Abstracts

Rationale: SSADH deficiency is a metabolic epilepsy that produces chronic elevation of GABA and GHB. No disease-specific treatment is available. Taurine, a partial GABA agonist, has been proposed as an intervention to reverse the decreased GABA(A) receptor activity in SSADH deficiency demonstrated using flumazenil PET (Pearl et al., 2009). Transcranial magnetic stimulation (TMS) provides information regarding cortical excitability in the motor cortex and recently revealed changes in patients with SSADH deficiency felt to be related to GABA(B) dysfunction (Reis et al., 2012).Methods: Selected individuals participating in an open-label crossover trial of taurine in patients with SSADH deficiency consented to physiologic studies at the NIH on and off taurine including CSF free and total GABA levels, TMS, and flumazenil-PET. Subjects were titrated weekly from 50 to a target 200mg/kg/day (maximum 10 grams/day). 'Off' testing was conducted after at least 3 months without taurine (one subject was already taking taurine at study enrollment), while 'on' testing was completed after at least 3 months of taurine therapy at the target dose. Six subjects completed TMS. Parameters evaluated include recruitment curve (RC) and motor evoked potential (MEP) amplitudes for various paired-pulse stimuli: short intra-cortical inhibition (SICI), intra-cortical facilitation (ICF), and long intra-cortical inhibition (LICI), expressed as a percentage of baseline MEP (determined at 120% motor threshold). Statistical analyses were performed using 2-tailed paired-sample t-tests.Results: During the 'off' taurine phase, mean and standard deviations for the various TMS measures were as follows: RC 0.028 0.015, SICI 0.69 0.26, ICF 1.29 0.27, LICI 0.96 1.1. During the 'on' taurine phase, mean and standard deviations were: RC 0.022 0.006, SICI 1.59 0.93, ICF 1.41 0.72, LICI 0.93 0.98. There were no significant differences for RC (p=0.40), ICF (p=0.68), or LICI (p=0.84). SICI showed a trend towards significance (p=0.08), with average values increased above baseline MEP on taurine.Conclusions: TMS results during the 'off' taurine phase approximate those found previously, confirming a fairly low recruitment curve slope and almost complete lack of LICI, felt to be GABA(B)-mediated. Chronic taurine administration was associated with a trend towards reversal of short intra-cortical inhibition (all but one patient exhibited a substantial increase in SICI), suggesting that taurine may inhibit GABA(A) neurotransmission in SSADH deficiency and/or reduce the interval at which ICF occurs. This study supports the use of TMS as a biomarker in therapeutic trials for individuals with epilepsy and provides baseline measures for the upcoming trial with SGS-742, a GABA(B) antagonist, in SSADH deficiency.