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11 Urea Cycle Enzymopathies

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Handbook of Neurochemistry and Molecular Neurobiology

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Abstract:

Inborn errors of urea cycle enzymes and transporters related to the urea cycle have been described. Ornithine transcarbamylase (OTC) deficiency, an X-linked genetic disorder is well characterised from the molecular genetic standpoint and over 100 mutations have been described. Clinical symptomatology varies according to the residual enzyme activity and may include seizures, mental retardation and cerebral palsy. Neuropathologic evaluation reveals brain atrophy, ventricular dilatation and delayed myelination. A well characterised animal model of OTC deficiency, the “sparse fur (spf)” mouse has been employed to study the neurochemistry of the disorder; abnormalities of the glutamatergic, cholinergic and serotoninergic neurotransmitter systems have been identified. Studies on the pathogenesis of the neuronal cell death in congenital OTC deficiency suggest that cerebral energy compromise and NMDA receptor-mediated excitotoxicity are implicated. Current therapy in congenital urea cycle disorders involves the reduction of circulating ammonia (using agents such as sodium benzoate and phenylacetate), L-carnitine administration to improve cellular energy metabolism and liver transplantation. Clinical trials using gene therapy are currently under evaluation.

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Abbreviations

ATP:

adenosine triphosphate

αKGOH:

α-ketoglutarate dehydrogenase

CP:

candate-puramen

CPSase:

carbamyl phosphate synthetase

CSF:

cerebrospinal fluid

CAT:

choline actyltransferase

CoA:

coenzyme A

CT:

computed tomographic

FC:

frontal cortex

GABA:

γ-aminobutyric acid

GP:

globus pallidus

5HIAA:

5-hydroxyindoleacetic acid

MAO:

monoamine oxidase

NMDA:

N-methyl-D-aspartate

NOS:

nitric oxide synthase

OTC:

ornithine transcarbamylase

OLT:

orthotopic liver transplantation

PC:

parietal cortex

5HT:

serotonin

spf :

sparse fur

References

  • Anholt RRH. 1986. Mitochondrial benzodiazepine receptors as potential modulators of intermediary metabolism. TiPS 7: 506–511.

    CAS  Google Scholar 

  • Arauja DM, Lapchak PA, Robitaille Y, Gauthier S, Quirion R. 1988. Differential alterations of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease. J Neurochem 50: 1914–1923.

    Article  Google Scholar 

  • Bachmann C, Colombo JP. 1984. Increase of tryptophan and 5-hydroxyindoleacetic acid in the brain of ornithine carbamoyl transferase deficient sparse-fur mice. Pediatr Res 18: 372–375.

    Article  CAS  PubMed  Google Scholar 

  • Bakker MHM, Foster AC. 1991. An investigation of the mechanisms of delayed neuron degeneration caused by direct injection of quinolinic acid into the rat striatum in vivo. Neuroscience 42: 387–395.

    Article  CAS  PubMed  Google Scholar 

  • Bassi S, Ferrarese C, Finola MG, Frattola L, Lannucelli M, et al. 1988. L-Acetyl-carnitine in Alzheimer disease (AD) and Senile Dementia of the Alzheimer type (SDAT). Senile Dementias (Second International Symposium). Agnoli A, Cahn J, Larsen N, Mayeux R, editors. Paris: John Libbey Eurotext; pp. 461–466.

    Google Scholar 

  • Batshaw ML, Hyman SL, Coyle JT, Robinson MB, Qureshi IA, et al. 1988. Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse. Pediatr Res 23: 368–374.

    Article  CAS  PubMed  Google Scholar 

  • Batshaw ML, Robinson MB, Hyland K, Djali S, Heyes MP. 1993. Quinolinic acid in children with congenital hyperammonemia. Ann Neurol 34: 676–681.

    Article  CAS  PubMed  Google Scholar 

  • Brusilow SW, Horwich AL. 1995. Urea cycle enzymes. The Metabolic and Molecular Basis of Inherited Disease, 7th edn. Scriver CR, Beaudet AL, Sly WS, et al. editors. New York: McGraw-Hill; pp.1187–1232.

    Google Scholar 

  • Brusilow SW, Valle DL, Batshaw M. 1979. New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2: 452–454.

