Prion diseases are a group of transmissible neurodegenerative disorders associated with the misfolded form of the prion protein, PrP Sc . The latter isoform is derived by conformational conversion of the normal prion protein, PrP c . The gene encoding the prion protein is highly conserved among species. There are several distinct types of prion diseases in humans: kuru, Creutzfeldt -Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) and Fatal Familial Insomnia (FFI) and its sporadic analogue, fatal sporadic insomnia. While human prion diseases are mostly sporadic, some 15% of CJD and all cases of GSS are hereditary disorders caused by mutations in the PRNP gene. There are two major types of mutations in PRNP: point mutations leading to amino acid substitutions and mutations leading to expansions of the octapeptide repeat region within the N-terminal part of the prion protein. This review describes different types of familial prion diseases linked to specific polymorphisms and mutation in PRNP.