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

摘要: 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 characterized by non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), not uniformly successful. Here we report the development Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia develop generalized seizures leading to rapid death. We observed increased amounts GHB total GABA urine, brain liver homogenates detected significant gliosis hippocampus found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions significantly enhanced survival mutant Because neurologic deterioration coincided weaning, hypothesized presence protective compound breast milk. Indeed, treatment amino taurine rescued These findings provide insight into pathomechanisms may have relevance for human disease overdose toxicity.