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Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase

Nature Genetics volume 29, pages 212–216 (2001)Cite this article

Abstract

Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful1. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16–22 Aldh5a1−/− mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1−/− mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1−/− mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

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Figure 1: Generation of Aldh5a1-deficient mice.
Figure 2: Gliosis in dorsal hippocampal commissure of Aldh5a1−/− and wildtype mice.
Figure 3

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Acknowledgements

The authors acknowledge the contribution of M. Baetscher and J. Dekoning from the OHSU transgenic core facility in the development of the animal model, M. Al-Dhalimy and M. Noll for assistance with genotyping and animal studies, S. Akaboshi for assistance in characterization of murine seizures, H. Bartels for assistance with behavioral studies and amino acid analysis and C. Fernandez-Canon for providing the pgk-TK vector. The expert technical assistance of W. Guerand, V. Pereira and D. Schor in determination of metabolite levels in tissues and physiologic fluids is gratefully acknowledged. This work was supported in part by Research Grants No. 9813 from the Oregon Health Sciences Foundation (K.M.G.), #1-FY00-352 from the March of Dimes Birth Defects Foundation (K.M.G.), and NS 40270 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (K.M.G.). R.D.-A. was supported by P30 AG12300 and RO3 AG16450, from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health Sciences University, 2525 SW Third Avenue, Portland, 97201, Oregon, USA

    Boris M. Hogema, Maneesh Gupta, Henry Senephansiri, Terry G. Burlingame, Melissa Taylor, Markus Grompe & K. Michael Gibson

  2. Department of Clinical Chemistry, Metabolic Unit, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Boris M. Hogema, Cornelis Jakobs & Ruud B. H. Schutgens

  3. Department of Biochemistry, Cardiovascular Research Institute COEUR, Medical Faculty, Erasmus University Rotterdam, The Netherlands

    Boris M. Hogema

  4. Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon, USA

    Markus Grompe & K. Michael Gibson

  5. Novartis Pharma Inc, Basle, CH-4002, Switzerland

    Wolfgang Froestl

  6. Department of Pediatrics, Division of Neurology and The Program in Brain and Behavior, Faculty of Medicine, Hospital for Sick Children, Ontario, Canada

    O. Carter Snead

  7. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ramon Diaz-Arrastia

  8. Institute for Metabolic Disease, Baylor University Medical Center, Dallas, Texas, USA

    Teodoro Bottiglieri

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Correspondence to K. Michael Gibson.

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Hogema, B., Gupta, M., Senephansiri, H. et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 29, 212–216 (2001). https://doi.org/10.1038/ng727

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