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 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.

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 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.

Figure 1. GABA degradation pathway

GABA is normally converted via GABA-transaminase to succinate semialdhyde, which is then broken down to succinic acid by succinate semialdehyde dehydrogenase (SSADH). In the absence of SSADH, succinate semialdehyde is converted to GHB rather than succinic acid, and this leads to a build up of both GHB and GABA in the brain.

Figure 2. Dentatopallidoluysian Pattern in SSADH Deficiency

Coronal short tau inversion recovery sections from MRI in patient with SSADH deficiency showing bilateral symmetric homogenous signal abnormalities in each globus pallidus pars lateralis (white arrow, A and B), pars medialis (black arrow, A), subthalamic nucleus (black arrows, B), and dentate nucleus (white arrows, C). (Reprinted with permission from Pearl et al: Neurology 2009;73:423–9.)

Figure 3. MRI of patient with SSADH deficiency- midsagittal and axial

Midsaggittal (left) and axial (right) 1.5 T MRI demonstrating cerebellar atrophy predominantly affecting the midline vermis. (Reproduced with permission from Acosta et al. J Child Neurol 2010 May 5. [Epub ahead of print].)

Figure 4. EEG abnormalities in SSADH deficiency

(a) Intermittent photic stimulation (IPS) at 1 Hz causes bilateral 2.5 Hz spike-waves with frontocentral predominance. (b) 9 Hz IPS causes bilateral, diffuse spike-and-wave discharges (Reproduced with permission from: Dervent et al: Clin Neurophysiol 2004;115:1417–22.)

Figure 5. Decreased GABA_A binding on FMZ-PET in SSADH deficiency

FMZ-PET shows marked reduction of cortical binding potential of [11C]-flumazenil in patient with SSADH deficiency (A) versus heterozygote control (B). (Reproduced with permission from Pearl et al. Neurology 2009;73:423–9.)

Figure 6. Transition from absence to tonic-clonic seizures in P20 SSADH(−/−) mice

(A) Baseline electrocorticogram (ECoG) recordings in P16 wild-type (+/+) mice show uneventful 35–50 uV and 5–7 Hz oscillations. (B) ECoG of P16 SSADH (−/−) mice reveals 250–300 uV, 5–7 Hz spike-and-wave discharges (SWD) lasting 3–6s duration. This was associated with frozen stare and vibrissal twitching, suggesting absence seizures. (C) ECoG recording in P20 SSADH(−/−) mice show a transition from absence to a generalized 600 uV at 5 Hz followed by 1.5 to 2 Hz SWD associated with tonic-clonic seizures (arrow). LF= left frontal, RF= right frontal, LP= left parietal, RP= right parietal. (Reproduced with permission from: Cortez et al. Pharmacol Biochem Behav 2004;79:547–53.)