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Diagnosis and treatment of urea cycle disorders

Year 2011, Volume: 3 Issue: 1, 2 - 11, 01.01.2011

Abstract

Urea cycle disorders (UCDs) comprise a group of inherited defects of metabolism affecting the detoxification of excess nitrogen and, hereby, leading to hyperammonemia. The urea cycle consists of six consecutive enzymatic steps and is located both in the mitochondria and cytosol of periportal hepatocytes. In addition, two transporters are required for the urea cycle function. Besides the detoxification of excess nitrogen, the endogenous synthesis of the amino acid arginine is the second role of the urea cycle. The clinical presentation of UCDs comprises a continuum ranging from early onset hyperammonemic decompensation in severe defects to late onset presentation in less severe affected patients at any age. Since ammonia is primarily toxic to the central nervous system, signs and symptoms of UCDs are mainly neurological but, unfortunately, highly unspecific. Therefore, it can be challenging to clinically diagnose patients suffering from UCDs. If a UCD is suspected, ammonia should be measured immediately. To confirm the diagnosis, a variety of biochemical, enzymatic and genetic tools exist. Most UCD patients need a strict treatment protocol consisting of dietary protein restriction, nitrogen scavenger drugs, and vitamin and amino acid supplementations. Treatment must be followed lifelong unless liver transplantation is performed. Patients with UCDs are still affected by a poor outcome quoad vitam et sanitam. To improve both survival rates as well as the quality of life in surviving patients will largely depend on an increased awareness of all medical professionals towards this group of inherited metabolic defects.

References

  • Brusilow S, Horwich A 2001 Urea cycle enzymes. In Scriver C, Beaudet A, Sly W, Valle
  • D (eds) The metabolic & molecular bases of inherited disease. McGraw-Hill, New York, pp 1963.
  • Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, et al. 2001 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. Embo J 2001; 20: 5069.
  • Salvi S, Santorelli FM, Bertini E, Boldrini R, Meli C, Donati A, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia- homocitrullinuria syndrome. Neurology 2001; 57: 914.
  • Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet ; 22: 159-163. Camacho JA, Obie C, Biery B, Goodman BK, Hu CA, Almashanu S, et al. Hyperornithinaemia- hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet ; 22: 151-158. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996; 43: 127-170.
  • Bachmann C. Mechanisms of hyperammonemia. Clin Chem Lab Med 2002; 40: 653-662.
  • Meyburg J, Hoffmann GF. Liver transplantation for inborn errors of metabolism. Transplantation ; 80: S135-137. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 2003; 162: 410-416.
  • Nassogne MC, Heron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005; 28: 407
  • Teufel U, Weitz J, Flechtenmacher C, Prietsch V, Schmidt J, Hoffmann GF, et al. High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure. Pediatr Transplant 2009. Apr 23 (Epub ahead of print)
  • Serrano M, Martins C, Perez-Duenas B, Gomez- Lopez Neuropsychiatric manifestations in late-onset urea cycle disorder patients. J Child Neurol 2010; 25: 358. Fons C, et al.
  • Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 2005; 21:S9-17.
  • Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, et al. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 2009; : 263-269.
  • Tuchman M. The clinical, biochemical, and molecular spectrum of ornithine transcarbamylase deficiency. J Lab Clin Med 1992; 120: 836-850.
  • Ahrens MJ, Berry SA, Whitley CB, Markowitz DJ, Plante RJ, Tuchman M. Clinical and biochemical heterogeneity in females of a large pedigree deficiency due to the R141Q mutation. Am J Med Genet 1996; 66: 311-315. transcarbamylase
  • Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 2005; 44: 61-98.
  • Schmidt J, Kroeber S, Irouschek A, Birkholz T, Schroth M, Albrecht S. Anesthetic management of patients with ornithine transcarbamylase deficiency. Paediatr Anaesth 2006; 16: 333-337.
  • Valle D, Simell O. The hyperornithinemias. In Scriver C, Beaudet A, Sly W, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill New York, 2001, pp –1896.
  • Barsotti RJ. Measurement of ammonia in blood. J Pediatr 2001; 138: S11-19;discussion S19-20.
  • Bachmann C. Interpretation of plasma amino acids in the follow-up of patients: the impact of compartmentation. J Inherit Metab Dis 2008; 31: 20.
  • Brown GW Jr, Cohen PP. Comparative biochemistry of urea synthesis. I. Methods for the quantitative assay of urea cycle enzymes in liver. J Biol Chem 1959; 234: 1769-1774.
  • Häberle J, Schmidt E, Pauli S, Rapp B, Christensen E, Wermuth B, et al. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Hum Mutat 2003; 21: 444.
  • Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat 2006; 27: 626-632.
  • Engel K, Nuoffer JM, Mühlhausen C, Klaus V, Largiader CR, Tsiakas K, et al. Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. Mol Genet Metab 2008; 94: 292-297.
  • Shchelochkov OA, Li FY, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, et al. High-frequency detection of deletions and variable transcarbamylase (OTC) locus by oligonucleotide array CGH. Mol Genet Metab 2009; 96: 97-105.
  • Häberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn 2004; 24: 378-383.
  • Chadefaux-Vekemans B, Rabier D, Cadoudal N, Lescoat A, Chabli A, Aupetit J, et al. Prenatal diagnosis of some metabolic diseases using early amniotic fluid samples: report of a 15 years, experience. Prenat Diagn 2006; 26: 814-818.
  • Kleijer WJ, Thoomes R, Galjaard H, Wendel U, Fowler B. First-trimester (chorion biopsy) diagnosis methylmalonicaciduria. Lancet 1984; 2: 1340. citrullinaemia and
  • Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N- acetylglutamate synthase deficiency. Eur J Pediatr ; 169: 197-199. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis ; 30: 880-887. Singh RH, Rhead WJ, Smith W, Lee B, Sniderman King L, Summar M. Nutritional management of urea cycle disorders. Crit Care Clin 2005; 21: S27-35.
  • Leonard JV. The nutritional management of urea cycle disorders. J Pediatr 2001; 138: S40-44.
  • 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: S79-85. Scaglia management and amino acid supplementation in urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1: S72-76. in nutritional
  • Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 1998; 21 Suppl 1: 101-111.
  • Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr 2003; 162 Suppl 1: S29
  • Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001; : S56-60.
  • Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith W, Summar ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin 2005; 21: S19-25.
  • Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of patients with urea cycle disorders from a 21- year, hyperammonaemic episodes. Acta Paediatr 2008; :1420-1425. study of acute
  • Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009; 11:823-835.
  • Bachmann C. Hyperammonaemia: review of current treatment strategies. In Bachmann C, Häberle J, Leonard JV (eds) Pathophysiology and management publications, pp 157-173. SPS Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, 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: 1332-1342.
  • Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010; 100 Suppl : S77-83.
  • Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009; 87: 636-641.
Year 2011, Volume: 3 Issue: 1, 2 - 11, 01.01.2011

