Chapter 15 - Fatal familial insomnia and sporadic fatal insomnia

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Abstract

Fatal familial insomnia (FFI) and sporadic fatal insomnia (sFI), or thalamic form of sporadic Creutzfeldt–Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene (PRNP) at chromosome 20. sFI is a phenocopy of FFI and likely its sporadic form. Both diseases are primarily characterized by progressive sleep impairment, disturbances of autonomic nervous system, and motor signs associated with severe loss of nerve cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of 19 kDa identified as resPrPTSE type 2. To date at least 70 kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is thought to cause FFI by destabilizing the mutated prion protein and facilitating its conversion to PrPTSE. The thalamus is the brain region first affected. A similar mechanism triggered spontaneously may underlie sFI.

Section snippets

History

Severe thalamic atrophy as a distinct clinical and pathologic entity has been reported from at least 1939 (Stern, 1939). In his review Jakob-Creutzfeldt Disease in 1968, Kirschbaum introduced the thalamic subgroup comprising five previously published cases (Stern, 1939; Poursines et al., 1953; Schulman, 1956; Garcin et al., 1962, Garcin et al., 1963; McMenemey et al., 1965). In Martin, 1975, Martin et al., 1983 and colleagues proposed a classification of Thalamic degenerations or Thalamic

Conclusions and future developments

FFI and sFI have well-established genetic, clinical, and histopathologic features. Basic biochemical characteristics of the mutated PrP and of the disease-associated PrP (PrPTSE), including propensity to transmit experimentally and the features of the transmitted disease, have also been examined. However, FFI and sFI, as with other neurodegenerative diseases, suffer from the lack of an accurate animal model and an effective treatment. Accurate disease modeling is critical to determine the mode

Acknowledgments

We are grateful to Drs. Mark Cohen (National Prion Disease Pathology Surveillance Center (NPDPSC), Case Western Reserve University, United States), Pietro Cortelli (University of Bologna, Italy), Xiao-Ping Dong (Chinese Center for Disease Control and Prevention, China), Jorge Iriarte (University of Navarra, Spain), Yi Li (Shandong University, China), Piero Parchi (University of Bologna, Italy), and Robert G. Will (University of Edinburgh, United Kingdom) for their invaluable cooperation. We

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    “To Professor Elio Lugaresi, the mentor who critically shaped my early professional life, the collaborator who initiated all this work and a precious friend throughout” Pierluigi.

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