title: Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism.
abstract: OBJECTIVE
  Succinic semialdehyde dehydrogenase (SSADH) deficiency is a gamma-aminobutyric acid (GABA) degradative defect. Epilepsy affects half of patients. The murine model is associated with a transition from absence to convulsive seizures in the third week, with fatal status epilepticus.
  
  
  METHODS
  The clinical phenotype is reported from a patient database. Flumazenil-Positron Emission Topography (FMZ-PET) and Transcranial Magnetic Stimulation (TMS) were used to study GABA neurotransmission. Electrocorticography, single cell electrophysiology, and radioligand binding studies are reported from animal studies.
  
  
  RESULTS
  Generalized seizures predominate, including tonic-clonic, atypical absence, and myoclonic. EEG discharges are typically generalized spike-wave. MRI shows a dentatopallidoluysian pattern. Sudden Unexpected Death in Epilepsy Patients (SUDEP) has occurred and the associated neuropathology reveals chronic excitotoxic injury in gloubus pallidus. Investigations using FMZ-PET and TMS support downregulation of GABA(A) and GABA(B) activity, respectively, in patients. Gamma-hydroxybutyrate (GHB) induces spike-wave discharges in homozygous null mice via GHB and GABA(B)-mediated mechanisms. These resemble absence seizures and are abolished by a GABA(B) receptor antagonist. Decreased binding of GABA(A) and GABA(B) receptor antagonists has been demonstrated in P19 and P14 null mice, respectively. Downregulation of GABA(A) and GABA(B) receptor subunits is observed by P14. GABA(A) and GABA(B) mediated potentials are reduced from P8-P14.
  
  
  CONCLUSIONS
  Generalized epilepsy and epileptiform discharges are characteristic of SSADH deficiency. Spontaneous absence seizures appear in null mice by the third week, which may be induced by GHB or GABA(B) activity. Subsequent overuse dependent downregulation of GABA(A) and GABA(B) receptor activity may be associated with hyperexcitability concomitant with the transition to generalized seizures.
authors.affiliation: Department of Neurology, Children's National Medical Center, George Washington University School of Medicine, Washington, DC, USA. ppearl@cnmc.org
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Pearl
authors.forename: Lovy
authors.initials: L
authors.lastname: Shukla
authors.forename: William H
authors.initials: WH
authors.lastname: Theodore
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: K
authors.initials: K
authors.lastname: Michael Gibson
mesh_terms: D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology*; D002675:Child, Preschool; D004827:Epilepsy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase