Decreased GABA-A binding on
FMZ-PET in succinic semialdehyde
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
C. Liew, MD
S. Shamim, MD
P. Herscovitch, MD
R. Carson, PhD
J. Butman, MD, PhD
C. Jakobs, PhD
W. Theodore, MD
Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal reces-
sive 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 electro-
physiology studies in the murine model demonstrate use-dependent downregulation of
GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utiliz-
ing [11C]-flumazenil (FMZ)-PET.
Methods: FMZ binding was measured in 7 patients, 10 unaffected parents, and 8 healthy con-
trols. 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
Results: In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, pa-
tients with SSADH deficiency had significant reductions in FMZ BPNDcompared 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 par-
ents in any cortical region.
Conclusions: Succinic semialdehyde dehydrogenase (SSADH) deficient patients show wide-
spread reduction in BZPR binding on [11C]-flumazenil-PET. Our results suggest that high endoge-
nous 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. Neurology®2009;73:423–429
FMZ ? flumazenil; MRS ? magnetic resonance spectroscopy; PVC ? partial volume correction; ROI ? region of interest;
SPGR ? spoiled gradient recall; SSADH ? succinic semialdehyde dehydrogenase.
Succinic semialdehyde dehydrogenase (SSADH) deficiency, also called 4-hydroxybutyric acid-
uria (McKusick 279180) and aldehyde dehydrogenase 5a1 (Aldh5a1), is an autosomal recessive
disorder. About 350 patients are known, with about 85% under 18, making this the most
prevalent pediatric neurotransmitter disorder.1In the absence of SSADH, transamination of
GABA to succinic semialdehyde is followed by its conversion to 4-hydroxybutryic acid
(gamma-hydroxybutyric acid, or GHB), leading to CNS GABA and ?-hydroxy butyrate
(GHB) accumulation.2Major clinical manifestations include developmental delay, hypotonia,
ataxia, and seizures. Hyperkinetic behavior, aggression, self-injurious behaviors, and hallucina-
tions have also been described; EEG abnormalities include generalized and focal epileptiform
discharges, photosensitivity, and background slowing.1
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.
Disclosure: Author disclosures are provided at the end of the article.
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-
Copyright © 2009 by AAN Enterprises, Inc.
Neuroimaging findings in SSADH defi-
ciency include T2 hyperintensities in multiple
regions, most commonly the globus pallidus. A
pattern of dentate-pallidal hyperintensity has
been described.3There are also areas of abnor-
mal T2-weighted signal in cerebral white matter
and brainstem. PET with [18F]-fluorodeoxy-
glucose ([18F]-FDG PET) showed decreased
cerebellar glucose metabolism in patients with
known cerebellar atrophy on structural MRI.1
Magnetic resonance spectroscopy (MRS) showed
elevated occipital GABA in 5 affected subjects,
but not in parents.4
A mouse model of SSADH deficiency
showed high GABA and GHB levels in neural
tissue, altered GABA binding in cerebral cor-
tex, and reduced expression of GABAAand
GABABreceptors.5,6Of interest, while the
GABAergic system is significantly altered in
this mouse model, the GHBergic system ap-
pears not to be affected.7
PET with [11C]-flumazenil ([11C]-FMZ-
PET) has been used to image the GABA-
benzodiazepine receptor complex in man.8–10
[11C]-FMZ binds with high affinity and se-
lectivity to the GABAAreceptor ?1, ?2, ?3,
and ?5 receptor subunits; in cerebellum,
binding is mainly to the ?1 subunit.11
In order to test the hypothesis that patients
with SSADH deficiency would demonstrate re-
duced GABA receptor binding, building di-
we used [11C]-FMZ-PET to study affected sub-
jects, parents, and healthy volunteers.
METHODS Subjects. We studied 7 affected patients (4
male; age 15.7 ? 5.7 years), 10 parents (6 male; age 43.6 ? 5.8),
and 8 healthy adult volunteer controls (4 male; 31.8 ? 10.2
years). All study participants provided informed consent.
Healthy volunteers were screened with general physical and neu-
rologic examination, and standard laboratory tests, by the Na-
tional Institute of Neurological Disorders and Stroke Clinical
Epilepsy Section. Age-matched pediatric controls were not re-
cruited for ethical reasons related to radiation exposure.
