Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency.
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 [(11)C]-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 (BP(ND)) 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 BP(ND) 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 [(11)C]-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.
Pearl
P L
PL
Department of Neurology, Children's National Medical Center, Washington, DC 20010-2970, USA. ppearl@cnmc.org
Gibson
K M
KM
Quezado
Z
Z
Dustin
I
I
Taylor
J
J
Trzcinski
S
S
Schreiber
J
J
Forester
K
K
Reeves-Tyer
P
P
Liew
C
C
Shamim
S
S
Herscovitch
P
P
Carson
R
R
Butman
J
J
Jakobs
C
C
Theodore
W
W
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000378:metabolism; D002648:Child; D005260:Female; D005442:Flumazenil / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002250:Carbon Radioisotopes; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase