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 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..
According 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. The deterioration of synaptic inhibition may be involved in the epileptiform activity seen in Creutzfeld-Jacob disease. It could, thereby deduce that the loss of function of the prion protein may contribute to the early synaptic loss and to neuronal degeneration observed in these diseases. In the clinical context, there are two variants of genetic fatal insomnia, one with a rapid course and dreamlike and myoclonus prevalence and the other a with a slower course and a prevalence of stupor and pyramidal signs. The mutation of codon 178 is found, moreover, in a subtype of Creutzfeld - Jacob disease (CJD) , which differs from the FFI in phenotypic expression, because there are neither insomnia nor selective thalamic atrophy, but widespread spongiosis, independent from the duration of the disease and different clinical manifestations. To understand the phenotypic eterotipia between FFI and 178 CJD and between the two clinico-pathological variants in the context of FFI was extended the analysis of the prion gene in affected members from these diseases. It was observed a difference at codon 129 of the prion gene, which shows a polymorphism methionine / valine, common to the Caucasian population: 62% for allele methionine and 38% for the allele valine. If the prion gene not present mutations at codon 178, homozygosity or heterozygosity at codon 129 expresses a normal phenotype. If, instead, the prion gene has mutation at codon 178, you have different phenotypic expressions for allele eterotipia at codon 129. The clinical, pathologic and genetic definition of FFI has allowed the following considerations: 1.It gave credibility to the theory of prions, already formulated by Prusiner in 1982-83 and it is from studies on scrapie. Theory opposed by supporters of the slow virus diseases. However, in pathological brains has never been found traces of viral genetic material. The infectivity of prion diseases is not the transmission of a hypothetical viral genome in the host brain. Prusiner's prion hypothesis provides a new concept of infectivity, which exceeds Koch's postulates, that is of molecular kind rather than viral. The mutant prion protein would act as a mold for the normal protein, changing it in turn. It is therefore an infectivity for contact, likely to induce a "mutation" in the normal protein.
This phenomenon is reflected in nature in the crystallization cascade of some minerals, the front of crystallization induces a mutation of the adjacent amorphous material..
This model would answer two questions: A) Why do you need large quantities of pathological prion protein to mutate (according to Prusiner, “to infect”) the normal one. B) Why are the carriers of the mutation sick while having a normal allele. 2.It has redefined the role of the thalamus. The thalamic degenerate formations in this disease have been until now, "unknown land." Hess in 1953 found that the medial thalamic stimulation induced a physiological sleep in animals. The selectivity of thalamic lesion in this disease allows for anatomical-clinical correlations much more precise, previously impossible. First of all, this thalamic abiotrofia is family-based, it is isolated and selective, in short, a natural experimental model, integrates into a single view scattered observations and places them with the utmost importance. The anterior thalamic and dorsal-medial nucleus are a fundamental sleep-inducing and organizational sleep structure, coordinate the entire autonomic nervous system and endocrine system. In this disease occurs an imbalance of the whole ergotropo system, in the direction of an abnormal energy expenditure: hypertension, hyper-therm, tachycardia, hyper-cortisol, disorder that ultimately ends with death. The anterior and medial thalamus, therefore, constitutes a supplementary station, a real network, of vegetative life in trophic sense, that is of reconstruction and conservation of energy reserves. It is therefore clear that it is a structure essential for life itself. 3.It has complicated genetics. He came to fall the axiom "a mutation a disease", ie a mutation = a phenotype. The gene polymorphism of a normal allele can, in the presence of the same mutation, give different phenotypes.