Affected patients and family members were screened for in-
clusion by the Children’s National Medical Center Department
of Neurology. Screening was performed by an experienced pedi-
atric neurologist (P.L.P.) who has clinical expertise in this condi-
tion, and has followed the families personally. Family and social
histories were reviewed carefully and paternity established by ap-
propriate methods if deemed necessary. Inclusion criteria were
clinical characteristics consistent with SSADH deficiency, persis-
tent 4-hydroxybutyric aciduria (gamma-hydroxybutyric acid-
uria), and confirmed leukocyte extract SSADH enzyme
deficiency and/or identification of a pathogenic mutation in
DNA samples.12,13All electrophysiologic and imaging studies
were performed at the NIH Clinical Center.
MRI. All subjects underwent MRI using a 1.5-T Signa scanner
(GE Healthcare). T1-weighted spoiled gradient images (repetition
coronal orientation. Standard coronal T2 and fluid-attenuated in-
version recovery short tau inversion recovery and three-dimensional
were read by an experienced neuroradiologist who was unaware of
PET results. In addition, magnetic resonance–based partial volume
correction (PVC) and region of interest (ROI) coregistration were
PET scanning. Patients fasted for at least 3 hours before each
PET scan. As part of standard procedure, EEG leads were at-
tached to the scalp for monitoring during scanning, and a ther-
moplastic facemask used for positioning.
PET scans were acquired using a GE Advance scanner with
septa retracted (35 contiguous slices; 4.25 mm plane separation;
reconstructed 3-dimensional spatial resolution 6–7 mm full-width
at half-maximum). A transmission scan was acquired to correct for
attenuation. Following transmission scanning, a target dose of
0.285 mCi/kg with a maximum of 20 mCi of high specific activity
[11C]-FMZ was injected by IV bolus, and a 60-minute dynamic
emission image of the brain acquired.
Subject motion correction during the PET acquisition was per-
formed with mutual-information registration of each scan time-
frame to a standard frame before attenuation correction.15Based on
the calculated motion, the transmission images were resliced and
projected for final reconstruction and realignment.16
A summed PET image (0–10 minutes post injection) was
registered to each subject’s MRI with a mutual information algo-
rithm and all the PET images were resliced. Binding potential
(BPND) images were created using the 2-step version of the sim-
plified reference tissue model (SRTM2).17The time-activity
curve for the reference tissue was derived from the pons (drawn
on the MRI), where the [11C]-FMZ binding is predominantly
accounted for by free and nonspecifically bound radiotracer.
This method also produces images of relative tracer delivery
(R1), an index related to cerebral blood flow.
Anesthetic. In order to avoid possible interference with [11C]-
FMZ binding, we used an agent that does not affect GABA levels
or GABA receptors. For patients who needed sedation during
PET, we used dexmedetomidine (Precedex, Hospira, Lake For-
est, IL), a highly selective ?2-adrenoreceptor agonist that exerts
its hypnotic effects at the locus coeruleus, and has minimal car-
diovascular and respiratory effects.18,19A bolus dose of 1 mg/kg
was infused over 10 minutes and followed by an infusion of
0.7–2 mcg/kg/hour. The drug has no effect on release or extra-
cellular levels of glutamate, aspartate, and GABA.20The sedation
was used in 5 of the 7 patients and in no controls.
Data analysis. We used a simplified reference region method.17
This approach uses the time-activity curve from the pons, a region
functional images of binding potential equivalent to
where fNDis a measure of the fraction of free intracerebral con-
centration of tracer, Bavailis the maximum available (unoccu-
pied) receptor concentration, and KDis the tracer dissociation
equilibrium constant. Functional images were corrected for par-
Neurology 73 August 11, 2009
tial volume effects and gray-white matter ratios on a pixel by
pixel basis.14Operators blinded to subject status (affected, par-
ent, or control) drew ROIs on coregistered three-dimensional
SPGR MRI scans. ROIs were frontal and occipital cortex,
amygdala, hippocampus, caudate nucleus, globus pallidus,
thalamus, midbrain, dentate nucleus, and cerebellar vermis.
The Duvernoy Brain Atlas was used to identify structures.21
Regional BPNDand R1were compared among patients, con-
trols and parents, with one-way analysis of variance and post hoc
Tukey test, using Systat (Systat Inc., Richmond, CA).
This study was approved by the institutional review boards
of the NIH (National Institute of Neurological Disorders and
Stroke) and Children’s National Medical Center.
RESULTS Neurologic examination of parents and
Affected subjects had a variety of neurologic find-
ings (table 1). Two affected subjects had standard
21-channel EEG with hyperventilation and photic
stimulation that was normal for age. Five had diffuse
Structural MRI. Five patients had a consistent pattern
tate nuclei (figure 1). Both the pars medialis and pars
medialis, the pars interna and externa were not distin-
guishable. The signal abnormality appeared as hypoin-
tensity on T1- and hyperintensity on T2-weighted
sequences, but was most clearly discernible using the
short tau inversion recovery sequence, which combines
T1 and T2 effects.
One patient had marked ventriculomegaly, and
asymmetric involvement of the globus pallidus. In the
globus pallidus, the signal abnormality was heteroge-
Table 1 Clinical and imaging data of affected subjects
no. Age, y
diagnosis Neurologic examination SeizuresStructural MRI Drugs at time of study
10 3 y ID, Hypot, ATX, HA, ADD, SD, ANXAbsence (rare) GP, sub, den: bilateral symmetric
homogeneous signal abnormalities
27 21 yID, Hypot, ATX, AGG, HALL, SD GTCS, absence GP volume loss, ex vacuo dilation
of the third ventricle
15 7 y ID, Hypot, ANX, ADDNone GP, sub, den: bilateral symmetric
homogeneous signal abnormalities
13 5 yID, ADD, HA None GP, sub, den: bilateral symmetric
homogeneous signal abnormalities
14 2 y ID, Hypot, ATX, ANX, ADD, OCD None Ventriculomegaly, GP signal
abnormality L ? R
19 16 yID, ATX, ANX, HALL, SDNone GP, sub, den: bilateral symmetric
homogeneous signal abnormalities
12 4 mo ID, Hypot, ATX, ADD, AGG, HA,
None GP, sub, den: bilateral symmetric
homogeneous signal abnormalities
All patients had hyporeflexia and motor dyspraxia on examination.
*Patients 3 and 4 are sisters.
ID ? intellectual disability; Hypot ? hypotonia; ATX ? ataxia; HA ? hyperactivity; ADD ? attention deficit; SD ? sleep disturbance; ANX ? anxiety; GP ?
globus pallidus (bilaterally symmetric unless noted otherwise); sub ? subthalamic nucleus; den ? dentate nucleus; AGG ? aggression; HALL ? hallucina-
tions; GTCS ? generalized tonic-clonic seizures; OCD ? obsessive compulsive disorder.
Figure 1 Coronal short tau inversion recovery sections from MRI in patient 1 showing bilateral symmetric
homogeneous signal abnormalities in each globus pallidus pars lateralis (white arrowhead, A and
B), pars medialis (black arrowheads, A), subthalamic nucleus (black arrows, B), and dentate
nucleus (white arrows, C)
Neurology 73 August 11, 2009
neous, with normal and abnormal portions. There was
minimal abnormality present on the right, and a
marked abnormality on the left, which was clearly ex-
previously revealed the same degree of pallidal asymme-
try and ventriculomegaly, and follow-up studies over 2
years showed completely stable findings.
In the oldest (27 years old) patient, the signal ab-
normality in the globus pallidus was subtle, but there
was clear volume loss, with commensurate ex vacuo
dilation of the third ventricle. Abnormalities of the
STN and the dentate nuclei could not be identified.
No cortical or pontine abnormalities were identi-
fied on MRI.
PET. There were statistically significant differences
in11C FMZ binding among patients, parents, and
controls in all ROIs except midbrain; in the globus
pallidus, a trend toward significance was found (table
2 and figure 2). Since no significant left-right differ-
ence in cortical BPNDwere found, left and right
ROIs were averaged. Using a strict Bonferroni proce-
dure to correct for 10 independent regional analyses
of variance, significance is lost in dentate, and be-
group difference in the globus pallidus was due to par-
ticularly low values in one parent. Omitting this sub-
ject, the group difference was highly significant (F ratio
33.8). Overall cortical binding was significantly dimin-
ished in patients, with values about 70% of parents and
between the parent and control groups.
Table 2 Regional ?11C?-flumazenil binding potential (BPND) data in patients,
parents, and healthy controls
6.2 ? 1.19.4 ? 1.59.6 ? 2.0 0.001
5.9 ? 1.18.6 ? 0.8 8.9 ? 0.80.001
3.4 ? 1.15.6 ? 1.6 5.5 ? 1.30.008
3.9 ? 1.0 9.2 ? 7.58.6 ? 2.50.07
4.6 ? 1.66.9 ? 1.88.5 ? 0.70.001
2.0 ? 0.7 3.6 ? 1.34.2 ? 0.6 0.023
3.4 ? 0.7 6.6 ? 2.5 6.1 ? 0.4 0.003
3.5 ? 0.8 4.0 ? 1.65.0 ? 2.3NS
3.5 ? 0.7 4.8 ? 0.64.7 ? 0.5 0.001
3.3 ? 0.74.7 ? 0.64.8 ? 0.5 0.001
*One-way analysis of variance with post hoc Tukey test.
