Federica Perrone, Hung Phuoc Nguyen, Sara Van Mossevelde, Matthieu Moisse, Anne Sieben, Patrick Santens, Jan De Bleecker, Mathieu Vandenbulcke, Sebastiaan Engelborghs, Jonathan Baets, Patrick Cras, Rik Vandenberghe, Peter De Jonghe, Peter P. De Deyn, Jean-Jacques Martin, Philip Van Damme, Christine Van Broeckhoven, Julie van der Zee
Neurobiology of Aging,
Mutation screen and phenotypic profiling of two amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated genes, CHCHD10 and TUBA4A, was performed in a Belgian cohort of 459 FTD, 28 FTD-ALS and 429 ALS patients. In CHCHD10, we identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson’s disease (1/459, 0.22%) leading to loss of transcript. We further observed three previously described missense variants (p.Pro34Ser, p.Pro80Leu and p.Pro96Thr) that were also present in the matched control series. In TUBA4A, we detected a novel frameshift mutation (p.Arg64Glyfs*90) leading to a truncated protein in one FTD patient (1/459 of 0.22%) with family history of Parkinson’s disease and cognitive impairment, and a novel missense mutation (p.Thr381Met) in two sibs with familial ALS and memory problems (1 index patient/429, 0.23%) in whom we previously identified a pathogenic C9orf72 repeat expansion mutation. The present study confirms the role of CHCHD10 and TUBA4A in the FTD-ALS spectrum, although genetic variations in these two genes are extremely rare in the Belgian population and often associated with symptomatology of related neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease.