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

Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in human s as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is character ized by a non-specific neurological disorder including psychomotor retardat ion, language delay, seizures, hypotonia and ataxia. The current therapy, v igabatrin (VGB), is not uniformly successful(1). Here we report the develop ment of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1(-/-) mice di splay ataxia and develop generalized seizures leading to rapid death. We ob served increased amounts of GHB and total GABA in urine, brain and liver ho mogenates and detected significant gliosis in the hippocampus of Aldh5a1(-/ -) mice. We found therapeutic intervention with phenobarbital or pherytoin ineffective, whereas intervention with vigabatrin or the GABA(B) receptor a ntagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and signifi cantly enhanced survival of the mutant mice. Because neurologic deteriorati on coincided with weaning, we hypothesized the presence of a protective com pound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1(-/-) mice. These findings provide insight into path omechanisms and may have therapeutic relevance for the human SSADH deficien cy disease and GHB overdose and toxicity.