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Journal of Inherited Metabolic Disease

, Volume 31, Issue 2, pp 194–204 | Cite as

Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism

  • S. Kölker
  • S. W. Sauer
  • G. F. Hoffmann
  • I. Müller
  • M. A. Morath
  • J. G. Okun
SSIEM Symposium 2007

Summary

Inherited disorders of amino and organic acid metabolism have a high cumulative frequency, and despite heterogeneous aetiology and varying clinical presentation, the manifestation of neurological disease is common. It has been demonstrated for some of these diseases that accumulating pathological metabolites are directly involved in the manifestation of neurological disease. Various pathomechanisms have been suggested in different in vitro and in vivo models including an impairment of brain energy metabolism, an imbalance of excitatory and inhibitory neurotransmission, altered transport across the blood–brain barrier and between glial cells and neurons, impairment of myelination and disturbed neuronal efflux of metabolic water. This review summarizes recent knowledge on pathomechanisms involved in phenylketonuria, glutaric aciduria type I, succinic semialdehyde dehydrogenase deficiency and aspartoacylase deficiency with examples, highlighting general as well as disease-specific concepts and their putative impact on treatment.

Keywords

GABAB Receptor Large Neutral Amino Acid Glutaric Aciduria Type Canavan Disease Organic Aciduria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CD

