Genetik und Neurochemische Biomarker bei Amyotropher Lateralsklerose und Frontotemporaler Lobärdegeneration

Zusammenfassung

Die Amyotrophe Lateralsklerose (ALS) und die Gruppe der Frontotemporalen Lobärdegenera­tionen (FTLD) sind progredient neurodegenera­tive Erkrankungen, die bei der ALS zu einer schweren kontinuierlich fortscheitenden Lähmung der Muskulatur und schließlich respiratorischer Insuffizienz und bei der FTLD zu einer zunehmenden Störung des Verhaltens, der Sprache und in manchen Fällen der Motorik führt. In den letzten Jahren rückte die klinische Überlappung der beiden Krankheitsbilder wieder in den Vordergrund, nachdem man aggregiertes TDP-43 im Zytoplasma von Nervenzellen als gemeinsame histopathologische Veränderung gefunden hat. Es wurde die Hypothese formuliert, dass es sich bei beiden Krankheitsbildern um die Pole eines sowohl klinischen als auch pathophysiologischen Kontinuums handelt. Zunächst konnten als möglicher molekularer Mechanismus Mutationen im TDP-43-Gen nachgewiesen werden. Weiterhin wurde eine pathologische Repeat-Expansion auf Chromosom 9 – C9orf72 – beschrieben, die in Europa mit etwa 25 bis 30% aller genetisch bedingten ALS-Erkrankungen und etwa 11% aller genetisch bedingten FTLD-Erkrankungen assoziiert ist. Interessant ist, dass auch bis zu 20% der zunächst sporadisch Erkrankten eine C9orf72 Expansion aufweisen. Bei asymptomatischen Genträgern und bei sporadischen Formen der Erkrankung bereitet vor allem im Frühstadium der Erkrankungen das rechtzeitige Erkennen und richtige Einordnen der Symptome von ALS und FTLD Schwierigkeiten. Zur besseren differen­zialdiagnostischen und prognostischen Einschätzung sind daher zuverlässige Biomarker nötig.

Abstract

Both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are progressive neurodegenerative diseases. In ALS, neurodegeneration results in progressive paralysis of muscles and finally in respiratory insufficiency. FTLD, on the other hand, progressively affects behavior, speech, and in some cases the motor system. Over recent years, some clinical overlapping of these syndromes with their common histopathology of aggregated TDP-43 in the cytoplasm of neurons resulted in the hypothesis that both syndromes are parts of a clinical as well as pathophysiological continuum. As a first step, mutations of the TDP-43 gene have been identified as possible molecular mechanism. Furthermore, a pathological repeat expansion of chromosome 9 – C9orf72 – is associated with 25–30 percent of all genetically determined cases of ALS and about 11 percent of the FTLD cases in Europe. However, 20% of the sporadic cases also have a C9orf72 expansion. Particularly in asymptomatic mutation carriers and in sporadic cases, the diagnosis at an early stage of the disease and reliable classification of the symptoms of ALS and FTLD is usually difficult. Therefore, it would be desirable to develop reliable and specific biomarkers that allow valid diagnosis and evaluation of prognosis.

Schlüsselwörter

Amyotrophe Lateralsklerose - Frontotemporale Lobär­degeneration - Biomarker - Genetik - C9orf72

Keywords

amyotrophic lateralsclerosis - frontotemporal lobar ­degeneration - biomarker - genetics - C9orf72

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