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

Boris M. Hogema, Maneesh Gupta, Henry Senephansiri, Terry G. Burlingame, Melissa Taylor, Cornelis Jakobs, Ruud B.H. Schutgens, Wolfgang Froestl, O. Carter Snead, Ramon Diaz-Arrastia, Teodoro Bottiglieri, Markus Grompe, K. Michael Gibson

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126 Scopus citations

Abstract

Succinate semialdehyde dehydrogenase (ALDHSA1, 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 successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-1- 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 Aldh5a1-1- 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 Aldh5a1-1- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

Original languageEnglish (US)
Pages (from-to)212-216
Number of pages5
JournalNature genetics
Volume29
Issue number2
DOIs
StatePublished - Oct 22 2001

ASJC Scopus subject areas

  • Genetics

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    Hogema, B. M., Gupta, M., Senephansiri, H., Burlingame, T. G., Taylor, M., Jakobs, C., Schutgens, R. B. H., Froestl, W., Snead, O. C., Diaz-Arrastia, R., Bottiglieri, T., Grompe, M., & Gibson, K. M. (2001). Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nature genetics, 29(2), 212-216. https://doi.org/10.1038/ng727