Summary
Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine-dependent seizures (?glutamic acid decarboxylase deficiency) (>50 patients); (2) GABA-transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain-specific dipeptide of GABA andl-histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA-transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.
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Baekkeskov S, Aanstoot H-J, Christgau S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.Nature 347: 151–156.
Bartsch K, von Johnn-Marteville A, Schulz A (1990) Molecular analysis of two genes of theEscherichia coli gab cluster: nucleotide sequence of the glutamate: succinic semialdehyde transaminase gene (gabT) and characterization of the succinic semialdehyde dehydrogenase gene (gabD).J Bacteriol 172: 7035–7042.
Brown GK, Cromby CH, Manning NJ, Pollitt RJ (1987) Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: evidence of α-oxidation of 4-hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial β-oxidation.J Inher Metab Dis 10: 367–375.
Bu D-F, Erlander MG, Hitz BC et al (1992) Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene.Proc Natl Acad Sci USA 89: 2115–2119.
Carchon HA, Jaeken J, Jansen E, Eggermont E (1991) Reference values for free gammaminobutyric acid determined by ion-exchange chromatography and fluorescence detection in the cerebrospinal fluid of children.Clin Chim Acta 201: 83–88.
Chambliss KL, Lee CF, Ogier H, Rabier D, Jakobs C, Gibson KM (1993) Enzymatic and immunologic demonstration of normal and defective succinic semialdehyde dehydrogenase activity in fetal brain, liver and kidney.J Inher Metab Dis 16: 523–526.
Cohen M, Hartlage PL, Krawiecki N, Roesel RA, Carter AL, Hommes FA (1985) Serum carnosinase deficiency: a non-disabling phenotype?J Ment Defic Res 29: 383–389.
Coker SB (1992) Postneonatal vitamin B6-dependent epilepsy.Pediatrics 90: 221–223.
Erdo SL (1985) Peripheral GABAergic mechanisms.Trends Pharmacol Sci 6: 205–208.
Gibson KM, Sweetman L, Nyhan WL, Jansen I, Jaeken J (1985) Demonstration of 4-aminobutyric acid aminotransferase deficiency in lymphocytes and lymphoblasts.J Inher Metab Dis 8: 204–208.
Gibson KM, Nyhan WL, Jaeken J (1986) Inborn errors of GABA metabolism.BioEssays 4: 24–27.
Gibson KM, Aramaki S, Sweetman L et al (1990) Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria.Biomed Environ Mass Spectrom 19: 89–93.
Hodson AK, Gibson KM, Jakobs C (1990) Developmental resolution of ataxia in succinic semialdehyde dehydrogenase deficiency.Ann Neurol 28: 438.
Howells D, Jakobs C, Kok RM, Wrennall J, Thompson GN (1992) Vigabatrin therapy in succinic semialdehyde dehydrogenase deficiency.Mol Neuropharmacol 2: 181–184.
Iversen LL (1982) Neurotransmitters and CNS disease.Lancet 2: 914–918.
Jaeken J (1990) Disorders of neurotransmitters. In Fernandes J, Saudubray J-M, Tada K, eds.Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 637–648.
Jaeken J, Casaer P, de Cock P et al (1984) Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism.Neuropediatrics 15: 165–169.
Jaeken J, Casaer P, Haegele KD, Schechter PJ (1990) Review: Normal and abnormal central nervous system GABA metabolism in childhood.J Inher Metab Dis 13: 793–801.
Jakobs C, Bojasch M, Moench 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.
Jakobs C, Smit LME, Kneer J, Michael T, Gibson KM (1990) The first adult case with 4-hydroxybutyric aciduria.J Inher Metab Dis 13: 341–344.
Jakobs C, Michael T, Jaeger E, Jaeken J, Gibson KM (1992) Further evaluation of Vigabatrin therapy in 4-hydroxybutyric aciduria.Eur J Pediatr 151: 466–468.
Jakobs C, Ogier H, Rabier D, Gibson KM (1993) Prenatal detection of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).Prenat Diagn 13: 150.
Johnston MV, Singer HS (1982) Brain neurotransmitters and neuromodulators in pediatrics.Pediatrics 70: 57–68.
Kok RM, Howells DW, Heuvel CCM vd, Guérand WS, Thompson GN, Jakobs C (1993) Stable isotope dilution analysis of GABA in CSF using simple solvent extraction and electron capture negative ion mass fragmentography.J Inher Metab Dis 16: 508–512.
Kwon O-S, Park J, Churchich JE (1992) Brain 4-aminobutyrate aminotransferase.J Biol Chem 267: 7215–7216.
Lenney JF, Peppers SC, Kucera CM, Sjaastad O (1983) Homocarnosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine.Clin Chim Acta 132: 157–165.
Lunde H, Sjaastad O, Gjessing L (1982) Homocarnosinosis: hypercarnosinuria.J Neurochem 38: 242–245.
Mamelak M (1989) Gammahydroxybutyrate: an endogenous regulator of energy metabolism.Neurosci Biobehav Rev 13: 187–198.
Marek LE, Henson JM (1988) Cloning and expression of theEscherichia coli K-12GAD gene.J Bacteriol 170: 991–994.
Murphey WH, Lindmark DG, Patchen LI, Housler ME, Harrod EK, Mosovich L (1973) Serum carnosinase deficiency concomitant with mental retardation.Pediatr Res 7: 601–606.
Pattarelli PP, Nyhan WL, Gibson KM (1988) Oxidation of [U14C]succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria.Pediatr Res 24: 455–460.
Scriver CR, Perry TL (1989) Disorders of ω-amino acids in free and peptide-linked forms. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill, 755–771.
Sjaastad O, Berstad J, Gjesdahl P, Gjessing L (1976) Homocarnosinosis. 2. A familial metabolic disorder associated with spastic paraplegia, progressive mental deficiency, and retinal pigmentation.Acta Neurol Scand 53: 275–290.
Sjaastad O, Gjessing L, Berstad JR, Gjesdahl P (1977) Homocarnosinosis. 3. Spinal fluid amino acids in familial spastic paraplegia.Acta Neurol Scand 55: 158–162.
Skaper SD, Das S, Marshall FD (1973) Some properties of a homocarnosine-carnosine synthetase isolated from rat brain.J Neurochem 21: 1429–1445.
Sweetman FR, Gibson KM, Sweetman L et al (1986) Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for first trimester prenatal diagnosis.Prenat Diagn 6: 187–194.
Tanaka R, Okumura M, Arima J, Yamakura S, Momoi T (1992) Pyridoxine-dependent seizures: report of a case with atypical clinical features and abnormal MRI scans.J Child Neurol 7: 24–28.
Vamecq J, Draye J-P, Poupaert JH (1990) Studies on the metabolism of glycolyl-CoA.Biochem Cell Biol 68: 846–851.
Yoshida T, Tada K, Arakawa T (1971) Vitamin B6 dependency of glutamic acid decarboxylase in the kidney from a patient with vitamin B6-dependent convulsion.Tohoku J Exp Med 104: 195–198.
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Jakobs, C., Jaeken, J. & Gibson, K.M. Inherited disorders of GABA metabolism. J Inherit Metab Dis 16, 704–715 (1993). https://doi.org/10.1007/BF00711902
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DOI: https://doi.org/10.1007/BF00711902