Molecular biology

The molecular biology studies on autopsy and moody material of the cases were made by Prof. Pierluigi Gambetti at Case Western Reserve University in Cleveland. The presence of spongiform degeneration in the cerebral cortex led to the identification of an abnormal isoform of the prion protein (PrP) in the brain of the patients with FFI. PrP is encoded by a gene (PRNP) located on the short arm of chromosome 20.

The prion is a normal protein located on the cytoplasmic membrane of the cells, which appears in the evolution of all mammals and it is expressed in most tissues, but especially in the brain. Unlike the normal isoform, the one that is abnormal is protease resistant. The resistance is the hallmark of what are called prion diseases, which, as we have seen, can be hereditary, sporadic or transmitted. Protease resistant PrP was found in patients with FFI. Processing the gene, a mutation at codon 178 was discovered, that involves the replacement of aspartic acid with aspargine in the PrP. The mutation was found in all affected members. The presence of protease resistant PrP and the gene mutation define FFI as a prion disease, which is a new chapter of encephalopathy that were hereditary and infective. Accordin to recent developments, the prion protein is part of the receptor for GABA-ergico system; it, therefore, would activate the inhibitory tone. The abnormal isoform of PrP would not have the ability to bind to synapses. In the absence of inhibitory tone , the thalamic neurons in FFI would remain under constant hyper-activity, until the functional breakdown and necrosis.