Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

  • P. L. Pearl
  • K. M. Gibson
  • M. A. Cortez
  • Y. Wu
  • O. Carter SneadIII
  • I. Knerr
  • K. Forester
  • J. M. Pettiford
  • C. Jakobs
  • W. H. Theodore
Symposium on Neurotransmitter Disorders

DOI: 10.1007/s10545-009-1034-y

Cite this article as:
Pearl, P.L., Gibson, K.M., Cortez, M.A. et al. J Inherit Metab Dis (2009) 32: 343. doi:10.1007/s10545-009-1034-y

Summary

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials.

Abbreviations

ECoG

electrocorticography

FMZ

flumazenil

GABA

γ-amino-butyric acid

GHB

γ-hydroxybutyrate

PET

positron emission tomography

SSADH

succinic semialdehyde dehydrogenase

TMS

transcranial magnetic stimulation

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • P. L. Pearl
    • 1
    • 5
    • 7
  • K. M. Gibson
    • 2
  • M. A. Cortez
    • 3
  • Y. Wu
    • 3
  • O. Carter SneadIII
    • 3
  • I. Knerr
    • 4
  • K. Forester
    • 1
  • J. M. Pettiford
    • 1
  • C. Jakobs
    • 5
  • W. H. Theodore
    • 6
  1. 1.Department of Neurology, Children’s National Medical CenterGeorge Washington University School of MedicineWashingtonUSA
  2. 2.Biochemical Genetics Laboratory, Children’s Hospital of Pittsburgh, Departments of Pediatrics, Pathology and Human Genetics, Division of Medical GeneticsUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Division of Pediatric Neurology, Brain and Behavior InstituteHospital for Sick Children and the University of TorontoTorontoCanada
  4. 4.Children’s and Adolescents’ HospitalUniversity of Erlangen-NurembergErlangenGermany
  5. 5.Metabolic Unit, Department of Clinical ChemistryVU University Medical CenterAmsterdamThe Netherlands
  6. 6.Clinical Epilepsy Section, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA
  7. 7.Department of NeurologyChildren’s National Medical CenterWashingtonUSA

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