Genetik der epileptischen Enzephalopathien

Zusammenfassung

Epileptische Enzephalopathien sind durch einen Anfallsbeginn in den ersten Lebensjahren, einen therapierefraktären Verlauf sowie das Auftreten von psychomotorischen Entwicklungsstörungen gekennzeichnet. Zum Teil handelt es sich um wohl definierte elektroklinische Syndrome wie bspw. das West-Syndrom, das Dravet-Syndrom oder das Lennox-Gastaut-Syndrom, welche durch charakteristische EEG-Merkmale, Anfallstypen und Erkrankungsbeginn gekennzeichnet sind. Im klinischen Alltag ist jedoch eine eindeutige Zuordnung zu diesen spezifischen Syndromen in vielen Fällen nicht möglich. Diese „nicht-klassischen“ epileptischen Enzephalopathien zeigen häufig Überschneidungen zu den klassischen Syndromen jedoch auch distinkte Charakteristika. Neben strukturellen und metabolischen Ursachen konnten in den letzten Jahren zahlreiche neue Genveränderungen in Zusammenhang mit epileptischen Enzephalopathien nachgewiesen werden. Hierbei wird zunehmend die genetische Heterogenität dieser Erkrankungsgruppe deutlich. So verursachen verschiedene Gene gleichartige Krankheitsbilder und im Gegenzug können Veränderungen im gleichen Gen sehr unterschiedliche Phänotypen bedingen. Um dieser Tatsache auch im klinischen Alltag gerecht zu werden, bieten das next-generation sequencing und hierbei insbesondere die Gen-Panel-Diagnostik eine effektive und schnelle diagnostische Methode. Die Bedeutung der Sicherung der genetischen Diagnose liegt nicht nur in der Ersparnis weiterer, möglicherweise belastender Diagnostik, sie dient auch der genetischen und prognostischen Beratung und eröffnet zudem zunehmend spezifische Therapieoptionen. In dieser Übersichtsarbeit werden neue genetische Erkenntnisse der letzten Jahre auf dem Gebiet der epileptischen Enzephalopathien dargestellt – sowohl in Hinblick auf die klassischen Syndrome als auch die „nicht-klassischen“ Enzephalopathie-Formen.

Abstract

Epileptic encephalopathies are conditions characterized by seizure onset in the first years of life, pharmacoresistance and cognitive and behavioural deficits. They comprise well-defined electroclinical syndromes such as West syndrome, Dravet syndrome and Lennox-Gastaut syndrome that are defined by specific electroencephalographic findings, seizure types and age of onset. However, in clinical routine, assignment of cases to one of these defined syndromes is often not possible. These cases of ‘non-classical’ epileptic encephalopathy frequently show a certain overlap with the classical syndromes but display distinct features as well. Beside structural and metabolic causes, genetic changes constitute the main etiology of this disease group. In the last years, the genetic heterogeneity of these syndromes has become more and more evident. Thus, different genes may cause similar conditions and, vice versa, variants of the same gene may lead to widely differing phenotypes. Gene panel analyses, a next generation sequencing technique, provide a fast and efficient method to deal with this complex situation in clinical routine. Establishing a genetic diagnosis can prevent additional, possibly harmful or distressing diagnostic tests, allows genetic and prognostic counseling, and increasingly offers opportunities for targeted treatment. This review provides an overview of recent genetic discoveries in the field of genetic encephalopathies – with focus on classical as well as ‘non-classical’ forms.

Schlüsselwörter

West-Syndrom - Dravet-Syndrom - Lennox-Gastaut-Syndrom - Ohtahara-Syndrom - Early-infantile epileptic encephalopathy

Keywords

West syndrome - Dravet syndrome - Lennox Gastaut-syndrome - Ohtahara syndrome - early-infantile epileptic encephalopathy

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