title: [Fatal familial insomnia].
abstract: Since its description in 1986, Fatal Familial Insomnia (FFI) became the third most common inherited prion diseases (23 described families, 3 isolated cases). It is characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. Insomnia, dysautonomia, disruption of circadian rhythms and motor dysfunctions (myoclonus, ataxia, dysarthria, spasticity) are the main clinical symptoms in the homozygote patients (met/met at codon 129). Heterozygotes have motor dysfunctions from onset and cognitive changes. Pheno-typic variability does not appear to be strictly related to codon 129 polymorphism as recently stressed in some reports. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially in the medio-dorsal and antero-ventral nuclei, without any amyloïd deposits. Some spongiosis may be seen essentially in the cerebral cortex, in patients with longer duration disease. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease. However, in these two phenotypically different diseases, two protease resistant fragments of the pathogenic PrP (PrPres) are accumulated. They differ in molecular mass. In FFI PrPres, the unglycosylated form is underrepresented. This particularity does not result from the preferential conversion of the glycosylated forms but from an inaccessibility of non glycosylated form to conversion. PrPres has been shown to be form allelic origin. Neuronal apoptosis was found to contribute to neuronal loss in FFI. Its presence correlates with neuronal loss, being invariably noticed in the thalamus and medullary nuclei. It is not correlated with PrPres accumulation. The quantity of deposits is globally low in FFI brains and rarely immunohistochemically detected. Pathogenesis of lesions and clinical signs remain to be assessed. Protein dysfunction could be hypothesized according to some clinical and experimental data as well as to the discordance between protein accumulation and programmed cell death. Neurotoxicity is also postulated. Studies on this pathology led to consider the existence of "strains" in human prion diseases. Despite remarkable advances, many issues remain unsolved in this non spongiform prion disease.
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, CHU Rangueil, Toulouse.
authors.forename: M B
authors.initials: MB
authors.lastname: Delisle
authors.forename: E
authors.initials: E
authors.lastname: Uro-Coste
authors.forename: F
authors.initials: F
authors.lastname: Gray
authors.forename: C
authors.initials: C
authors.lastname: Vital
mesh_terms: D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D003062:Codon; D006801:Humans; D017096:Prion Diseases / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology
chemical_list: D003062:Codon