Abstracts

Rationale: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of gamma-aminobutyric acid (GABA) metabolism characterized by elevated levels of GABA and gamma-hydroxybutyric acid (GHB). Clinical findings include mental retardation with disproportionate expressive language dysfunction, hypotonia, hyporeflexia, hallucinations, autistic behaviors and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model provide evidence for use-dependent down-regulation of the GABA(a) receptor. To investigate whether there is down-regulation of the GABA(a) receptor in human patients with SSADH deficiency, we investigated benzodiazepine receptor (BZPR) binding using [11C] flumazenil (FMZ) and positron emission tomography (PET).Methods: FMZ binding was measured in 6 patients with SSADH deficiency, 10 unaffected parents (obligate heterozygotes) and 6 healthy controls. We performed PET on a GE Advance Scanner (35 simultaneous slices with 4.25 mm inter-slice distance; reconstructed resolution 6 mm). A bolus dose of 1mg/kg of dexmedetomidine, a selective alpha-2 adrenergic agonist that does not appear to have GABAergic effects, infused over 10 min, was followed by a continuous infusion, ranging from 0.7- 2 mcg/kg/hr. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BP2) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on co-registered MRI. Results: In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BP compared to parents and controls. Mean cortical values were 6.96 ± 0.79 (controls), 6.89 ± 0.71 (parents), 4.88 ± 0.77 (patients) (F-ratio 16.1; p<0.001). There were no differences between controls and parents in any cortical region. In thalamus, there was a non-significant trend for parents (6.9 ± 1.8) to have values intermediate between patients (4.9 ± 1.5) and controls (8.3 ± 0.53). There was no effect of gender. Conclusions: SSADH deficient patients show widespread reduction in BZPR binding on 11C-FMZ PET. Previous studies of FMZ PET have shown that binding is higher in children. Our results suggest that high endogenous brain GABA levels in SSADH deficiency down-regulate GABA(a)-BZPR binding site availability.