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Inherited disorders of GABA metabolism

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Journal of Inherited Metabolic Disease

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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Authors and Affiliations

  1. Department of Pediatrics, Free University Hospital, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    C. Jakobs

  2. Department of Pediatrics, University Hospital Gasthuisberg, 49 Herestraat, B-3000, Leuven, Belgium

    J. Jaeken

  3. Metabolic Disease Center, Baylor Research Institute and Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas, USA

    K. M. Gibson

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  1. C. Jakobs
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  2. J. Jaeken
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  3. K. M. Gibson
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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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