SHORT REPORT GABAA receptor active steroids are altered in epilepsy patients with tuberous sclerosis

Background: The neuroactive steroid 3α,5αtetrahydroprogesterone is the most potent endogenous positive modulator of γ-amino-butyric acid (GABA)A receptors. There is evidence for a relation between neuroactive steroids and seizure susceptibility. Objective: To evaluate the putative role of counteregulator neuroactive steroids in the occurrence of seizures in patients with tuberous sclerosis. Methods: Plasma concentrations of the enantiomers 3α,5αand 3α,5β-tetrahydroprogesterone (3αs-THP), which are positive modulators of GABAA receptors, were measured in 18 patients, along with their endogenous functional antagonists 3β,5αand 3β,5β-THP (3βs-THP), to assess their possible modification compared with control subjects. Neuroactive steroids were assayed using a highly sensitive and specific gas chromatographic/mass spectrometric method. Results: In the tuberous sclerosis patients with poorly controlled seizures, there was a significantly lower 3αs/3βsTHP ratio than in seizure-free patients or control subjects. Conclusions: The reduced 3αs/3βs-THP ratio may decrease GABAergic tone, contributing to the appearance of seizures in tuberous sclerosis patients with epilepsy.