Ein Geschwisterpaar mit frontotemporaler Lobärdegeneration und amyotropher Lateralsklerose und einer neuen Mutation im TBK1-Gen (Thr462Lysfs)

Zusammenfassung

Wir berichten über ein Geschwisterpaar mit den Krankheitsbildern einer frontotemporalen Lobärdegeneration (FTLD) und einer amyotrophen Lateralsklerose und einer neuen Mutation im TANK-bindende-Kinase-1(TBK1)-Gen (c.1385_1388CAGA, Thr462Lysfs), die durch ein Screening des „European Early-Onset Dementia Consortium“ identifiziert wurde. Die Patienten stellten sich mit 77 bzw. 75 Jahren mit einem demenziellen Syndrom sowie begleitenden bulbären Symptomen und progredienten Paresen vor. Beide verstarben bei progredienter Symptomatik wenige Monate nach Diagnosestellung. Kürzlich wurde eine Assoziation von Mutationen im TBK1-Gen mit dem Auftreten familiärer Formen von FTLD und ALS beschrieben. Ursächlich ist ein Funktionsverlust eines Allels, der zu einer verminderten Produktion des TBK1-Proteins führt. Für künftige Therapiestudien ist die Charakterisierung von TBK1-Mutationsträgern in präsymptomatischen Kohorten, wie z. B. in der „genetic frontotemporal dementia initiative“ (GENFI), von großer Bedeutung.

Abstract

We report on a pair of siblings with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and a novel Thr462Lysfs mutation in the TANK-binding kinase 1 (TBK1) gene identified through the European Early-Onset Dementia Consortium. The patients presented at the age of 77 and 75 years and displayed dementia and bulbar symptoms as well as progressive paresis. After a progressive course, both of them died only a few months after diagnosis. Most recently, TBK1 mutations were identified in patients with FTD and ALS. A loss of expression of the mutant allele, leading to 50 % reduced TBK1 protein levels, seems to be causative. The occurrence of TBK1 mutations in FTD and ALS underlines the fact that FTD and ALS are part of the same disease spectrum. For future therapeutic trials, characterization of TBK1 mutation carriers in presymptomatic cohorts, such as the genetic frontotemporal dementia initiative (GENFI), is of great importance.

Schlüsselwörter

TBK1-Mutation - C9orf72 - GRN - FTLD - ALS - genetische Testung

Key words

TBK1-mutation - C9orf72 - GRN - FTD - ALS - genetic testing

^* geteilte Letztautoren

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