Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

The role of CHMP2BIntron5 in autophagy and frontotemporal dementia

“…However, FTD has numerous monogenic causes, most of which are caused by mutations in genes other than CHMP2B (Benussi et al, 2015; Roberson, 2012). The most common mutations associated with FTD are in C9ORF72 (chromosome 9 open reading frame 72; up to 50% of familial case; (Majounie et al, 2012), PGRN (progranulin; 5–20% of cases; (Rademakers et al, 2012), and MAPT (microtubulin associated protein Tau; 5–20% of cases; (Rademakers et al, 2004; Sieben et al, 2012).…”

“…Although mutations in several different genes can cause FTD (see (Benussi et al, 2015), this review will focus on the recent findings on the CHMP2B Intron5 mutant isoform. Though it is a relatively uncommon mutation in FTD patients (Benussi et al, 2015; Roberson, 2012), it is still widely studied due to its robust pathology.…”

“…Though it is a relatively uncommon mutation in FTD patients (Benussi et al, 2015; Roberson, 2012), it is still widely studied due to its robust pathology. Because of this, the CHMP2B Intron5 mutant isoform and its resulting pathology are well characterized.…”

GRN mutation in a patient with a behavioral variant of frontotemporal lobar degeneration (bvFTD)

“…Frontotemporal lobar degeneration (FTLD) is the second most common cause of early onset dementia after Alzheimer's disease. Frontotemporal lobar degeneration is a highly heritable disorder, with about 25-50% of patients having a positive family history and about 10% showing clear autosomal-dominant inheritance, even though a genetic cause can be demonstrated in less than 20% of patients [2]. This neurodegenerative disorder shows genetic and pathological heterogeneity, is characterized by behavior and language disturbances, and is associated with variable frontal, temporal, and basal ganglia atrophy with neuronal loss and gliosis [2,16].…”

“…Frontotemporal lobar degeneration is a highly heritable disorder, with about 25-50% of patients having a positive family history and about 10% showing clear autosomal-dominant inheritance, even though a genetic cause can be demonstrated in less than 20% of patients [2]. This neurodegenerative disorder shows genetic and pathological heterogeneity, is characterized by behavior and language disturbances, and is associated with variable frontal, temporal, and basal ganglia atrophy with neuronal loss and gliosis [2,16]. The redefined clinical criteria recognize different phenotypes based on the clinical symptoms at presentation, including a possible behavioral variant of FTLD (bvFTD), two language variants, primary progressive nonfluent aphasia (PNFA), and a semantic variant.…”