Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis

Abstract

Human prion diseases are a group of rare neurodegenerative disorders characterized by the conversion of the constitutively expressed prion protein, PrP(C), into an abnormally aggregated isoform, called PrP(Sc). While most people who develop a prion disease have no identifiable cause and a few acquire the disease through an identified source of infection, about 10-15% of patients are affected by a genetic form and carry either a point mutation or an insertion of octapeptide repeats in the prion protein gene. Prion diseases show the highest extent of phenotypic heterogeneity among neurodegenerative disorders and comprise three major disease entities with variable though overlapping phenotypic features: Creutzfeldt-Jakob disease (CJD), fatal insomnia and the Gerstmann-Sträussler-Scheinker syndrome. Both CJD and fatal insomnia are fully transmissible diseases, a feature that led to the isolation and characterization of different strains of the agent or prion showing distinctive clinical and neuropathological features after transmission to syngenic animals. Here, we review the current knowledge of the effects of the pathogenic mutations linked to genetic CJD and fatal familial insomnia on the prion protein metabolism and physicochemical properties, the disease phenotype and the strain characteristics. The data derived from studies in vitro and from those using cell and animal models are compared with those obtained from the analyses of the naturally occurring disease. The extent of phenotypic variation in genetic prion disease is analyzed in comparison to that of the sporadic disease, which has recently been the topic of a systematic and detailed characterization.

Familial fatal insomnia with atypical clinical features in a patient with D178N mutation and homozygosity for Met at codon 129 of the prion protein gene

“…5,6 At present, descriptions of patients with the D178N/Met129 PRNP phenotype are few. 7 We report a patient with the D178N/Met129 PRNP mutation, affected by FFI without typical refractory insomnia early in the disease course or MRI changes in the thalamus.…”

Cyclin-dependent Kinase 5 Phosphorylation of Familial Prion Protein Mutants Exacerbates Conversion into Amyloid Structure

“…The N terminus of PrP is also clearly involved in familial and transmissible prion diseases. Additional octapeptide repeats are observed in familial human PrP diseases (33), and mice lacking the N-terminal amino acids 32-93 and 23-31 are less susceptible to transmissible prion diseases (34,35). Furthermore, the N terminus of PrP has been associated with numerous cellular features such as lipid rafts (36), RNA binding (37), micropinocytosis (38), and neuroprotection (39,40).…”

Past and Future of Diagnosis and Therapy of Transmissible Spongiform Encephalopathy

“…Note that codon 129 encodes for two amino acids, methionine (M) and valine (V). A phenotypic influence in inherited prion diseases associated with codon 129 has been investigated and summarized in (Kovacs et al, 2002;Capellari et al, 2011). Regarding to second characteristic, Paramithiotis et al showed that the Tyr-Tyr-Arg motif in PrP, which is a hydrophilic-like fragment, will be exposed to solvent when PrPC is converted into PrPSc.…”