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Review: Normal and abnormal central nervous system GABA metabolism in childhood

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Journal of Inherited Metabolic Disease

Summary

The metabolism and function of central nervous system GABA is briefly reviewed. Hereditary disorders of the GABA metabolism presenting in childhood are discussed with particular emphasis on the recently identified succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency, and on diseases associated with low CSF GABA which await further unravelling. Low CSF GABA concentrations are not always associated with convulsions. A separate section is devoted to the CSF as a tool in the diagnosis of these disorders. Finally, we present a few diagnostic and therapeutic guidelines.

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References

  • Balcar, V. J., Mark, J., Borg, J. and Mandel, P. High-affinity uptake ofγ-aminobutyric acid in cultured glial and neuronal cells.Neurochem. Res. 4 (1979) 339–359

    Google Scholar 

  • Böhlen, P., Schechter, P. J., Van Damme, W., Coquillat, G., Dosch, J. C. and Koch-Weser, J. Automated assay ofγ-aminobutyric acid in human cerebrospinal fluid.Clin. Chem. 24 (1978) 256–260

    Google Scholar 

  • Coursin, D. B. Vitamin B6 deficiency in infants: a follow-up study.Am. J. Dis. Child. 90 (1955) 344–348

    Google Scholar 

  • Daune, G. and Seiler, N. Interrelationships between ornithine, glutamate and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain.Neurochem. Res. 13 (1988) 69–75

    Google Scholar 

  • Enna, S. J., Wood, J. H. and Snijder, S. H.γ-Aminobutyric acid (GABA) in human cerebrospinal fluid: radioreceptor assay.J. Neurochem. 28 (1977) 1121–1124

    Google Scholar 

  • Fagg, G. E. and Foster, A. C. Amino acid neurotransmitters and their pathways in the mammalian central nervous system.Neuroscience 9 (1983) 701–719

    Google Scholar 

  • Fussi, F., Savoldi, F. and Curti, M. Identification of N-carboxyethylγ-aminobutyric acid in bovine brain and human cerebrospinal fluid.Neurosci. Lett. 77 (1987) 308–310

    Google Scholar 

  • Gibson, K. M., Sweetman, L., Nyhan, W. L., Jakobs, C., Rating, D. Siemes, H. and Hanefeld, F. Succinic semialdehyde dehydrogenase deficiency: an inborn error ofγ-aminobutyric acid metabolism.Clin. Chim. Acta 133 (1983) 33–42

    Google Scholar 

  • Gibson, K. M., Sweetman, L., Nyhan, W. L., Jansen, I, and Jaeken, J. Demonstration of 4-aminobutyric acid aminotransferase deficiency in lymphocytes and lymphoblasts.J. Inher. Metab. Dis. 8 (1985) 204–208

    Google Scholar 

  • Gibson, K. M., Nyhan, W. L. and Jaeken, J. Inborn errors of GABA metabolism.BioEssays 4 (1986) 24–27

    Google Scholar 

  • Goldsmith, R. F., Earl, J. W. and Cunningham, A. M. Determination ofγ-aminobutyric acid and other amino acids in cerebrospinal fluid of pediatric patients by reversed-phase liquid chromatography.Clin. Chem. 33 (1987) 1736–1740

    Google Scholar 

  • Goutiers, F. and Aicardi, J. Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants.Ann. Neurol. 17 (1985) 117–120

    Google Scholar 

  • Grove, J., Schechter, P. J., Tell, G., Koch-Weser, J., Sjoerdsma, A., Warter, J. M., Marescaux, C. and Rumbach, L. Increasedγ-aminobutyric acid (GABA), homocarnosine andβ-alanine in cerebrospinal fluid of patients treated withγ-vinyl GABA (4-amino-hex-5-enoic acid).Life Sci. 28 (1981) 2431–2439

    Google Scholar 

  • Grove, J., Schechter, P. J., Hanke, N. F., De Smet, Y., Agid, Y., Tell, G. and Koch-Weser, J. Concentration gradients of free and totalγ-aminobutyric acid and homocarnosine in human CSF: comparison of suboccipital and lumbar sampling.J. Neurochem. 39 (1982a) 1618–1622

    Google Scholar 

  • Grove, J., Schechter, P. J., Tell, G., Rumbach, L., Marescaux, C., Warter, J. M. and Koch-Weser. J. Artifactual increases in the concentration of free GABA in samples of human cerebrospinal fluid are due to degradation of homocarnosine.J. Neurochem. 39 (1982b) 1061–1065

    Google Scholar 

  • Grove, J., Palfreyman, M. G. and Schechter, P. J. Cerebrospinal fluid GABA as an index of brain GABA activity.Clin. Neuropharmacol. 6 (1983) 223–229

    Google Scholar 

  • Haegele, K. D., Schwartz, J.-J., Schoun, J., Schmitt, A. H. and Schechter, P. J. 2-Pyrrolidinone in human cerebrospinal fluid: a major constituent of totalγ-aminobutyric acid.J. Neurochem. 49 (1987) 1402–1406

    Google Scholar 

  • Jaeken, J. and Casaer, P. Pyridoxine non-responsive convulsions with CSF GABA and homocarnosine deficiency.Neuropediatrics 18 (1987) 126

    Google Scholar 

  • Jaeken, J., Casaer, P., De Cock, P., Corbeel, L., Eeckels, R., Eggermont, E., Schechter, P. J. and Brucher, J. M. Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism.Neuropediatrics 15 (1984) 165–169

    Google Scholar 

  • Jaeken, J., Casaer, P., De Cock, P. and François, B. Vigabatrin in GABA metabolism disorders.Lancet 1 (1989) 1074