Canavan–van Bogaert–Bertrand disease

CNS

central nervous system

GA I

glutaric aciduria type I

IEM

inborn error of metabolism

LNAA

large neutral amino acid

NAA

N-acetyl-l-aspartate

OAD

organic aciduria

PKU

phenylketonuria

SSADH

succinic semialdehyde dehydrogenase

TCA cycle

tricarboxylic acid cycle

References

  1. Adornato BT, O’Brien JS, Lampert PW, Roe TF, Neustein HB (1972) Cerebral spongy degeneration of infancy: a biochemical and ultrastructural study of affected twins. Neurology 22: 202–210.PubMedGoogle Scholar
  2. Aiello LC, Wheeler P (1995) The expensive tissue hypothesis: the brain and digestive system in human and primate evolution. Curr Anthropol 36: 199–221.Google Scholar
  3. Baslow MH (2000a) Canavan’s spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease. J Mol Neurosci 15: 61–69.Google Scholar
  4. Baslow MH (2000b) Functions of N-acetyl-l-aspartate and N-acetyl-l-aspartylglutamate in the vertebrate brain: role in glial cell-specific sigaling. J Neurochem 75: 453–459.Google Scholar
  5. Baslow MH (2002c) Evidence supporting a role for N-acetyl-l-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytic review. Neurochem Int 40: 295–300.Google Scholar
  6. Baslow MH, Suckow R, Sapirstein V, Hungrund BL (1999) Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes. J Mol Neurosci 13: 47–53.PubMedGoogle Scholar
  7. Bennett MJ, Marlow N, Pollitt RJ, Wales JK (1986) Glutaric aciduria type 1: biochemical investigations and post mortem findings. Eur J Pediatr 145: 403–405.PubMedGoogle Scholar
  8. Berton F, Brancucci A, Beghe F, et al (1999) Gamma-hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices. Eur J Pharmacol 380: 109–116.PubMedGoogle Scholar
  9. Bick U, Fahrendorf G, Ludolph AC, Vassallo P, Weglage J, Ullrich K (1991) Disturbed myelination in patients with untreated hyperphenylalaninemia: evaluation with magnetic resonance imaging. Eur J Pediatr 150: 185–189.PubMedGoogle Scholar
  10. Bickel H, Gerrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 265: 812–813.PubMedGoogle Scholar
  11. Bluml S, Moreno-Torres A, Shic F, Nguy CH, Ross BD (2002) Tricarboxylic acid cycle of glia in the in vivo human brain. NMR Biomed 15: 1–5.PubMedGoogle Scholar
  12. Bouzier-Sore AK, Voisin P, Canioni P, Magistretti P, Pellerin L (2003) Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J Cereb Blood Flow Metab 23: 1298–1306.PubMedGoogle Scholar
  13. Burnett JR (2007) Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria. IDrugs 10: 805–813.PubMedGoogle Scholar
  14. Canavan MM (1931) Schilder’s encephalitis perioxialis diffusa. Neurology 15: 299–308.Google Scholar
  15. Clark JB (1998) N-Acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20: 271–276.PubMedGoogle Scholar
  16. Collingridge GL, Kehl SJ, McLennan H (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol 334: 33–46.PubMedGoogle Scholar
  17. De Volder AG, Bol A, Blin J, et al (1997) Brain energy metabolism in early blind subjects: neural activity in the visual cortex. Brain Res 750: 235–244.PubMedGoogle Scholar
  18. Donarum EA, Stephan DA, Larkin K, et al (2006) Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 29: 143–156.PubMedGoogle Scholar
  19. Drasbek KR, Christensen J, Jensen K (2006) Gamma-hydroxybutyrate – a drug of abuse. Acta Neurol Scand 114: 145–156.PubMedGoogle Scholar
  20. Dyer CA, Kendler A, Philibotte T, et al (1996) Evidence for central nervous system glial cell plasticity in phenylketonuria. J Neuropath Exp Neurol 55: 795–814.PubMedCrossRefGoogle Scholar
  21. Erecinska M, Dagani F (1990) Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes. J Gen Physiol 95: 591–616.PubMedGoogle Scholar
  22. Erwald RC, van Keuren-Jensen KR, Aizenman CD, Cline HT (2008) Roles of NR2A and NR2B in the development of dendritic arbor morphology in vivo. J Neurosci 28: 850–861.Google Scholar
  23. Fiege B, Blau N (2007) Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 15: 627–630.Google Scholar
  24. Følling A (1934) Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Z Physiol Chem 227: 169–176.Google Scholar
