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Idiopathische generalisierte Epilepsien

Genetik und Pathophysiologie

Idiopathic generalized epilepsies

Genetics and pathophysiology

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Zusammenfassung

Idiopathische Epilepsien haben eine überwiegend genetische Ätiologie. Selten findet sich eine monogene Vererbung, bei der eine einzelne Genmutation für die Manifestation des Phänotyps verantwortlich ist. Meist liegt eine komplexe genetische Disposition vor, bei der das Zusammenspiel mehrerer genetischer Faktoren die Epilepsie verursacht. Die idiopathischen generalisierten Epilepsien (IGE) sind mit einer Heritabilität von 80% überwiegend komplex-genetisch bedingt. Klinisch sind die IGE-Subtypen durch primär generalisierte Anfallsformen, einen altersabhängigen Beginn, typische Veränderungen im EEG und eine meist normale psychomotorische Entwicklung gekennzeichnet. Die häufigsten Unterformen der IGE sind die kindlichen und juvenilen Absence-Epilepsien (CAE, JAE), die juvenile myoklonische Epilepsie (JME) und die Aufwach-Grand-Mal-Epilepsie (EGMA). Eng verwandt sind die früh beginnende Absence-Epilepsie (EOAE) und die generalisierte/genetische Epilepsie mit Fieberkrämpfen plus (GEFS+). In den letzten Jahren wurde eine zunehmende Zahl an Genen idenitifziert, die für Untereinheiten von spannungs- und ligandengesteuerten Ionenkanälen codieren und mit monogenen idiopathischen Epilepsien assoziiert sind, wie Mutationen in Natriumkanal- und GABA(A)-Rezeptor-Untereinheiten bei GEFS+. Selten wurden solche Mutationen auch bei den häufigsten IGE-Subtypen gefunden, v. a. in GABA(A)-Rezeptor-Untereinheiten, die zu einem partiellen Verlust der neuronalen Hemmung führen. Bei Absencen, insbesondere bei der EOAE wurden Mutationen des Glucosetransporters Typ 1 (GLUT1) identifiziert, die einen reduzierten Glucosetransport über die Blut-Hirn-Schranke bedingen. Kürzlich wurden auch bestimmte chromosomale Mikrodeletionen als prädisponierend bei bis zu 2,5% der häufigen IGE-Subtypen nachgewiesen. Aufgrund der Komplexität der Genetik bei IGE steht die Aufklärung der zugrunde liegenden Erbgutveränderungen noch in den Anfängen. Durch die neuen verfügbaren Sequenziertechniken besteht nun die Möglichkeit, exom- und genomweit die genetischen Veränderungen aufzudecken. Die Autoren hoffen, dass dies einen entscheidenden Beitrag zur Aufklärung der Pathophysiologie dieser wichtigen und häufigen Gruppe von Epilepsien leisten wird.

Abstract

Idiopathic epilepsies are genetically determined. The inheritance can be either monogenic, considering a single gene mutation as sufficient to cause the phenotype, or mainly complex, when the epileptic phenotype is determined by several genetic factors. The most important and most common subtypes of idiopathic generalized epilepsies (IGE) are childhood and juvenile absence epilepsies (CAE, JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal (generalized tonic-clonic) seizures on awakening (EGMA); closely related are early onset absence epilepsy (EOAE) and generalized/genetic epilepsy with febrile seizures plus (GEFS+). The IGE subtypes are characterized by primary generalized seizure types, an age-dependent onset, typical pathological EEG patterns, a benign course and normal psychomotor development. In recent years, an increasing number of mutations mainly associated with rare monogenic idiopathic epilepsy syndromes have been identified in genes encoding subunits of voltage- or ligand-gated ion channels, such as mutations in Na+ channel and GABA(A) receptor subunits in GEFS+. A few mutations have also been detected in the common forms of IGE, mainly in GABA(A) receptor subunits conferring a neuronal dysinhibition. For absence seizures, particularly EOAE, mutations in the glucose transporter type 1 (GLUT1) have been described, leading to a reduced transport rate of glucose across the blood-brain barrier. Recently, chromosomal microdeletions were found in up to 2.5% of IGE patients as a significant risk factor. Due to the complex genetic trait, the genetic enigma of IGE is just starting to be unraveled. The next generation sequencing techniques available now enable exome- and genome-wide sequence analyses, which the authors hope will contribute to understanding the pathophysiology of these common forms of epilepsy.

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Authors and Affiliations

  1. Abt. Neurologie mit Schwerpunkt Epileptologie, Zentrum für Neurologie, Hertie Institut für Klinische Hirnforschung,Universität Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Deutschland

    Y.G. Weber &  H. Lerche

  2. Cologne Center for Genomics, Universität zu Köln, Köln, Deutschland

    T. Sander

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  3. H. Lerche
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Correspondence to H. Lerche.

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Weber, Y., Sander, T. & Lerche, H. Idiopathische generalisierte Epilepsien. Z. Epileptol. 24, 100–107 (2011). https://doi.org/10.1007/s10309-011-0168-8

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