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

Department of Neurology, Children's National Medical Center, Washington, DC 20010-2970, USA.
Neurology (Impact Factor: 8.3). 09/2009; 73(6):423-9. DOI: 10.1212/WNL.0b013e3181b163a5
Source: PubMed

ABSTRACT 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.
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.
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.
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.


Available from: Peter Herscovitch, Apr 17, 2015
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(3):260-9. · 3.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive metabolic disorder affecting γ-aminobutyric acid degradation. We described a boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency and novel mutations of ALDH5A1 gene. He was referred because of developmental delay, focal seizures, and choreoathetosis at 6 months of age. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by increased level of γ-hydroxybutyric acid in urine and novel compound heterozygous mutations in the ALDH5A1 gene. His seizures were successfully controlled. However, the patient showed a slowly progressive clinical course with severe neurologic deficits. A magnetic resonance imaging (MRI) revealed abnormal high intensities in the putamen and globus pallidi on T2-weighted images when he was 6 months old, and more diffuse abnormal signal intensities over bilateral hemispheres were noted when he was 3 years old.
    Journal of Child Neurology 09/2014; 30(4). DOI:10.1177/0883073814544365 · 1.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal reces-sively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deficiency. The clinical presentation of succinic semialdehyde dehydrogenase deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deficiency is associated with a severe neonatal-infantile epileptic encephalopathy.