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

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Abstract

Human prion diseases are a group of rare neurodegenerative disorders characterized by the conversion of the constitutively expressed prion protein, PrPC, into an abnormally aggregated isoform, called PrPSc. 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.

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Acknowledgments

This study was supported by the University of Bologna (grant RFO) and the Gino Galletti Foundation.

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Authors and Affiliations

  1. Department of Neurological Sciences, University of Bologna, Via Foscolo 7, 40123, Bologna, Italy

    Sabina Capellari, Rosaria Strammiello, Daniela Saverioni & Piero Parchi

  2. Institut für Neuropathologie, Ludwig-Maximilians-Universität München, Munich, Germany

    Hans Kretzschmar

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  1. Sabina Capellari
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  2. Rosaria Strammiello
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  4. Hans Kretzschmar
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Correspondence to Piero Parchi.

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Capellari, S., Strammiello, R., Saverioni, D. et al. Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis. Acta Neuropathol 121, 21–37 (2011). https://doi.org/10.1007/s00401-010-0760-4

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