Fatal Familial Insomnia: A Disease Model Emphasizing the Role of the Thalamus in the Regulation of the Sleep-Wake Cycle and Other Circadian Rhythms

Abstract

Fatal Familial Insomnia (FFI) is a human hereditary prion disease due to a mutation at codon 178 of the prion protein gene located on chromosome 20, which cosegregates with a methionine polymorphism at codon 129 of the same gene on the mutated allele (Lugaresi et al., 1986; Medori et al., 1992). Prion diseases are characterized by the presence in the brain of an isoform of the prion protein, which is partially resistant to the action of proteases, so called PrPres, and is transmissible. The brains of FFI patients indeed demonstrate accumulation of a 19 kDa (after deglycosylation) PrPres (Parchi et al 1998), and FFI has been transmitted to transgenic mice. FFI has been found in at least 21 pedigrees around the world, and probably represents the third most common inherited human prion disease. FFI is also characterized by a unique set of clinical symptoms and pathological findings, which give rise to peculiar clinico-pathological correlations and interesting physiopathological conclusions concerning the role of the thalamus, especially its anterior and mediodorsal nuclei, in the regulation of circadian activities such as the sleep-wake cycle and the attending hormonal and vegetative functions.