Seminars in Pediatric Neurology
Volume 15, Issue 3 , Pages 132-139 , September 2008

Neurologic Damage and Neurocognitive Dysfunction in Urea Cycle Disorders

  • Gregory M. Enns, MB, ChB

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Gregory M. Enns, MB, ChB, Division of Medical Genetics, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94305

References 

  1. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007;30:865–879
  2. Harding BN, Leonard JV, Erdohazi M. Ornithine carbamoyl transferase deficiency: A neuropathological study. Eur J Pediatr. 1984;141:215–220
  3. Kornfeld M, Woodfin BM, Papile L, et al. Neuropathology of ornithine carbamyl transferase deficiency. Acta Neuropathol. 1985;65:261–264
  4. Dolman CL, Clasen RA, Dorovini-Zis K. Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol. 1988;7:10–15
  5. Shih VE. Hereditary urea-cycle disorders. In:  Grisolia S,  Báguena R,  Mayor F editor. The Urea Cycle. New York, NY: John Wiley; 1976;p. 367–414
  6. Brusilow SW, Valle DL, Batshaw M. New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet. 1979;2:452–454
  7. Batshaw ML, Brusilow S, Waber L, et al. Treatment of inborn errors of urea synthesis: Activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Med. 1982;306:1387–1392
  8. Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007;356:2282–2292
  9. Nassogne MC, Heron B, Touati G, et al. Urea cycle defects: management and outcome. J Inherit Metab Dis. 2005;28:407–414
  10. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21(suppl 1):151–159
  11. Bachmann CL. Outcome and survival of 88 patients with urea cycle disorders: A retrospective evaluation. Eur J Pediatr. 2003;162:410–416
  12. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in children with inborn errors of urea synthesis Outcome of urea-cycle enzymopathies. N Engl J Med. 1984;310:1500–1505
  13. Nicolaides P, Liebsch D, Dale N, et al. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002;86:54–56
  14. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr. 1999;134:268–272
  15. Maestri NE, Hauser ER, Bartholomew D, et al. Prospective treatment of urea cycle disorders. J Pediatr. 1991;119:923–928
  16. Msall M, Monahan PS, Chapanis N, et al. Cognitive development in children with inborn errors of urea synthesis. Acta Paediatr Jpn. 1988;30:435–441
  17. Enns GM, O'Brien WE, Kobayashi K, et al. Postpartum “psychosis” in mild argininosuccinate synthetase deficiency. Obstet Gynecol. 2005;105:1244–1246
  18. 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;66:311–315
  19. Gropman AL, Batshaw ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004;81(suppl 1):S58–S62
  20. Gyato K, Wray J, Huang ZJ, et al. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004;55:80–86
  21. Engel RC, Buist NR. The EEGs of infants with citrullinemia. Dev Med Child Neurol. 1985;27:199–206
  22. Brunquell P, Tezcan K, DiMario FJ. Electroencephalographic findings in ornithine transcarbamylase deficiency. J Child Neurol. 1999;14:533–536
  23. Bogdanovic MD, Kidd D, Briddon A, et al. Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus. J Neurol Neurosurg Psychiatry. 2000;69:813–815
  24. Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol. 2003;24:1184–1187
  25. Mamourian AC, du Plessis A. Urea cycle defect: A case with MR and CT findings resembling infarct. Pediatr Radiol. 1991;21:594–595
  26. Bindu PS, Sinha S, Taly AB, et al. Extensive cortical magnetic resonance signal change in proximal urea cycle disorder. J Child Neurol. 2007;22:238–239
  27. Gaspari R, Arcangeli A, Mensi S, et al. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma. Ann Emerg Med. 2003;41:104–109
  28. Majoie CB, Mourmans JM, Akkerman EM, et al. Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. AJNR Am J Neuroradiol. 2004;25:32–35
  29. Fitzpatrick SM, Hetherington HP, Behar KL, et al. Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo, measured by 1H and 31P nuclear magnetic resonance. J Neurochem. 1989;52:741–749
  30. Kanamori K, Ross BD. 15N n.m.r. measurement of the in vivo rate of glutamine synthesis and utilization at steady state in the brain of the hyperammonaemic rat. Biochem J. 1993;293:461–468
  31. Kanamori K, Ross BD. In vivo activity of glutaminase in the brain of hyperammonaemic rats measured by 15N nuclear magnetic resonance. Biochem J. 1995;305:329–336
  32. Sibson NR, Dhankhar A, Mason GF, et al. In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proc Natl Acad Sci U S A. 1997;94:2699–26704
  33. Connelly A, Cross JH, Gadian DG, et al. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res. 1993;33:77–81
  34. Takanashi J, Kurihara A, Tomita M, et al. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology. 2002;59:210–214
  35. Brusilow SW. Hyperammonemic encephalopathy. Medicine (Baltimore). 2002;81:240–249
  36. Kanamori K, Ross BD, Chung JC, et al. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem. 1996;67:1584–1594
  37. Sibson NR, Mason GF, Shen J, et al. In vivo (13)C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during. J Neurochem. 2001;76:975–989
  38. Kanamori K, Ross BD. Kinetics of glial glutamine efflux and the mechanism of neuronal uptake studied in vivo in mildly hyperammonemic rat brain. J Neurochem. 2006;99:1103–1113
