Das Parkinson-Syndrom und seine genetischen Ursachen - eine Standortbestimmung

Zusammenfassung

Intensive Forschung innerhalb des letzten Jahrzehnts hat die Rolle genetischer Veränderungen bei der Entstehung des Parkinsonsyndroms (PS) demonstriert. Bisher wurden Mutationen in sechs verschiedenen Genen identifiziert, die eindeutig die Erkrankung verursachen können und entweder autosomal-dominant oder autosomal-rezessiv innerhalb von betroffenen Familien vererbt werden. Zu den autosomal-rezessiven Formen gehören Mutationen in den Genen Parkin, PINK1, DJ-1 und ATP13A2, wobei Mutationen im Parkin-Gen am häufigsten zu finden sind. Diese Formen sind in der Regel durch einen frühen Erkrankungsbeginn (vor dem 40. Lebensjahr) gekennzeichnet. Mit einem autosomal-dominanten Vererbungsmuster wurden Mutationen im α-Synuklein- und im LRRK2-Gen assoziiert. Weitere ursächliche Gene wurden lokalisiert und die genetischen Formen werden entsprechend der Reihenfolge ihrer Entdeckung klassifiziert, zurzeit PARK1 bis PARK13. Zusätzlich gibt es Hinweise auf weitere mutierte Gene, denen bisher kein „PARK”-Akronym zugeordnet wurde. Die Identifizierung von genetischen PS-Formen hat zu einem besseren Verständnis der Pathophysiologie der Erkrankung beigetragen und häufige Varianten (Polymorphismen) in einigen dieser Gene scheinen auch eine Rolle bei der idiopathischen Erkrankung zu spielen. Sowohl klinisch als auch pathologisch können die genetischen Formen oft nicht vom typischen idiopathischen PS unterschieden werden, und Vorhersagen über den individuellen Krankheitsverlauf sind nicht möglich. Derzeit wird nur bei etwa 20 % der Patienten mit einem frühen Erkrankungsbeginn und weniger als 3 % der spät erkrankenden Personen eine monogene Ursache identifiziert, sodass unter Berücksichtigung des hohen technischen und finanziellen Aufwandes eine Untersuchung nur in ausgewählten Fällen erfolgen sollte. Eine vorherige und begleitende genetische Beratung ist dabei unerlässlich.

Abstract

Intense research efforts over the past decade have demonstrated the role of genetics in the aetiology of parkinsonism. To date, mutations in six different genes have been identified that can clearly cause the condition and that are inherited in an autosomal dominant or recessive fashion within affected families. Among the recessive forms are mutations in the Parkin, PINK1, DJ-1, and ATP13A2 genes with mutations in the Parkin gene being the most frequent. These forms are usually characterised by an early age of onset (before the age of 40 years). Mutations in the α-Synuclein and in the LRRK2 gene are associated with an autosomal dominant pattern of inheritance. Additional causative genes have been localised and the genetic forms have been classified in chronological order of their first description (PARK1 - 13). There is further evidence for additional mutated genes that have not yet been assigned a „PARK” acronym. The identification of genetic forms of parkinsonism has led to a better understanding of the pathophysiology of the disorder, and frequent variants (polymorphisms) in some of these genes appear to play a role also in the idiopathic form of the disease. Both clinically and pathologically, the genetic forms cannot be distinguished from typical idiopathic Parkinson's disease, and the individual disease course cannot be predicted. At present, a monogenic cause can be identified in about 20 % of the patients with an early age of onset and in less than 3 % of patients with a late onset of the disorder. Taking into account the considerable amount of time and effort and the high costs involved, genetic testing is recommended only in selected cases and should be accompanied by careful counselling.

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1 Diese beiden Autoren haben in gleicher Weise zur Entstehung des Manuskriptes beigetragen.