  25. Fox K, Daw N, Sato H, Czepita D (1991) Dark-rearing delays the loss of NMDA-receptor function in kitten visual cortex. Nature 350: 342–344.PubMedGoogle Scholar
  26. Funk CB, Prasad AN, Frosk P, et al (2005) Neuropathological, biochemical, and molecular findings in a glutaric acidemia type I cohort. Brain 128: 711–722.PubMedGoogle Scholar
  27. Galdikas BMF, Wood JW (1990) Birth sparing patterns in humans and apes. Am J Phys Anthropol 83: 185–191.PubMedGoogle Scholar
  28. George RL, Huang W, Naggar HA, Smith SB, Ganapathy V (2004) Transport of N-acetylasparate via murine sodium/dicarboxylate cotransporter NaDC3 and expression of this transporter and aspartoacylase II in ocular tissues in mouse. Biochim Biophys Acta 1690: 63–69.PubMedGoogle Scholar
  29. Gerstner B, Gratopp A, Marcinkowski M, Sifringer M, Obladen M, Bührer C (2005) Glutaric acid and its metabolites cause apoptosis in immature oligodendrocytes: a novel mechanism of white matter degeneration in glutaryl-CoA dehydrogenase deficiency. Pediatr Res 57: 771–776.PubMedGoogle Scholar
  30. Gibson KM, DeVivo DC, Jakobs C (1989) Vigabatrin therapy in patient with succinic semialdehyde dehydrogenase deficiency. Lancet 8671: 1105–1106.Google Scholar
  31. Gibson KM, Gupta M, Pearl PL, et al (2003) Significant behavioural disturbances in succinic semialdehyde dehydrogense (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psychiatry 54: 763–768.PubMedGoogle Scholar
  32. Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE (2003) l-Phenylalanine selectively depresses currents atglutamatergic excitatory synapses. J Neurosci Res 72: 116–124.PubMedGoogle Scholar
  33. Glushakov AV, Glushakova O, Varshney M, et al (2005) Long-term changes in glutamatergic synaptic transmission in phenylketonuria. Brain 128: 300–307.PubMedGoogle Scholar
  34. Goodman SI, Norenberg MD, Shikes RH, Breslich DJ, Moe PG (1977) Glutaric aciduria: biochemical and morphological considerations. J Pediatr 90: 746–750.PubMedGoogle Scholar
  35. Gropman A (2003) Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase (SSADH) deficiency (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria). Eur J Paediatr Neurol 8: 261–265.Google Scholar
  36. Gupta M, Hogema BM, Grompe M, et al (2003) Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol 54(Supplement 6): S81–90.PubMedGoogle Scholar
  37. Guthrie R, Susi A (1963) A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32: 338–343.PubMedGoogle Scholar
  38. Hassel B, Brathe A, Petersen D (2002) Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate. J Neurochem 82: 410–419.PubMedGoogle Scholar
  39. Hasselbalch S, Knudsen GM, Toft PB, et al (1996) Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria. Pediatr Res 40: 21–24.PubMedGoogle Scholar
  40. Heidenreich R, Natowicz M, Hainline BE, et al (1988) Acute extrapyramidal syndrome in methylmalonic acidemia: ‘Metabolic’ stroke involving the globus pallidus. J Pediatr 113: 1022–1027.PubMedGoogle Scholar
  41. Hofman MA (1983) Evolution of brain size in neonatal and adult placental mammals: a theoretical approach. J Theoret Biol 105: 317–322.Google Scholar
  42. Hoffmann GF, Athanassopoulos S, Burlina AB, et al (1996) Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 27: 115–123.PubMedGoogle Scholar
  43. Hogema BM, Gupta M, Senephansiri H, et al (2001) Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase deficiency. Nat Genet 29: 212–216.PubMedGoogle Scholar
  44. Hörster F, Schwab MA, Sauer SW, et al (2006) Phenylalanine reduces synaptic density in mixed cortical cultures from mice. Pediatr Res 59: 544–548.PubMedGoogle Scholar
  45. Huttenlocher PR (2000) The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159: S102–S106.PubMedGoogle Scholar
  46. Ikonomidou C, Bosch F, Miksa M, et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283: 70–74.PubMedGoogle Scholar
  47. Jakobs C, Bojasch M, Mönch E, Rating D, Siemes H, Hanefeld F (1981) Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta 111: 169–178.PubMedGoogle Scholar
  48. Janson C, McPhee S, Bilaniuk L, et al (2002) Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 13: 1391–1412.PubMedGoogle Scholar
