Genetics of Frontotemporal Dementia: an updated overview

Frontotemporal dementia (FTD) involves a category of disorders characterized by behavioral, linguistic, and mobility abnormalities resulting from neurodegeneration in the frontal and temporal lobes. FTD represents the second most common etiology of early-onset dementia, and is distinguished by a wide range of clinical features. Indeed, three clinical variants are well known: the behavioral variant (bvFTD), which is the most prevalent and predominantly associated with personality and behavioral changes, the semantic variant primary progressive aphasia (svPPA), which is associated with gradual loss of speech integrity and word meaning, and the non-fluent variant primary progressive aphasia (nfvPPA), in which patients have difficulties getting words out, with slurred speech and an abnormal voice. About 15% of FTD patients also have another neurodegenerative motor neuron disease, amyotrophic lateral sclerosis (ALS), and this co-occurrence is called FTD-ALS. About half of FTD cases are familial. The most common observed mode of inheritance for familial FTD is autosomal dominant. So far, at least ten causal genes have been implicated in the etiology of FTD. Three of these genes: the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72), are the most common and are responsible for more than half of familial FTD. The remaining genes are rarely reported, and the pathological mechanisms of many of them are unclear. The causes of the remainder of the familial FTD proportion, as well as the sporadic FTD, are to be determined. We conclude that despite all the breakthroughs in discovering the etiology of FTD, the majority of work is still to be done. The discovered causal FTD genes give insights toward a better understanding of the clinical and genetic heterogeneity of FTD, and help in its early and correct diagnosis. Despite the current management of FTD relies mainly on supportive treatment several promising clinical trials showed promising results in the correction of the harmful effects caused by the mutant genes.