The Bioenergetic Hypothesis of Idiopathic Generalized Epilepsy: A Testable Framework for Mitochondrial Insufficiency as a Primary Determinant of Seizure Threshold

This working paper proposes that, in a clinically significant subgroup of patients with idiopathic generalized epilepsy (IGE), a chronic subclinical deficit in mitochondrial oxidative phosphorylation reduces the energy margin available for membrane potential maintenance, thereby lowering the seizure threshold and predisposing to bilateral synchronous epileptiform discharges. The seizure threshold is formalized as a bioenergetic variable (ΔE = ATP produced − ATP required) rather than a purely electrical one. When ΔE approaches zero, the Na⁺/K⁺-ATPase—which consumes approximately 50% of total brain ATP—operates on the steep portion of its Michaelis–Menten curve, and small fluctuations in ATP availability produce large variations in membrane stability. Seven converging lines of indirect evidence are presented: (1) the high prevalence of epilepsy in primary mitochondrial diseases; (2) the efficacy of the ketogenic diet through metabolic mechanisms; (3) the preferential involvement of brain regions with the highest metabolic demand; (4) the therapeutic paradox of valproic acid as both the most effective and most mitotoxic antiepileptic drug; (5) spontaneous remission patterns consistent with metabolic compensation; (6) subclinical metabolic abnormalities detected by MR spectroscopy in IGE patients; and (7) the precedent of Parkinson's disease, where neurology already accepts mitochondrial dysfunction as a primary etiology. Five falsifiable predictions and three experimental protocols are proposed, including phosphorus-31 magnetic resonance spectroscopy (³¹P-MRS) in IGE cohorts as the critical test. The hypothesis does not require novel technology, invokes no mechanisms beyond established biophysics, and generates clinically actionable predictions regardless of whether it proves correct.