Genetik und Pathophysiologie idiopathischer Epilepsien

Zusammenfassung

Die idiopathischen Epilepsien sind genetisch determinierte Erkrankungen des Zentralnervensystems, die durch spezielle EEG-Veränderungen und Anfallstypen charakterisiert sind und nicht mit strukturellen Hirnläsionen einhergehen. Als Ursache wurden in den vergangenen Jahren zunehmend Mutationen in Genen identifiziert, die für verschiedene spannungs- und ligandengesteuerte Ionenkanäle kodieren. Da Ionenkanäle die Grundlage der Erregbarkeit im Zentralnervensystem bilden, erscheint dies als ein logisches pathophysiologisches Konzept. Die ersten Epilepsiegene wurden bei den sehr seltenen autosomal-dominant vererbten Syndromen in großen Familien identifiziert. Mittlerweile wurden aber auch Mutationen bei den häufigen klassischen idiopathischen generalisierten Epilepsien (IGE) gefunden, wie der kindlichen Absence-Epilepsie (Pyknolepsie), der juvenilen myoklonischen Epilepsie (Impulsiv-Petit-Mal) und dem Aufwach-Grand-Mal. Die Mutationen betreffen essenziell wichtige Ionenkanäle wie den spannungsgesteuerten Natriumkanal oder den GABA_A-Rezeptor, die auch Angriffspunkte für die medikamentöse Behandlung von Epilepsien sind. Als zentraler Pathomechanismus dieser genetischen Veränderungen kristallisiert sich zunehmend ein direkter oder indirekter Defekt der GABAergen Hemmung heraus, woraus sich molekulare Parallelen zur Pathogenese fokaler, läsioneller Epilepsien ergeben. Zudem werden über solche genetischen Untersuchungen neue Gene entdeckt, mit deren Hilfe neue Zielstrukturen für die Pharmakotherapie entwickelt werden können. Insgesamt tragen diese Untersuchungen wesentlich zum Verständnis der Epileptogenese bei und sollen langfristig helfen, die Therapie zu verbessern.

Summary

Idiopathic epilepsies are genetically determined diseases of the central nervous system characterized by typical epileptic seizures and EEG abnormalities but not associated with structural brain lesions. In recent years, an increasing number of epilepsy-causing mutations were identified in genes encoding different voltage- and ligand-gated ion channels. This arises as a plausible pathophysiological concept, as ion channels are the basis for the excitability of neurons. The first epilepsy genes were identified for rare autosomal dominant syndromes within large pedigrees. Recently, mutations were also found for the frequent classical forms of idiopathic generalized epilepsies (IGE), such as childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and epilepsy with grand-mal seizures on awakening (EGMA). The mutations affect ion channels crucial for neuronal function, for example the voltage-gated sodium channel or the GABA_A receptor, which are also major targets for pharmacotherapy. An increasing number of functional studies points to a central role of GABAergic synaptic inhibition in the pathophysiology of IGE suggesting molecular parallels to the pathogenesis of focal, lesional epilepsies. Furthermore, such investigations could serve to discover new genes suitable as novel targets for pharmacotherapy. Altogether, these investigations will enhance our knowledge about the understanding of epileptogenesis and should help to improve anticonvulsive therapy.

Schlüsselwörter

Genetik - Epilepsie - Ionenkanal

Keywords

Genetics - epilepsy - ion channel

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