Abstract

References

  • Brusilow S, Horwich A 2001 Urea cycle enzymes. In Scriver C, Beaudet A, Sly W, Valle
  • D (eds) The metabolic & molecular bases of inherited disease. McGraw-Hill, New York, pp 1963.
  • Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, et al. 2001 Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. Embo J 2001; 20: 5069.
  • Salvi S, Santorelli FM, Bertini E, Boldrini R, Meli C, Donati A, et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia- homocitrullinuria syndrome. Neurology 2001; 57: 914.
  • Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet ; 22: 159-163. Camacho JA, Obie C, Biery B, Goodman BK, Hu CA, Almashanu S, et al. Hyperornithinaemia- hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet ; 22: 151-158. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996; 43: 127-170.
  • Bachmann C. Mechanisms of hyperammonemia. Clin Chem Lab Med 2002; 40: 653-662.
  • Meyburg J, Hoffmann GF. Liver transplantation for inborn errors of metabolism. Transplantation ; 80: S135-137. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 2003; 162: 410-416.
  • Nassogne MC, Heron B, Touati G, Rabier D, Saudubray JM. Urea cycle defects: management and outcome. J Inherit Metab Dis 2005; 28: 407
  • Teufel U, Weitz J, Flechtenmacher C, Prietsch V, Schmidt J, Hoffmann GF, et al. High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure. Pediatr Transplant 2009. Apr 23 (Epub ahead of print)
  • Serrano M, Martins C, Perez-Duenas B, Gomez- Lopez Neuropsychiatric manifestations in late-onset urea cycle disorder patients. J Child Neurol 2010; 25: 358. Fons C, et al.
  • Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 2005; 21:S9-17.
  • Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, et al. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 2009; : 263-269.
  • Tuchman M. The clinical, biochemical, and molecular spectrum of ornithine transcarbamylase deficiency. J Lab Clin Med 1992; 120: 836-850.
  • Ahrens MJ, Berry SA, Whitley CB, Markowitz DJ, Plante RJ, Tuchman M. Clinical and biochemical heterogeneity in females of a large pedigree deficiency due to the R141Q mutation. Am J Med Genet 1996; 66: 311-315. transcarbamylase
  • Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 2005; 44: 61-98.
  • Schmidt J, Kroeber S, Irouschek A, Birkholz T, Schroth M, Albrecht S. Anesthetic management of patients with ornithine transcarbamylase deficiency. Paediatr Anaesth 2006; 16: 333-337.
  • Valle D, Simell O. The hyperornithinemias. In Scriver C, Beaudet A, Sly W, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill New York, 2001, pp –1896.
  • Barsotti RJ. Measurement of ammonia in blood. J Pediatr 2001; 138: S11-19;discussion S19-20.
  • Bachmann C. Interpretation of plasma amino acids in the follow-up of patients: the impact of compartmentation. J Inherit Metab Dis 2008; 31: 20.
  • Brown GW Jr, Cohen PP. Comparative biochemistry of urea synthesis. I. Methods for the quantitative assay of urea cycle enzymes in liver. J Biol Chem 1959; 234: 1769-1774.
  • Häberle J, Schmidt E, Pauli S, Rapp B, Christensen E, Wermuth B, et al. Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset. Hum Mutat 2003; 21: 444.
  • Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat 2006; 27: 626-632.
  • Engel K, Nuoffer JM, Mühlhausen C, Klaus V, Largiader CR, Tsiakas K, et al. Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. Mol Genet Metab 2008; 94: 292-297.
  • Shchelochkov OA, Li FY, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, et al. High-frequency detection of deletions and variable transcarbamylase (OTC) locus by oligonucleotide array CGH. Mol Genet Metab 2009; 96: 97-105.
  • Häberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn 2004; 24: 378-383.
  • Chadefaux-Vekemans B, Rabier D, Cadoudal N, Lescoat A, Chabli A, Aupetit J, et al. Prenatal diagnosis of some metabolic diseases using early amniotic fluid samples: report of a 15 years, experience. Prenat Diagn 2006; 26: 814-818.
  • Kleijer WJ, Thoomes R, Galjaard H, Wendel U, Fowler B. First-trimester (chorion biopsy) diagnosis methylmalonicaciduria. Lancet 1984; 2: 1340. citrullinaemia and
  • Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N- acetylglutamate synthase deficiency. Eur J Pediatr ; 169: 197-199. Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis ; 30: 880-887. Singh RH, Rhead WJ, Smith W, Lee B, Sniderman King L, Summar M. Nutritional management of urea cycle disorders. Crit Care Clin 2005; 21: S27-35.
  • Leonard JV. The nutritional management of urea cycle disorders. J Pediatr 2001; 138: S40-44.
  • 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: S79-85. Scaglia management and amino acid supplementation in urea cycle disorders. Mol Genet Metab 2010; 100 Suppl 1: S72-76. in nutritional
  • Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 1998; 21 Suppl 1: 101-111.
  • Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr 2003; 162 Suppl 1: S29
  • Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001; : S56-60.
  • Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith W, Summar ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin 2005; 21: S19-25.
  • Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of patients with urea cycle disorders from a 21- year, hyperammonaemic episodes. Acta Paediatr 2008; :1420-1425. study of acute
  • Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009; 11:823-835.
  • Bachmann C. Hyperammonaemia: review of current treatment strategies. In Bachmann C, Häberle J, Leonard JV (eds) Pathophysiology and management publications, pp 157-173. SPS Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, 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: 1332-1342.
  • Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 2010; 100 Suppl : S77-83.
  • Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation 2009; 87: 636-641.
There are 39 citations in total.

Details

Primary Language English
Journal Section Reviews
Authors

Johannes Haberle

Publication Date January 1, 2011
Published in Issue Year 2011 Volume: 3 Issue: 1

Cite

APA Haberle, J. (2011). Diagnosis and treatment of urea cycle disorders. Journal of Pediatric Sciences, 3(1), 2-11. https://doi.org/10.17334/jps.57192
AMA Haberle J. Diagnosis and treatment of urea cycle disorders. Journal of Pediatric Sciences. January 2011;3(1):2-11. doi:10.17334/jps.57192
Chicago Haberle, Johannes. “Diagnosis and Treatment of Urea Cycle Disorders”. Journal of Pediatric Sciences 3, no. 1 (January 2011): 2-11. https://doi.org/10.17334/jps.57192.
EndNote Haberle J (January 1, 2011) Diagnosis and treatment of urea cycle disorders. Journal of Pediatric Sciences 3 1 2–11.
IEEE J. Haberle, “Diagnosis and treatment of urea cycle disorders”, Journal of Pediatric Sciences, vol. 3, no. 1, pp. 2–11, 2011, doi: 10.17334/jps.57192.
ISNAD Haberle, Johannes. “Diagnosis and Treatment of Urea Cycle Disorders”. Journal of Pediatric Sciences 3/1 (January 2011), 2-11. https://doi.org/10.17334/jps.57192.
JAMA Haberle J. Diagnosis and treatment of urea cycle disorders. Journal of Pediatric Sciences. 2011;3:2–11.
MLA Haberle, Johannes. “Diagnosis and Treatment of Urea Cycle Disorders”. Journal of Pediatric Sciences, vol. 3, no. 1, 2011, pp. 2-11, doi:10.17334/jps.57192.
Vancouver Haberle J. Diagnosis and treatment of urea cycle disorders. Journal of Pediatric Sciences. 2011;3(1):2-11.