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NEUROLOGY 2009;73:423-429
© 2009 American Academy of Neurology

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

P. L. Pearl, MD, K. M. Gibson, PhD, Z. Quezado, MD, I. Dustin, RN, J. Taylor, BA, S. Trzcinski, MD, J. Schreiber, MD, K. Forester, BA, P. Reeves-Tyer, C. Liew, MD, S. Shamim, MD, P. Herscovitch, MD, R. Carson, PhD, J. Butman, MD, PhD, C. Jakobs, PhD and W. Theodore, MD

From the Children’s National Medical Center (P.L.P., J.T., S.T., J.S., K.F.), Washington, DC; Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke (P.L.P., I.D., P.R.-T., C.L., S.S., W.T.), and Department of Anesthesia and Surgical Services (Z.Q.), Positron Emission Tomography Department and Diagnostic Radiology Department (P.H., R.C., J.B.), Clinical Center, NIH, Bethesda, MD; Division of Medical Genetics (K.M.G.), Departments of Pediatrics, Pathology, and Human Genetics, University of Pittsburgh School of Medicine, PA; and Department of Clinical Chemistry (C.J.), VU University Medical Center, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Dr. Phillip L. Pearl, Department of Neurology, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010-2970 ppearl{at}cnmc.org

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gamma-hydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utilizing [11C]-flumazenil (FMZ)-PET.

Methods: FMZ binding was measured in 7 patients, 10 unaffected parents, and 8 healthy controls. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BPND) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on coregistered MRI.

Results: In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BPND compared to parents and controls. Mean cortical values were 6.96 ± 0.79 (controls), 6.89 ± 0.71 (parents), and 4.88 ± 0.77 (patients) (F ratio 16.1; p < 0.001). There were no differences between controls and parents in any cortical region.

Conclusions: Succinic semialdehyde dehydrogenase (SSADH) deficient patients show widespread reduction in BZPR binding on [11C]-flumazenil-PET. Our results suggest that high endogenous brain GABA levels in SSADH deficiency downregulate GABA(A)-BZPR binding site availability. This finding suggests a potential mechanism for neurologic dysfunction in a serious neurodevelopmental disorder, and suggests that PET may be useful to translate studies in animal models to human disease.

Abbreviations: FMZ = flumazenil; MRS = magnetic resonance spectroscopy; PVC = partial volume correction; ROI = region of interest; SPGR = spoiled gradient recall; SSADH = succinic semialdehyde dehydrogenase.

Disclosure: Author disclosures are provided at the end of the article.

Received December 18, 2008. Accepted in final form April 22, 2009.






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