GABAB-ergic motor cortex dysfunction in SSADH deficiency
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Abstract
Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.
Methods: We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).
Results: Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.
Conclusions: Since long interval intracortical inhibition and cortical silent period are thought to reflect GABAB receptor–mediated inhibitory circuits, our results point to a particularly GABAB-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABAB receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABAB-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders. Neurology® 2012;79:47–54
GLOSSARY
- ANOVA=
- analysis of variance;
- CSP=
- cortical stimulation–induced silent period;
- FDI=
- first dorsal interosseus;
- GHB=
- γ-hydroxybutyric acid;
- ICF=
- intracortical facilitation;
- ISI=
- interstimulus interval;
- LICI=
- late intracortical inhibition;
- M1=
- primary motor cortex;
- MEP=
- motor evoked potential;
- MVC=
- maximal voluntary contraction;
- REC=
- recruitment curve;
- RMT=
- resting motor threshold;
- SICI=
- short intracortical inhibition;
- SSADH=
- succinic semialdehyde dehydrogenase;
- TMS=
- transcranial magnetic stimulation
Footnotes
Supplemental data at www.neurology.org
- Received December 21, 2011.
- Accepted February 23, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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