  49. Janson CG, Assadi M, Francis J, Bilaniuk L, Shera D, Leone P (2005) Lithium citrate for Canavan disease. Pediatr Neurol 33: 235–244.PubMedGoogle Scholar
  50. Knerr I, Pearl PL, Bottiglieri T, Snead OC, Jakobs C, Gibson KM (2007) Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1 −/− mice and characterization of γ-hydroxybutyric acid pharmacology. J Inherit Metab Dis 30: 279–294.PubMedGoogle Scholar
  51. Koeller DM, Woontner M, Crnic LS, et al (2002) Biochemical, pathological and behavorial analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet 11: 347–357.PubMedGoogle Scholar
  52. Kölker S, Hoffmann GF, Schor DS, et al (2003) Glutaryl-CoA dehydrogenase deficiency: regional-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 34: 253–260.PubMedGoogle Scholar
  53. Kölker S, Koeller DM, Okun JG, Hoffmann GF (2004) Pathomechanisms of neurodegeneration in glutaryl-CoA dehydrogenase deficiency. Ann Neurol 55: 7–12.PubMedGoogle Scholar
  54. Kölker S, Sauer SW, Surtees RA, Leonard JV (2006a) The aetiology of neurological complications of organic acidemias – a role for the blood–brain barrier. J Inherit Metab Dis 29: 701–704.Google Scholar
  55. Kölker S, Garbade SF, Greenberg CR, et al (2006b) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59: 840–847.Google Scholar
  56. Kölker S, Garbade SF, Boy N, et al (2007) Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by neonatal screening in Germany. Pediatr Res 62: 357–362.PubMedGoogle Scholar
  57. Külkens S, Harting, Sauer S, et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64: 2142–2144.PubMedGoogle Scholar
  58. Leibel RL, Shih VE, Goodman SI, et al (1980) Glutaric aciduria type I: a metabolic disorder causing progressive choreoathetosis. Neurology 30: 1163–1168.PubMedGoogle Scholar
  59. Leonard JV, Walter JH, McKiernan PJ (2001) The management of organic acidaemias: the role of transplantation. J Inherit Metab Dis 24: 309–311.PubMedGoogle Scholar
  60. Leonard WR, Robertson ML (1992) Nutritional requirements and human evolution: a bioenergetics model. Am J Hum Biol 4: 179–195.Google Scholar
  61. Lingenhoehl K, Brom R, Heid J, et al (1999) Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology 38: 1667–1673.PubMedGoogle Scholar
  62. Madhavarao CN, Arun P, Moffett JR, et al (2005) Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan’s disease. Proc Natl Acad Sci U S A 102: 5221–5226.PubMedGoogle Scholar
  63. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283: 496–497.PubMedGoogle Scholar
  64. Martin E, Capone A, Schneider J, Hennig J, Thiel T (2001) Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy. Ann Neurol 49: 518–521.PubMedGoogle Scholar
  65. Matalon R, Michals K, Sebesta D, Deanching M, Gashkoff P, Casanova J (1988) Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 29: 463–471.PubMedGoogle Scholar
  66. Matalon R, Surendran S, Michals Matalon K, et al (2003) Future role of large neutral amino acids in transport of phenylalanine into the brain. Pediatrics 112: 1570–1574.PubMedGoogle Scholar
  67. McAdams HP, Geyer CA, Done SL, Deigh D, Mitchell M, Ghaed VN (1990) CT and MR imaging of Canavan disease. Am J Neuroradiol 11: 397–399.PubMedGoogle Scholar
  68. McKean CM (1972) The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res 47: 469–476.PubMedGoogle Scholar
  69. McPhee SW, Janson CG, Li C, et al (2006) Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 8: 577–588.PubMedGoogle Scholar
  70. Meador KJ (2007) The basic science of memory as it applies to epilepsy. Epilepsia 48(Supplement 9): 23–25.PubMedGoogle Scholar
  71. Miller SL, Daikhin Y, Yudkoff M (1996) Metabolism of N-acetyl-l-aspartate in rat brain. Neurochem Res 21: 615–618.PubMedGoogle Scholar
  72. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AA (2007) N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81: 89–131.PubMedGoogle Scholar
  73. Möller HE, Weglage J, Wiedermann D, Ullrich K (1998) Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria. J Cereb Blood Flow Metab 18: 1184–1191.PubMedGoogle Scholar
  74. Moreno A, Ross BD, Bluml S (2001) Direct determination of the N-acetyl-l-aspartate synthesis rate in the human brain by 13C MRS and [1-13C]glucose infusion. J Neurochem 77: 347–350.PubMedCrossRefGoogle Scholar
