Institute of Clinical Neurology, University of Bologna, Bologna, Italy
Gambetti, P., Division of Neuropathology, Institute of Pathology, Case Western Reserve University School of Medicine
Cleveland, OH, U.S.A.
FI is a prion disease linked to the 178ASP129Met haplotype. The disease begins between 20 and 71 years of age (mean = 49) and may have either a relatively short (between 6 and 13 months) of relatively long duration (between 24 and 48 months). The disease duration is shorter in 129 homozygotes (129Met-Met), longer in 129 heterozygotes (129Met-Val). In addition FFI patients homozygous for methionine at codon 129 manifest prominent sleep and autonomic disturbances. In contrast, the methionine-valine heterozygous at codon 129 manifest motor signs as a prominent clinical feature. The PrPRes fragments associated with FFI differ in size and glycosylation from the PrPRes fragment associated with CJD linked to same point mutation at codon 178, but codifying valine at codon 129 in the affected allele. The preferential atrophy of the antero-ventral and medio-dorsal thalamic nuclei determines:
1 ) inability to generate physiological sleep;
2) sympathetic hyperactivation;
3) progressive attenuation of the vegetative and endocrine circadian oscillations.
The antero-ventral and medio-dorsal thalamic nuclei atrophy interrupt the most important circuits connecting the limbic and paralimbic cortex with the hypothalamus. This determines vegetative and endocrine homeostatic dysregulation. Prion protein may play a role in the mechanisms regulating the activity-rest cycles in living organisms.
