Boyle JT, Molleston JP, Rosenthal P, Emond JC, et al. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis 1998;21:112-8.
Leonard JV, McKiernan PJ. The role of liver transplantation in urea cycle disorders. Mol Genet Metab 2004;81:74-8.
Bigot A, Tchan MC, Thoreau B, Blasco H, Maillot F. Liver involvement in urea cycle disorders: A review of the literature. J Inherit Metab Dis 2017;40:757-69.
Soria LR, Ah Mew N, Brunetti-Pierri N. Progress and challenges in development of new therapies for urea cycle disorders. Hum Mol Genet 2019;28:42-8.
Piccolo P, Rossi A, Brunetti-Pierri N. Liver-directed gene-based therapies for inborn errors of metabolism. Exp Opin Biol Ther 2020;1-12.
Alexander IE, Kok C, Dane AP, Cunningham SC. Gene therapy for metabolic disorders: An overview with a focus on urea cycle disorders. J Inherit Metab Dis 2012;35:641-5.
Kok CY, Cunningham SC, Kuchel PW, Alexander IE. Insights into gene therapy for urea cycle defects by mathematical modeling. Hum Gene Ther 2019;30:1385-94.
Lee B, Singh RH, Rhead WJ, Smith W, Summar ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin 2005;21 Suppl 4:19-25.
Plass AM, van El CG, Pieters T, Cornel MC. Neonatal screening for treatable and untreatable disorders: Prospective parents opinions. Pediatrics 2010;125:99-106.
Stepien KM, Geberhiwot T, Hendriksz CJ, Treacy EP. Challenges in diagnosing and managing adult patients with urea cycle disorders. J Inherit Metab Dis 2019;42:1136-46.
Cederbaum JA, LeMons C, Rosen M, Ahrens M, Vonachen S, Cederbaum SD. Psychosocial issues and coping strategies in families affected by urea cycle disorders. J Pediatr 2001;138:72-80.