  75. Mühlhausen C, Ott N, Chalajour F, et al (2006) Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. Pediatr Res 59: 196–202.PubMedGoogle Scholar
  76. Muntau AC, Röschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.PubMedGoogle Scholar
  77. Nikolaides P, Leonard J, Surtees R (1998) Neurological outcome of methylmalonic acidemia. Arch Dis Child 78: 508–512.Google Scholar
  78. Okun JG, Hörster F, Farkas LM, et al (2002) Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. J Biol Chem 277: 14674–14680.PubMedGoogle Scholar
  79. Paine RS (1957) The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 20: 290–302.PubMedGoogle Scholar
  80. Pardridge WM (1998) Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23: 635–644.PubMedGoogle Scholar
  81. Pawlak V, Schupp BJ, Single FN, Seeburg PH, Köhr G (2005) Impaired synaptic scaling in mouse hippocampal neurones expressing NMDA receptors with reduced calcium permeability. J Physiol 562: 771–783.PubMedGoogle Scholar
  82. Pearl PL, Gibson KM, Acosta MT, et al (2003) Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 60: 1413–1417.PubMedGoogle Scholar
  83. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood-brain barrier: structural components and function under physiologic and pathophysiologic conditions. J Neuroimmune Pharmacol 1: 223–236.PubMedGoogle Scholar
  84. Pietz J, Kreis R, Rupp A, et al (1999) Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 103: 1169–1178.PubMedGoogle Scholar
  85. Porciuncula LO, Dal-Pizzol A Jr, Coitinho AS, Emanuelli T, Souza DO, Wajner M (2000) Inhibition of synaptosomal [3H]glutamate uptake and [3H]glutamate binding to plasma membranes from brain of young rats by glutaric acid in vitro. J Neurol Sci 73: 93–96.Google Scholar
  86. Quin M, Smith CB (2007) Regionally selective decreases in cerebral glucose metabolism in a mouse model of phenylketonuria. J Inherit Metab Dis 30: 318–325.Google Scholar
  87. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL (2001) A default mode in brain function. Proc Natl Acad Sci U S A 98: 676–682.PubMedGoogle Scholar
  88. Ren X, Mody I (2003) Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus. J Biol Chem 278: 42006–42011.PubMedGoogle Scholar
  89. Rowland LM, Astur RS, Jung RE, et al (2005) Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology 30: 633–639.PubMedGoogle Scholar
  90. Roy CS, Sherrington CS (1890) On the regulation of the blood supply of the brain. J Physiol (London) 11: 85–108.Google Scholar
  91. Sauer SW, Okun, Schwab MA, et al (2005) Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency, a role for glutaryl-coenzyme A. J Biol Chem 280: 21830–21836.PubMedGoogle Scholar
  92. Sauer SW, Okun JG, Fricker G, et al. (2006) Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97: 899–910.PubMedGoogle Scholar
  93. Schousboe A, Westergaard N, Sonnewald U, et al (1993) Glutamate and glutamine metabolism and compartmentation in astrocytes. Dev Neurosci 15: 359–366.PubMedGoogle Scholar
  94. Schousboe A, Westergaard N, Waagepetersen HS, Larsson OM, Barken IJ, Sonnewald U (1997) Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. Glia 21: 99–105.PubMedGoogle Scholar
  95. Schwab MA, Sauer SW, Okun JG, et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398: 107–112.PubMedGoogle Scholar
  96. Shefer S, Tint GS, Jean-Guillaume D, et al (2000) Is there a relationship between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and forebrain pathology in the PKU mouse? J Neurosci Res 61: 549–563.PubMedGoogle Scholar
  97. Sherwood CC, Stimpson CD, Raghanti MA, et al (2006) From the cover: evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 103: 13606–13611.PubMedGoogle Scholar
  98. Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L (1988) Measurement of local cerebral protein synthesis in vivo: influence of amino acids derived from protein degradation. Proc Natl Acad Sci U S A 85: 9341–9345.PubMedGoogle Scholar
  99. Snead OC, Gibson KM (2005) γ-Hydroxybutyric acid. N Engl J Med 352: 2721–2732.PubMedGoogle Scholar
