PT  - JOURNAL ARTICLE
AU  - Janine Reis
AU  - Leonardo G. Cohen
AU  - Phillip L. Pearl
AU  - Brita Fritsch
AU  - Nikolai H. Jung
AU  - Irene Dustin
AU  - William H. Theodore
TI  - GABA<sub>B</sub>-ergic motor cortex dysfunction in SSADH deficiency
AID  - 10.1212/WNL.0b013e31825dcf71
DP  - 2012 Jul 03
TA  - Neurology
PG  - 47--54
VI  - 79
IP  - 1
4099  - http://n.neurology.org/content/79/1/47.short
4100  - http://n.neurology.org/content/79/1/47.full
SO  - Neurology2012 Jul 03; 79
AB  - 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 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