    Article  CAS  PubMed  Google Scholar 

  • Chaouloff F, Laude D, Mignot E, Kamoun P, Elghozi JL. 1985. Tryptophan and serotonin turnover rate in the brain of genetically hyperammonemic mice. Neurochem Int 7: 143–153.

    Article  CAS  PubMed  Google Scholar 

  • Christodoulou J, Qureshi IA, Mclnnes RF, Clarke JTR. 1993. Ornithine transcarbamylase deficiency presenting with stroke-like episodes. J Pediatr 122: 423–425.

    Article  CAS  PubMed  Google Scholar 

  • Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, et al. 1993. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 33: 77–81.

    Article  CAS  PubMed  Google Scholar 

  • Demars R, Levan SL, Trend BL, Russel LB. 1976. Abnormal ornithine carbamyl transferase in mice having the sparse-fur mutation. Proc Natl Acad Sci USA 23: 1693–1698.

    Article  Google Scholar 

  • Dolman CL, Clasen RA, Dorovini-Zis K. 1988. Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol 7: 10–15.

    CAS  PubMed  Google Scholar 

  • Filloux F, Townsend JJ, Leonard C. 1986. Ornithine transcarbamylase deficiency: Neuropathologic changes acquired in utero. J Pediat 108: 942–945.

    Article  CAS  PubMed  Google Scholar 

  • Gropman AL, Batshaw ML. 2004. Cognitive outcome in urea cycle disorders. Mol Genet Metab 81 (Suppl. 1): S58–S62.

    Article  CAS  PubMed  Google Scholar 

  • Harding BN, Leonard JV, Erdohazi M. 1984. Ornithine transcarbamylase deficiency: Neuropathological study. Eur J Pediatr 141: 215.

    Article  CAS  PubMed  Google Scholar 

  • Harper CG, Butterworth RF. 1997. Nutritional and metabolic disorders. Greenfield's Neuropathology. Graham DI, Lantos PL, editors. London: Arnold; pp. 601–655.

    Google Scholar 

  • Hasegawa T, Tzakis AG, Todo S, Reyes J, Nour B, et al. 1995. Orthotopic liver transplantation for ornithine transcarbamylase deficiency with hyperammonemic encephalopathy. J Pediat Surg 30: 863–865.

    Article  CAS  PubMed  Google Scholar 

  • Horslen SP, McGowan TC, Goertzen TC, Warkentin PI, Cai HB, et al. 2003. Isolated hepatocyte transplantation in an infant with severe urea cycle disorder. Pediatrics 111 (6 Part 1): 1262–1267.

    Article  PubMed  Google Scholar 

  • Hyman SL, Porter CA, Page JJ, Iwata BA, Kissel R, et al. 1988. Behavioral management of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 111: 558–562.

    Article  Google Scholar 

  • Inoue I, Shimizu T, Saheki T, Noda T, Fukuda T. 1989. Serotonin- and catecholamine-related substances in the brain of ornithine transcarbamylase-deficient sparse-fur mice in the hyperammonemic state: comparison of two procedures for obtaining brain extract, decapitation and microwave irradiation. Biochem Med Metab Biol 42: 232–239.

    Article  CAS  PubMed  Google Scholar 

  • Kalbag SS, Palekar AG. 1988. Sodium benzoate inhibits fatty acid oxidation in rat liver. Effect on ammonia levels. Biochem Med Metab Biol 40: 133–142.

    Article  CAS  PubMed  Google Scholar 

  • Kendall BE, Kingsley DPE, Leonard JV, Lingam S, Oberholzer VG. 1983. Neurological features and computed tomography of the brain in children with ornithine carbamoyl transferase deficiency. J Neurol Neurosurg Psychiatry 46: 28–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai JCK, Cooper AJL. 1986. Brain a-ketoglutarate dehydrogenase complex: Kinetic properties, regional distribution and effects of inhibitors. J Neurochem 47: 1376–1386.

    Article  CAS  PubMed  Google Scholar 

  • Lee B, Dennis JA, Healy PJ, Mull B, Pastore L, et al. 1999. Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia. Proc Natl Acad Sci USA 96(7): 3981–3986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuoka M, Igisu H. 1993. Effects of L- and d-carnitine on brain energy metabolites in mice given sublethal doses of ammonium acetate. Pharmacol Toxicol 72: 145–147.