Figure 2 [11C]-flumazenil PET scans in an affected subject (A) and the subject’s parent (B) showing marked
reduction of cortical binding potential in A
The color scale shows BPND.
Neurology 73August 11, 2009
After analysis of variance, the post hoc Tukey pro-
cedure was used to determine intergroup differences.
Setting the significance level at p ? 0.05, after strict
Bonferroni correction for multiple comparisons,
there were significant control vs patient differences in
frontal, occipital, thalamic, amygdala, and hip-
pocampal regions; there were differences between
parents and patients in frontal, occipital, amygdala,
and hippocampal regions. There were no significant
control vs parent differences either before or after
In order to ensure that systematic differences in
the pons time-activity curves did not affect the re-
sults, we compared the average pons activity counts,
corrected for dose administered and patient weight
among the 3 groups. There were no significant inter-
group differences (F ratio 0.568; p ? 0.50). We also
calculated regional R1 tracer delivery values and
found no difference among the groups in any region.
Two patients had scans without anesthesia. Both
had cortical values below parents and controls; one
was outside the mean plus 2 standard deviations
(mean cortical values for controls, parents, and pa-
tients were 6.9 ? 0.7, 7.0 ? 0.7, and 4.7 ? 0.8,
respectively). Values for these 2 patients were 5.0 and
6.3. Anesthesia did not affect tracer delivery R1.
Only one patient was on an antiepileptic drug at
the time of the study; 4 (including both who had
scans without anesthesia) were taking a selective sero-
tonin reuptake inhibitor (table 1). Although FMZ
binding tended to be higher in the patients on selec-
tive serotonin reuptake inhibitors, the differences
were not significant.
We did not detect any relation of FMZ binding
to age among the patients, who had a relatively re-
stricted range, except for one outlier. Among parents
and controls, age had no relation to binding.
DISCUSSION We found that patients with
SSADH deficiency have reduced benzodiazepine
receptor binding measured with11C-FMZ-PET.
Parents, clinically unaffected, showed no binding
reduction. This finding parallels results in SSADH
null mice and suggests a potential mechanism for
neurologic dysfunction in a serious neurodevelop-
The subcortical reductions we found could have
been related in part to structural abnormalities, be-
cause the PVC procedure is less accurate for subcor-
tical structures.14However, the patients had no
cortical abnormalities on MRI, and PVC is reliable
in these regions. The cortical binding reductions are
unlikely to be due to partial volume effect.
Anesthesia and age were unlikely to have affected
our results. Dexmedetomidine has been shown to
have no interaction with GABA-benzodiazepine re-
ceptors.22Of the 2 patients who did not receive anes-
thesia, BPNDvalues were still below the parent and
control range. Moreover, tracer delivery, measured
by R1, did not differ across the groups. We were
unable to study healthy child volunteers. However,
previous studies have shown that [11C]-FMZ bind-
ing is high in young children, decreasing with age,
but not reaching adult cortical values until age 20.23
The children studied (aged 2–17 years, mean 9.4 ?
SD 4.1 years) had partial epilepsy and used only
drugs that do not increase brain GABA. They were
compared to adults (29 ? 7 years) with partial epi-
lepsy matched with the children for the same anti-
convulsant medications, as well as normal adults
(40 ? 9 years) with no history of neurologic or psy-
chiatric disorders. There was no difference between
the adult normal and epilepsy groups. Thus, children
without metabolic disease would be expected to have
higher binding than adults.
