- To characterise in detail the clinical, laboratory and neuropathological features of Fatal Familial Insomnia (FFI), a rare hereditary human prion encephalopathy with a 178 codon mutation in the prion protein gene (PRNP) leading to prominent degeneration of the anteroventral (AV) and dorsomedian (DM) thalamic nuclei.
- To correlate the spectrum of clinico-pathological features to the genetic background, in particular the codon 129 polymorphism in the PRNP.
- To describe in the experimental animal the neural circuitry connecting the MD and AV thalamic nuclei to the cerebral cortex and other subcortical regions, in order to characterise neural pathways possibly relevant to the spread of prions.
FFI is a rare hereditary disorder clinically characterised by early and intractable loss of sleep (insomnia), prominent autonomic activation with tachycardia, hypertension, diaphoresis, pyrexia and sphyncter loss, and motor impairment (ataxia, dysarthria, myoclonus, pyramidal signs). The disease is pathologically characterised by neuronal loss and gliosis in the MD and AV thalamic nuclei, and variable neuronal degeneration and spongiosis in the cerebral, especially frontal, temporal and parietal, and cerebellar cortex. The participants aim at defining the clinical and pathological features of such a disease by pooling all together the cases observed in France and in Italy (a total of 5 families) which have undergone a series of uniform investigations, in order to minimise the interfamilial variability and to establish a common definition of the disease and set certain diagnostic criteria. Accordingly, all the relevant clinical, laboratory and neuropathological features, when available, will be subjected to a detailed and quantified scrutiny in relation to the disease course. Possible phenotypic variability will also be detected and the full spectrum of disease described by this method. Once the full phenotypic characterisation of FFI be achieved, the second objective shall be that of correlating clinical features and neuropathological changes to genetic background. By definition, all FFI patients show the 178 codon mutation in the PRNP associated with the met polymorphism at codon 129 of the mutated allele. Preliminary clinical data suggest that the 129 codon polymorphism on the non-mutated allele may also have some influence in the clinical expression of the disease, in particular disease duration. Therefore, all patients will be genetically characterised also in regard of the 129 polymorphism on the wild-type PRNP allele, in order to check for a possible cause of phenotypic variability in the disease. Finally, as the peculiar features of FFI indicate that the disease process originates in the thalamus, spreading later to the cortex, the participants aim at resolving some pathogenetic aspects of the disease by tracing the neural pathways leading to and from the AV and MD thalamic nuclei in the experimental animal (by means of lesioning brain studies in the cat), in order to check whether the neural circuitry connecting these 2 thalamic nuclei may compare with the pathological changes observed in the autopsy cases of FFI.