Murine succinate semialdehyde dehydrogenase deficiency

Maneesh Gupta, Boris M. Hogema, Markus Grompe, Teodoro G. Bottiglieri, Alessandra Concas, Giovanni Biggio, Cristiana Sogliano, Antonello E. Rigamonti, Phillip L. Pearl, O. Carter Snead, Cornelis Jakobs, K. Michael Gibson

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Inherited succinic semialdehyde dehydrogenase (SSADH) deficiency (γ-hydroxybutyric aciduria) is one of the few neurogenetic disorders of GABA metabolism, and one in which tonic-clonic seizures associate with increased central nervous system GABA and γ-hydroxybutyrate (GHB). To explore pathomechanisms and develop new preclinical treatment approaches, we developed a murine knockout model of SSADH deficiency. In the absence of intervention, SSADH-/- mice suffer 100% mortality at week 3 to 4 of life from generalized tonic-clonic seizures. In this report, we summarize earlier studies indicating disruption of the GABA/glutamine axis in SSADH-/- mouse brain, effective pharmacotherapeutic approaches, preliminary gene-therapy results, and electrophysiological analyses of mutant mice. We also present new evidence for oxidative stress in SSADH-/- mice, significant alterations of dopamine metabolism, and abnormal neuro- steroid levels in brain, potentially implicating the GABAA receptor in pathogenesis. In SSADH deficiency, the accumulation of two neuroactive species, GABA and GHB, is significant because GABA is one of the earliest transmitters expressed in mammals, with key roles in synaptogenesis and myelination, whereas GHB displays a vast array of pharmacological actions. The SSADH-/- mouse may represent a useful model in which to explore the effect of GABA and GHB accumulation on central nervous system development and function.

Original languageEnglish (US)
Pages (from-to)S81-S90
JournalAnnals of Neurology
Issue numberSUPPL. 6
StatePublished - 2003

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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