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

Neurology. 2009 Aug 11;73(6):423-9. doi: 10.1212/WNL.0b013e3181b163a5.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Brain / enzymology
  • Brain / metabolism*
  • Brain / pathology
  • Carbon Radioisotopes / metabolism
  • Child
  • Female
  • Flumazenil / metabolism*
  • GABA-A Receptor Antagonists*
  • Humans
  • Male
  • Middle Aged
  • Positron-Emission Tomography* / methods
  • Protein Binding / physiology
  • Receptors, GABA-A / metabolism*
  • Succinate-Semialdehyde Dehydrogenase / deficiency*
  • Succinate-Semialdehyde Dehydrogenase / metabolism
  • Young Adult
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Carbon Radioisotopes
  • GABA-A Receptor Antagonists
  • Receptors, GABA-A
  • Flumazenil
  • gamma-Aminobutyric Acid
  • Succinate-Semialdehyde Dehydrogenase