Genetische Ursachen bei Dystonien

Zusammenfassung

Dystonien sind eine klinisch und genetisch heterogene Gruppe von Bewegungsstörungen, bei denen es durch unwillkürliche, anhaltende oder intermittierende Muskelkontraktionen zu abnormen Bewegungen oder Haltungen kommt. Die Ursache einer Dystonie oder dystonen Bewegungsstörung bleibt zurzeit bei den meisten Patienten ungeklärt, doch scheinen genetische Faktoren eine große Rolle zu spielen. Zwar werden mehr und mehr Dystoniegene identifiziert (aktuell sind es bis zu 200 verschiedene), so sind diese doch nur für einige wenige und zum großen Teil sehr seltene Unterformen von Dystonien von Bedeutung. Dazu gehören v. a. die Dystonien, die früh, d. h. in der Kindheit oder Jugend beginnen und häufig auch mehrere Körperregionen betreffen. In der Vergangenheit wurden wiederholt mögliche gemeinsame Pathomechanismen der einzelnen genetischen Dystonien untersucht. Bis auf wenige Ausnahmen scheinen die kodierten Proteine aber dabei keinem gemeinsamen Wirkkreislauf anzugehören, sondern beeinflussen ganz unterschiedliche zelluläre Prozesse. Für die Mehrzahl der Dystonien mit bisher unbekannter Ursache wird eine Kombination aus verschiedenen genetischen und äußeren Einflüssen angenommen. Hier stellen wir die bekannten Dystoniegene vor, die v. a. bei isolierten (Dystonie als einzige Krankheitsmanifestation mit Ausnahme eines Tremors) oder kombinierten (Dystonie plus eine andere Bewegungsstörung wie Parkinson, Myoklonus oder Chorea) Dystonien relevant sind. Beispielhaft werden auch einige der Gene, die komplexe Dystonien verursachen, vorgestellt, bei denen, neben einer Dystonie, häufig auch eine Entwicklungsstörung oder Erkrankung anderer Organsysteme vorliegen. Abhängig von der klinischen Ausprägung der dystonen Symptome und weitestgehend unabhängig von genetischen Befunden kann die Dystonie auf eine orale Pharmakotherapie, intramuskuläre Botulinumtoxininjektionen oder eine tiefe Hirnstimulation ansprechen.

Abstract

Dystonia is a clinically and genetically heterogeneous movement disorder that is characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures. Although the cause of the disease remains unknown in most patients, genetic causes seem to play an important role. To date, mutations in more than 200 genes have been linked to dystonic phenotypes that often present rare and specific subforms of dystonia including early onset, generalized dystonia. Known dystonia genes encode proteins that affect mostly diverse cellular functions and a common molecular pathways of all monogenic dystonias has not (yet) been elucidated. The majority of dystonias seems to be caused by a combination of genetic and environmental factors. In this review, we will introduce several well-established dystonia genes for isolated dystonias (dystonia as the only movement disorder except for dystonic tremor) and combined dystonias (dystonia in combination with parkinsonsim, myoclonus, or chorea). Moreover, we will present selected genes that cause complex dystonias, in which dystonia is accompanied by non-neurological disorder and/or developmental delay. Therapeutic strategies include oral medication, botulinum toxin, and deep brain stimulation and depend on the patientsʼ needs. Notably, treatment outcome in dystonia is only slightly influenced by the genetic status.

Schlüsselwörter

Dystonie - Genetik - Diagnostik

Keywords

dystonia - genetic - diagnostic tools

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