    Google Scholar 

  • Jakobs, C., Bojasch, M., Monch, E., Rating, D., Siemes, H. and Hanefeld, F. Urinary excretion ofγ-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism.Clin. Chim. Acta. 111 (1981) 169–178

    Google Scholar 

  • Kurlemann, G., Löscher, W., Dominick, H. C. and Palm, G. D. Disappearance of neonatal seizures and low CSF GABA levels after treatment with vitamin B6.Epilepsy Res. 1 (1987) 152–154

    Google Scholar 

  • Lott, I. T., Coulombe, T., Di Paolo, R. V., Richardson, E. P. and Levy, H. L. Vitamin B6-dependent seizures: pathology and chemical findings in brain.Neurology 28 (1978) 47–54

    Google Scholar 

  • Manyam, B. V. and Hare, T. A. Cerebrospinal fluid GABA measurements: basic and clinical considerations.Clin. Neuropharmacol. 6 (1983) 25–36

    Google Scholar 

  • Martin, D. L. Regulatory properties of brain glutamate decarboxylase.Cell Mol. Neurobiol. 7 (1987) 237–253

    Google Scholar 

  • McGeer, P. L., McGeer, E. G. and Wada, J. A. Glutamic acid decarboxylase in Parkinson's disease and epilepsy.Neurology 21 (1971) 1000–1007

    Google Scholar 

  • Murrin, L. C. Ornithine as a precursor for GABA in mammalian brain.J. Neurochem. 34 (1980) 1779–1781

    Google Scholar 

  • Pattarelli, P. P., Nyhan, W. L. and Gibson, K. M. Oxidation of [U-14C]succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria.Pediatr. Res. 24 (1988) 455–460

    Google Scholar 

  • Perry, T. L., Berry, K., Hansen, S., Diamond, S. and Mok, C. Regional distribution of amino acids in human brain obtained at autopsy.J. Neurochem. 18 (1971) 513–519

    Google Scholar 

  • Perry, T. L, Hansen, S. and Kennedy, J. CSF amino acids and plasma-CSF amino acid ratios in adults.J. Neurochem. 24 (1975) 587–589

    Google Scholar 

  • Perry, T. L., Hansen, S., Schier, G. M. and Halpern, B. Isolation and identification ofγ-aminobutyryl-cystathionine from human brain and CSF.J. Neurochem. 29 (1977) 791–795

    Google Scholar 

  • Perry, T. L., Dunn, H. G., Ho, H. H. and Crichton, J. Cerebrospinal fluid values for monoamine metabolites,γ-aminobutyric acid, and other amino compounds in Rett syndrome.J. Pediatr. 112 (1988) 234–238

    Google Scholar 

  • Phillis, J. W. and O'Regan, M. H. Benzodiazepine interaction with adenosine systems explains some anomalies in GABA hypothesis.Trends Pharmacol. Sci. 9 (1988) 153–154

    Google Scholar 

  • Schofield, P. R., Darlison, M. G., Fujita, N., Burt, D. R., Stephenson, F. A., Rodriguez, H., Rhee, L. M., Ramachandran, J., Reale, V., Glencorse, T. A., Seeburg, P. H. and Barnard, E. A. Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family.Nature 328 (1988) 221–227

    Google Scholar 

  • Scriver, C. R. Vitamin B6-dependency and infantile convulsions.Pediatrics 26 (1960) 62–74

    Google Scholar 

  • Sigel, E., Stephenson, F. A., Mamalaki, C. and Barnard, E. A. The purified GABA/benzodiazepine/barbiturate receptor complex: four types of ligand binding sites, and the interactions between them, are preserved in a single isolated protein complex.J. Receptor Res. 4 (1984) 175–188

    Google Scholar 

  • Stephenson, J. B. P. and Byrne, K. E. Pyridoxine responsive epilepsy: expanded pyridoxine dependency?Arch. Dis. Child. 58 (1983) 1034–1036

    Google Scholar 

  • Strange, P. G. The structure and mechanism of neurotransmitter receptors. Implications for the structure and function of the central nervous system.Biochem. J. 249 (1988) 309–318

    Google Scholar 

  • Sweetman, F. R., Gibson, K. M., Sweetman, L., Nyhan, W. L., Chin, H., Schwartz, W. and Jones, O. W. Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for 1st trimester prenatal diagnosis.Prenat. Diagn. 6 (1986) 187–194

    Google Scholar 

  • Walker, J. E. Glutamate, GABA, and CNS disease. A review.Neurochem. Res. 8 (1983) 521–550

    Google Scholar 

  • Yoshida, T., Tada, K. and Arakawa, T. Vitamin B6-dependency of glutamic acid decarboxylase in the kidney from a patient with vitamin B6-dependent convulsions.Tohoku J. Exp. Med. 104 (1971) 195–198

    Google Scholar 

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Authors and Affiliations

  1. Department of Paediatrics, University of Leuven, University Hospital Gasthuisberg, 49 Herestraat, B-3000, Leuven, Belgium

    J. Jaeken & P. Casaer

  2. Merrell Dow Research Centre, 16 rue d'Ankara, 67084, Strasbourg, France

    K. D. Haegele & P. J. Schechter

Authors
  1. J. Jaeken
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  2. P. Casaer
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  3. K. D. Haegele
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  4. P. J. Schechter
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Additional information

Based upon a contribution at the workshop on Neurotransmitters (SSIEM meeting, Glasgow, September 1988).

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Jaeken, J., Casaer, P., Haegele, K.D. et al. Review: Normal and abnormal central nervous system GABA metabolism in childhood. J Inherit Metab Dis 13, 793–801 (1990). https://doi.org/10.1007/BF01800202

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  • DOI: https://doi.org/10.1007/BF01800202

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