Profilo Genetico ed Epigenetico in pazienti con Demenza Frontotemporale

The genetics of neurodegenerative diseases has an important role to clarify the pathogenetic mechanism, the diagnosis and finally the therapeutic and ethical implications. Up to now, the genetics of familial forms of Frontotemporal dementia (FTD) is mainly related to 3 genes: the microtubule-associated protein tau (MAPT) progranulin (GRN) and the last hexanucleotide expansion (G4C2) repeats in the open reading frame of chromosome 9 (C9orf72). The study describes clinical cases carrying mutations in these genes and, particularly, carriers of the Cys139Arg in GRN gene to clarify the pathogenic role of the mutation. Moreover, we investigated the methylation levels of the 5’CpG-island in C9orf72 promoter near the G4C2 repeat expansion in 86 Italian subjects: 45 FTLD patients (17 expansion carriers, 28 non carriers) and 41 controls. Our study reveals that hypermethylation of the CpG island is expansion-specific, since in any of the 69 non carriers (patients and controls) a high level of methylation was observed. Moreover, the study shows that DNA methylation is not a major modifying factor for disease. Further validation will be necessary to confirm the role of this or other epigenetic mechanisms in the C9orf72 linked diseases.