Genetic research in frontotemporal dementia
World-wide systematic characterization of TMEM106B and ATXN2 genetic status towards implementation of genetic testing of modifiers in clincal practice.
AbstractFrontotemporal lobar degeneration (FTLD) is a quickly progressing debilitating neurodegenerative disease and one of the leading causes of young-onset dementia. There are no treatments available that delay the onset or slow down disease progression. The most common form causes changes in behavior and personality, hence FTLD imposes a dramatic impact on social life. In about 30% of patients, a strong family history is present. Autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72) gene, the microtubule-associated protein tau (MAPT) gene and the progranulin (GRN) gene are the most common causes of genetic frontotemporal dementia (FTD). FTD is characterized by variability in age at onset and clinical presentation, even within families. This variability remains poorly understood. Previous studies suggest the transmembrane protein 106 B (TMEM106B) and ataxin 2 (ATXN2) loci as genetic modifiers of disease risk, especially in patients who already carry dominant disease mutations. The discovery of these loci is exciting; however, studies have been limited in sample size and detailed characterization of the patient cohorts. As collaborator in the two largest international FTD research efforts (GENFI and ALLFTD) and under the supervision of prof. Rosa Rademakers, a world-renowed expert on FTD genetics, I am uniquely positioned to tackle the role of these genetic modifiers. As such, in this project I will perform systematic genotype screens in well-characterized world-wide FTD cohorts to validate the modifying roles of TMEM106B and ATXN2. In a next step, carrier status will be correlated with longitudinally collected clinical, neurophysiological and imaging data, to investigate modifying effects on disease progression measures. Ultimately, I will provide the necessary data to allow implementation of genetic testing for modifiers in clinical practice. This will aid genetic counsellors in informing an individual on its genetic risk of developing FTD and might lead to novel therapeutic strategies to prevent onset or slow down disease progression.
- Promoter: Vandebergh Marijne
- Research Project