  100. Sokoloff L (1960) The metabolism of the central nervous system in vivo. In: Field J, Magoun HW, Hall VE, eds. Handbook of Physiology, Sect 1, Vol II. New York: Raven Press, 161–168.Google Scholar
  101. Sokoloff L (1991) Measurement of local cerebral glucose utilization and its relation to local functional activity in the brain. Adv Exp Med Biol 291: 21–42.PubMedGoogle Scholar
  102. Stellmer F, Keyser B, Burckardt BC, et al (2007) 3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3. J Mol Med 85: 763–770.PubMedGoogle Scholar
  103. Stokke O, Goodman SI, Moe PG (1976) Inhibiton of brain glutamate decarboxylase by glutarate, glutaconate, and beta-hydroxyglutarate: explanation of the symptoms in glutaric aciduria? Clin Chim Acta 66: 411–415.PubMedGoogle Scholar
  104. Strauss KA, Puffenberger EG, Robinson DL, Morton DH (2003) Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet 121: 38–52.PubMedGoogle Scholar
  105. Strauss KA, Mazariegos GV, Sindhi R, et al (2006) Elective liver transplantation of classical maple syrup urine disease. Am J Transplant 6: 557–564.PubMedGoogle Scholar
  106. Strauss KA, Lazovic J, Wintermark M, Morton DH (2007) Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain 130: 1905–1920.PubMedGoogle Scholar
  107. Surtees RA, Matthews EE, Leonard JV (1992) Neurologic outcome of propionic acidemia. Pediatr Neurol 8: 333–337.PubMedGoogle Scholar
  108. Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP (1993) Brain MRI changes in phenylketonuria. Associations with the dietary status. Brain 116: 811–821.PubMedGoogle Scholar
  109. Trefz FK, Cipcic-Schmidt K, Koch R (2000) Final intelligence in late treated patients with phenylketonuria. Eur J Pediatr 159(Supplement 2): S145–S148.PubMedGoogle Scholar
  110. Trefz FK, Scheible D, Frauendienst-Egger G, Korall H, Blau N (2005) Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Mol Genet Metab 86(Supplement 1): S75–S80.PubMedGoogle Scholar
  111. Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF (2005) Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 30: 1861–1869.PubMedGoogle Scholar
  112. Ullrich K, Flott-Rahmel B, Schluff P, et al (1999) Glutaric aciduria type I: pathomechanisms of neurodegeneration. J Inherit Metab Dis 22: 392–403.PubMedGoogle Scholar
  113. Van Bogaert L, Bertrand I (1949) Sur une idiotie familiale avec degerescence sponglieuse de neuraxe (note preliminaire). Acta Neurol 49: 572–587.Google Scholar
  114. Weber G (1969) Inhibition of human brain pyruvate kinase and hexokinase by phenylalanine and phenylpyruvate: possible relevance to phenylketonuric brain damage. Proc Natl Acad Sci U S A 63: 1365–1369.PubMedGoogle Scholar
  115. Weglage J, Wiedermann D, Denecke J, et al (2002) Individual blood brain–barrier phenylalanine transport in siblings with classical phenylketonuria. J Inherit Metab Dis 25: 431–436.PubMedGoogle Scholar
  116. Wu Y, Buzzi A, Shen L, et al (2004) Differential expression of AMPA-type glutamate receptors in the brain of mice deficient for succinate semialdehyde dehydrogenase. 34th Meeting of the Society for Neuroscience, San Diego, CA. Online (http://sfn.scholarone.com/itin2004).
  117. Wu Y, Buzzi A, Frantseva M, et al (2006) Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms. Ann Neurol 59: 42–52.PubMedGoogle Scholar
  118. Yodoya E, Wada M, Shimada A, et al (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary rat cultured cerebrocortical astrocytes and neurons. J Neurochem 97: 162–173.PubMedGoogle Scholar
  119. Zinnanti WJ, Lazovic J, Wolpert EB, et al (2006) A diet-induced mouse model for glutaric aciduria type I. Brain 129: 899–910.PubMedGoogle Scholar
  120. Zinnanti WJ, Lazovic J, Housman C, et al (2007) Mechanism of age-dependent susceptibility and novel treatment strategies in glutaric acidemia type I. J Clin Invest 117: 3258–3270.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • S. Kölker
    • 1
  • S. W. Sauer
    • 1
  • G. F. Hoffmann
    • 1
  • I. Müller
    • 1
  • M. A. Morath
    • 1
  • J. G. Okun
    • 1
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseaseUniversity Children’s Hospital HeidelbergHeidelbergGermany

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