can detect alterations in GABA receptor binding. Pro-
binding in children with epilepsy.10Since vigabatrin in-
creases synaptic GABA availability by inhibiting enzy-
matic degradation, this study supports the concept of
receptor downregulation of GABA receptors due to in-
creased GABA levels, potentially exacerbated by eleva-
tions of other metabolites (e.g., GHB). Alternatively,
reduced binding could be due to altered receptor prop-
erties rather than number. In a familial generalized epi-
lepsy syndrome, patients with the GABRG2 (R43Q)
Figure 3 Global mean ? SD cortical binding in
affected subjects, parents, and
Neurology 73 August 11, 2009
particularly in anterior cortical regions.24However,
significant alterations of GABAAR ?2 subunit levels
and functional GABAAR activity have been demon-
strated in murine SSADH-deficient hippocampal
Several lines of evidence suggest a relationship be-
tween altered GABA receptor binding and the phe-
notype in SSADH deficiency. Evidence from the
murine SSADH knockout suggests that GABA is sig-
nificantly increased during embryonic develop-
ment.25During early development, and most likely
in the early postnatal period, GABA is excitatory
rather than inhibitory.26,27The SSADH null animals
have markedly smaller brains, with cerebellum par-
ticularly affected.28The murine neurologic pheno-
type is characterized by ataxia and an epileptic
transition from absence seizures to ultimately fatal
convulsive status epilepticus by 3 weeks of age.29
GHB also may contribute to downregulation of
presynaptic and postsynaptic GABA receptor expres-
sion, perhaps leading to the seizures and hyperactive
behavior in SSADH deficiency. At the nonphysi-
ologic concentrations (?200–1000 ?M) in SSADH
deficiency, GHB acts as a weak GABABR agonist.30
This may lead to inhibition of GABABinterneurons,
disinhibition of glutamatergic neurons, and patho-
logic hyperexcitability. Other intermediates accumu-
lating in the mouse and human disorders may further
heighten GABAergic effects. The GABA-analogues
guanidinobutyrate, homocarnosine, succinic semial-
dehyde, and 4,5-dihydroxyhexanoic acid (DHHA)
accumulate both in patient physiologic fluids and
knockout mouse CNS.4,25,31–34These species may ex-
ert previously undefined GABA receptor binding ef-
fects, and it has been shown that DHHA binds the
high-affinity GHB receptor, albeit with low to mod-
A number of studies have shown reduced FMZ
binding in patients with partial seizures, closely cor-
related with EEG distribution of epileptiform dis-
charges.9,35In some cases, reduced FMZ binding has
been found in patients with normal MRI, as well as
after partial volume correction in patients with me-
sial temporal sclerosis.9,36The current study lays the
groundwork for future clinical interventions in
SSADH-deficient patients through identification of
an important therapeutic endpoint. Along those
lines, the nonphysiologic amino acid taurine has
shown benefit in a single SSADH-deficient case.37
Among its many reported roles, taurine may activate
GABA receptors.38Other orally bioactive GABA re-
ceptor antagonists, such as SGS-742, can now also be
considered in SSADH-deficient patients with moni-
toring of FMZ binding.39
Supported by the National Institutes of Health, National Institute of Neuro-
logical Diseases and Stroke, Division of Intramural Research; National Insti-
tutes of Health NS40270 (Dr. Gibson); Pediatric Neurotransmitter Disease
Association (Dr. Pearl); and Delman Family Fund for Pediatric Neurology
Research (Dr. Pearl). Dr. Pearl receives research support from the Pediatric
ited Metabolic Disease; receives royalties from Physician’s Guide to the
Laboratory Diagnosis of Metabolic Diseases [1996, Springer, Berlin] and Labo-
ratory Guide to the Methods in Biochemical Genetics [2008, Springer, Berlin];
and receives research support from the NIH [NS 40270] and the Pediatric
from the NIH [NIH Clinical Center Intramural Research]. I. Dustin reports
no disclosures. J. Taylor reports no disclosures. Dr. Trzcinski reports no dis-
closures. Dr. Schreiber reports no disclosures. K. Forester reports no disclo-
sures. P. Reeves-Tyer reports no disclosures. Dr. Liew reports no disclosures.
Dr. Shamim reports no disclosures. Dr. Herscovitch is employed full-time by
the NIH and supervises all PET imaging for clinical research at NIH, has
Society of Nuclear Medicine, and the Crozer-Chester Medical Center, and
Nuclear Medicine and the Journal of Cerebral Blood Flow and Metabolism; has
received honoraria for lectures from Columbia University, the Connecticut
PET Society, and the Japanese Society of Nuclear Medicine; and receives
research support from Siemens Medical Systems, Pfizer Inc., GlaxoSmithK-
line Inc., Lilly Inc., NINDS [5R01NS058360], and Yale University. Dr.
Butman is employed by the NIH and holds stock in Medtronic. Dr. Jakobs
reports no disclosures. Dr. Theodore serves as Co-Editor-in-Chief of Epilepsy
Research; serves on the editorial boards of Neurotherapeutics and Lancet Neu-
rology; receives honoraria from Elsevier for editing epilepsy research; con-
ducts research based in large part on PET scanning; owns stock in
General Electric; and receives research support from NINDS [PI-
Intramural Research Program].
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