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka M, Igisu H, Kohriyama K, Inoue N. 1991. Suppression of neurotoxicity of ammonia by L-carnitine. Brain Res 567: 328–331.

    Article  CAS  PubMed  Google Scholar 

  • McBride KL, Miller G, Carter S, Karpen S, Gross J, et al. 2004. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 114(4): e523–e526.

    Article  PubMed  Google Scholar 

  • Michalak A, Qureshi IA. 1995a. Free and esterified coenzyme A in the liver and muscles of chronically hyperammonemic mice treated with sodium benzoate. Biochem Mol Med 54: 96–104.

    Article  CAS  PubMed  Google Scholar 

  • Michalak A, Qureshi IA. 1995b. Tissue acylcarnitine and acyl-coenzyme A profiles in chronically hyperammonemic mice treated with sodium benzoate and supplementary L-carnitine. Biomed Pharmacother 49: 350–357.

    Article  CAS  PubMed  Google Scholar 

  • Morsy MA, Caskey CT. 1994. Ornithine transcarbamylase deficiency: A model for gene therapy. editors. Hepatic Encephalopathy, Hyperammonemia and Ammonia Toxicity. Felipo V, Grisolia S, editors. New York: Plenum Press; pp. 145–154.

    Chapter  Google Scholar 

  • Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. 1984. Neurologic outcome in children with inborn errors of urea synthesis. New Engl J Med 310: 1500–1505.

    Article  CAS  PubMed  Google Scholar 

  • Nagasaka H, Yorifuji T, Egawa H, Kikuta H, Tanaka K, et al. 2001. Successful living-donor liver transplantation from an asymptomatic carrier mother in ornithine transcarbamylase deficiency. J Pediatr 138(3): 432–434.

    Article  CAS  PubMed  Google Scholar 

  • O'Connor JE, Costell M, Miguez MP, Grisolia S. 1986. Influence of the route of administration on the protective effect of L-carnitine on acute hyperammonemia. Biochem Pharmacol 35: 3173–3176.

    Article  CAS  PubMed  Google Scholar 

  • Patejunas G, Lee B, Dennis JA, Healy PJ, Reeds PJ, et al. 1998. Evaluation of gene therapy for citrullinaemia using murine and bovine models. J Inherit Metab Dis 21 (Suppl. 1): 138–150.

    Article  CAS  PubMed  Google Scholar 

  • Qureshi IA. 1992. Animal models of hereditary hyperammonemias. Neuromethods, Vol. 22: Animal Models of Neurological Disease, II. Boulton A, Baker G, Butterworth R, editers. Clifton, NJ: Humana Press; pp. 329–356.

    Google Scholar 

  • Raghavendra Rao VL, Qureshi IA, Butterworth RF. 1993. Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand PH]PK11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse. Pediatr Res 34: 777–780.

    Article  Google Scholar 

  • Raghavendra Rao VL, Qureshi IA, Butterworth RF. 1994. Activities of monoamine oxidase-A and -B are altered in the brains of congenitally hyperammonemic sparse-fur (spf) mice. Neurosci Lett 170: 27–30.

    Article  Google Scholar 

  • Raper SE, Yudkoff M, Chirmule N, Gao GP, Nunes F, et al. 2002. A pilot study of in vivo liver-directed transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 13(1): 163–175.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi LA, Butterworth RF. 1992. Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice. Biochem Biophys Res Commun 184: 746–751.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1993a. Evidence for a severe cholinergic neuronal deficit in brain in congenital ornithine transcarbamylase (OTC) deficiency. Soc Neurosci Abstr 19: 122.

    Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1993b. Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia. Biochem Pharmacol 45: 137–146.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1993c. Effect of L-carnitine on cerebral and hepatic energy metabolites in congenitally hyperammonemic sparse-fuce mice and its role during benzoate therapy. Metabolism 42: 1039–1046.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1994a. Regional amino acid neurotransmitter changes in brains of spf Pi mice with congenital ornithine transcarbamylase deficiency. Metab Brain Dis 9: 43–51.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1994b. Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency. Neurosci Lett 178: 63–65.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Maysinger D, Butterworth RF. 1995a. Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: Effect of acetyl-L-carnitine. J Pharmacol Exp Ther 274: 437–443.

    CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1995b. Loss of [3H]MK801 binding sites in brain in congenital ornithine transcarbamylase deficiency. Metab Brain Dis 10: 249–255.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF. 1996a. Central muscarinic cholinergic M, and M2 receptor changes in congenital ornithine transcarbamylase deficiency. Pediatr Res 40: 25–28.

    Article  CAS  PubMed  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF, Marescau B, De Deyn PP. 1996b. Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine transcarbamylase deficient spf mutant mouse: Effect of metabolic arginine deficiency. Guanidino Compounds. De Deyn PP, et al. editors. John Libby and Co.; pp. 17–20.

    Google Scholar 

  • Robinson MB, Anegawa NJ, Gorry E, et al. 1992. Brain serotonin2 and serotonin, receptors are altered in the congenitally hyperammonemic sparse fur mouse. J Neurochem 58: 1016–1022.

    Article  CAS  PubMed  Google Scholar 

  • Robinson MB, Hopkins K, Batshaw ML, McLaughlin BA, Heyes MP, et al. 1995a. Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse. Dev Brain Res 90: 35–44.

    Article  CAS  Google Scholar 

  • Robinson MB, Batshaw ML, Ye X, Wilson JM. 1995b. Prospects for gene therapy in ornithine carbamoyltransferase deficiency and other urea cycle disorders. MRDS Res Rev 1: 62–70.

    Google Scholar 

  • Schwarcz R, Whetsell WO Jr, Mangano RM. 1983. Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219: 316–318.

    Article  CAS  PubMed  Google Scholar 

  • Simmonds MA. 1991. Modulation of the GABAA receptor by steroids. Semin Neurosci 3: 231–239.

    Article  Google Scholar 

  • Takayanagi M, Ohtake A, Ogura N, Nakajima H, Hoshino M. 1984. A female case of ornithine transcarbamylase deficiency with marked computed tomographic abnormalities of the brain. Brain Dev 6: 58.

    Article  CAS  PubMed  Google Scholar 

  • Takenaka K, Yasuda I, Araki H, Naito T, Fukutomi Y, et al. 2000. Type II citrullinemia in an elderly patient treated with living related partial liver transplantation. Intern Med 39(7): 553–558.

    Article  CAS  PubMed  Google Scholar 

  • Todo S, Starzl IE, Tzakis A, Benkov KJ, Kalousek P, et al. 1992. Orthotopic liver transplantation for urea cycle enzyme deficiency. Hepatology 15: 419–422.

    Article  CAS  PubMed  Google Scholar 

  • Tucek S. 1985. Regulation of acetylcholine synthesis in the brain. J Neurochem 44: 11–24.

    Article  CAS  PubMed  Google Scholar 

  • Tuchman M, Plante RJ, Garcia-Perez MA, Rubio V. 1996. Relative frequency of mutation causing ornithine transcarbamylase deficiency in 78 families. Hum Genet 97: 274–276.

    Article  CAS  PubMed  Google Scholar 

  • Veres G, Gibbs RA, Scherer SE, Caskey CT. 1987. The molecular basis of the sparse fur mutation. Science 237: 415–417.

    Article  CAS  PubMed  Google Scholar 

  • Ye X, Robinson MB, Batshaw ML, Furth EE, Smith I, Wilson JM. 1996. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors. J Biol Chem 271: 3639–3646.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Studies from the authors’ research unit were funded by The Canadian Institute of Health Research and the Canadian Liver Foundation.

Authors
  1. R. Butterworth
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, Orangeburg, New york, USA

    Abel Lajtha (Director) (Director)

  2. The Centre for Laboratory Medicine, Tampere University Hospital, PB 2000, FI-33520, Tampere, Finland

    Simo S. Oja

  3. Inst. for Pharmacology, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Arne Schousboe

  4. Brain Research Center, Medical School, University of Tampere, FI-33014, Espoo, Finland

    Pirjo Saransaari

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Butterworth, R. (2007). 11 Urea Cycle Enzymopathies. In: Lajtha, A., Oja, S.S., Schousboe, A., Saransaari, P. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30373-4_11

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