Genotype-phenotype correlations in frontotemporal lobar degeneration with TDP-43 inclusions

Date: 21 March 2018

Venue: Promotiezaal (UAntwerp, Campus Drie Eiken, Building Q) - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken)

Time: 4:00 PM - 6:00 PM

PhD candidate: Sara Van Mossevelde

Principal investigator: Christine Van Broeckhoven, Sebastiaan Engelborghs

Short description: PhD defence Sara Van Mossevelde - Department of Biomedical Sciences

Frontotemporal lobar degeneration (FTLD) is a remarkably heterogeneous neurodegenerative disease accounting for 10% of all dementia cases. In frontotemporal dementia (FTD), patients progressively develop behavioral and personality changes and/or language deficits. More than half of all FTLD patients have protein inclusions containing TAR-DNA binding protein (TDP-43) as the major constituent (FTLD-TDP). Causal mutations for FTLD-TDP have been identified in four genes: progranulin (GRN), chromosome 9 open reading frame 72 (C9orf72), TANK binding kinase 1 (TBK1), and valosin containing protein gene (VCP).

One of the major aims of this doctoral thesis was to perform in-depth phenotype descriptions of patients with a known genetic cause leading to FTLD-TDP, and to identify genotype-phenotype correlations. Further, phenotype heterogeneity was studied as an indicator of the presence of phenotype modifiers.

In a previous study our research group was able to provide molecular evidence for increasing expansion sizes in a limited amount of C9orf72 parent-offspring transmissions in accordance with the occurrence of disease anticipation. In this thesis, clinical-based evidence was provided for the occurrence of disease anticipation in extensive C9orf72 families by means of a decrease in onset age across successive generations.

In 2006 one single GRN mutation was identified in several Belgian families all originating from one single ancestor. In this thesis the clinical phenotype of patients in this pedigree, now containing 29 branches, was described. Three quarters received a clinical diagnosis of FTD with an equal relative frequency of the behavioral and the language variant, and apathy and non-fluent progressive aphasia as the most frequent features. Onset age ranged from 45 to 80 years. Only a small part of this onset age variability could be explained by variations in GRN, MAPT and C9orf72, suggesting the presence of (an)other, yet unidentified, genetic modifier(s).

In this thesis, 10 index patients and six of their affected relatives carrying a mutation in TBK1, a causal gene for FTLD and amyotrophic lateral sclerosis (ALS) identified in 2015, were clinically and pathologically described and compared with C9orf72 and GRN mutation carriers. The majority of the TBK1 FTD patients presented at a rather high onset age with the behavioral variant, early memory impairment and frequent extrapyramidal symptoms.

Genotype-phenotype correlations can aid the clinician in diagnostics and prognostics of (pre)symptomatic carriers, but also in future therapy stratification. Also phenotype heterogeneity is of interest because it suggests the presence of phenotype modifiers which are potential targets for disease-delaying therapies.