  39. Takahashi H, Koehler RC, Brusilow SW, et al. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol. 1991;261:H825–H829
  40. Tanigami H, Rebel A, Martin LJ, et al. Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience. 2005;131:437–449
  41. Zwingmann C, Butterworth R. An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: Further studies using NMR spectroscopy. Neurochem Int. 2005;47:19–30
  42. Albrecht J, Norenberg MD. Glutamine: A Trojan horse in ammonia neurotoxicity. Hepatology. 2006;44:788–794
  43. Felipo V, Butterworth RF. Mitochondrial dysfunction in acute hyperammonemia. Neurochem Int. 2002;40:487–491
  44. Kosenko E, Venediktova N, Kaminsky Y, et al. Sources of oxygen radicals in brain in acute ammonia intoxication in vivo. Brain Res. 2003;981:193–200
  45. Norenberg MD, Rama Rao KV, Jayakumar AR. Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr. 2004;36:303–307
  46. Norenberg MD, Jayakumar AR, Rama Rao KV, et al. New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis. 2007;22:219–234
  47. Bender AS, Norenberg MD. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res. 1998;54:673–680
  48. Rama Rao KV, Chen M, Simard JM, et al. Suppression of ammonia-induced astrocyte swelling by cyclosporin A. J Neurosci Res. 2003;74:891–897
  49. Jayakumar AR, Rao KV, Murthy ChR, et al. Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int. 2006;48:623–628
  50. Pichili VB, Rao KV, Jayakumar AR, et al. Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity. Glia. 2007;55:801–809
  51. Rama Rao KV, Chen M, Simard JM, et al. Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport. 2003;14:2379–2382
  52. Szerb JC, Butterworth RF. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol. 1992;39:135–153
  53. Ratnakumari L, Qureshi IA, Butterworth RF. Regional amino acid neurotransmitter changes in brains of spf/Y mice with congenital ornithine transcarbamylase deficiency. Metab Brain Dis. 1994;9:43–51
  54. Robinson MB, Hopkins K, Batshaw ML, et al. Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse. Brain Res Dev Brain Res. 1995;90:35–44
  55. Bergeron M, Swain MS, Reader TA, et al. Effect of ammonia on brain serotonin metabolism in relation to function in the portacaval shunted rat. J Neurochem. 1990;55:222–229
  56. Butterworth RF. Glutamate transporter and receptor function in disorders of ammonia metabolism. Ment Retard Dev Disabil Res Rev. 2001;7:276–279
  57. Christodoulou J, Qureshi IA, McInnes RR, et al. Ornithine transcarbamylase deficiency presenting with strokelike episodes. J Pediatr. 1993;122:423–425
  58. Itzhak Y, Roig-Cantisano A, Dombro RS, et al. Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res. 1995;705:345–348
  59. Kosenko E, Llansola M, Montoliu C, et al. Glutamine synthetase activity and glutamine content in brain: Modulation by NMDA receptors and nitric oxide. Neurochem Int. 2003;43:493–499
  60. Kosenko E, Kaminski Y, Lopata O, et al. Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med. 1999;26:1369–1374
  61. Bachmann C, Braissant O, Villard AM, et al. Ammonia toxicity to the brain and creatine. Mol Genet Metab. 2004;81(suppl 1):S52–S57
  62. Izumi Y, Izumi M, Matsukawa M, et al. Ammonia-mediated LTP inhibition: Effects of NMDA receptor antagonists and L-carnitine. Neurobiol Dis. 2005;20:615–624
  63. Monfort P, Munoz MD, Felipo V. Molecular mechanisms of the alterations in NMDA receptor-dependent long-term potentiation in hyperammonemia. Metab Brain Dis. 2005;20:265–274
  64. Picker JD, Puga AC, Levy HL, et al. Arginase deficiency with lethal neonatal expression: Evidence for the glutamine hypothesis of cerebral edema. J Pediatr. 2003;142:349–352
  65. Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet. 2006;142:113–120
  66. Gungor S, Akinci A, Firat AK, et al. Neuroimaging findings in hyperargininemia. J Neuroimaging. 2008;Jan 7; [Epub ahead of print]
  67. Wyse AT, Bavaresco CS, Hagen ME, et al. In vitro stimulation of oxidative stress in cerebral cortex of rats by the guanidino compounds accumulating in hyperargininemia. Brain Res. 2001;923:50–57
  68. Deignan JL, Marescau B, Livesay JC, et al. Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. Mol Genet Metab. 2008;93:172–178
  69. 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(suppl):2775S–2782S
  70. Niemi AK, Enns GM. Sodium phenylacetate and sodium benzoate in the treatment of neonatal hyperammonemia. NeoReviews. 2006;7:e486–e3495
  71. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat Rev Drug Discov. 2006;5:160–170
  72. Natale JE, Guerguerian AM, Joseph JG, et al. Pilot study to determine the hemodynamic safety and feasibility of magnesium sulfate infusion in children with severe traumatic brain injury. Pediatr Crit Care Med. 2007;8:1–9
  73. Whitelaw A, Bridges S, Leaf A, et al. Emergency treatment of neonatal hyperammonaemic coma with mild systemic hypothermia. Lancet. 2001;358:36–38

 Dr Enns reports serving on the Scientific Advisory Board and being on the speaker's bureau for Hyperion Therapeutics, Inc.

PII: S1071-9091(08)00050-8

doi: 10.1016/j.spen.2008.05.007

Seminars in Pediatric Neurology
Volume 15, Issue 3 , Pages 132-139 , September 2008

Article Tools

* Image Usage & Resolution