Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Abstract Objectives 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 GABAA and GABAB activity, respectively, in patients. Gamma-hydroxybutyrate (GHB) induces spike-wave discharges in homozygous null mice via GHB and GABAB -mediated mechanisms. These resemble absence seizures and are abolished by a GABAB receptor antagonist. Decreased binding of GABAA and GABAB receptor antagonists has been demonstrated in P19 and P14 null mice, respectively. Downregulation of GABAA and GABAB receptor subunits is observed by P14. GABAA and GABAB mediated potentials are reduced from P8-P14. Conclusion 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 GABAB activity. Subsequent overuse dependent downregulation of GABAA and GABAB receptor activity may be associated with hyperexcitability concomitant with the transition to generalized seizures.