Fatal Familial Insomnia: A Brief Overview of a Human Prion Disease

Prion diseases are described as inevitably fatal neurodegenerative disorders as the result of the normal cellular protein PrPC misfolding into the abnormal PrPSc form. Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS), and Kuru are among the most well-known human prion diseases. Fatal Familial Insomnia (FFI) is rare among the prion diseases and has a devastating disease course and followed by a fatal outcome. FFI has been identified to be genetically passed down through generations; however, there have also been reported cases of Sporadic Familial Insomnia (SFI). SFI patients have no identifiable family history of any neurodegenerative disorders or prion diseases. The disease course of FFI heavily depends on whether it is a homozygous (Methionine-Methionine) or a heterozygous (Methionine-Valine) genotype. FFI and SFI share similar clinical features of disrupted sleep, autonomic hyperactivation, and motor abnormalities. Neuropathological assessments have revealed severe neuronal loss of the mediodorsal and anteroventral nuclei of the thalamus with excessive accumulation of protease-resistant PrPSc. While FFI does share the same D178N mutation with CJD, there are varying distinct effects due to the polymorphism at codon 129 of the Prnp gene, resulting in different pathological features. Knockout mice have been genetically created to identify the role of the Prnp gene and the PrPC protein. While questions remain on the definitive role of the two, findings have identified potential roles in development and sleep regulation. The involvement of the thalamus and sleep regulation suggest a potential relationship of the thalamo-limbic system in FFI. FFI affects various systems in the body including cardiovascular, circadian hormonal rhythm, gastrointestinal, and genitourinary. Limited case studies have been published in detail, but those of which that are published share common clinical and pathological features. Doxycycline is the only ongoing clinical trial to date for treatment, but there are no approved preventative or treatment options for prion diseases.