Familial and sporadic fatal insomnia

Lancet Neurol. 2003 Mar;2(3):167-76. doi: 10.1016/s1474-4422(03)00323-5.


Familial fatal insomnia (FFI)--a hereditary prion disease caused by a mutation at codon 178 of the prion-protein (PrP) gene (PRNP) that leads to a D178N substitution in the protein--and its sporadic form, sporadic fatal insomnia (SFI), have similar disease phenotypes. Both disorders have clinical features of disrupted sleep (loss of sleep spindles and slow-wave sleep and enacted dreams during rapid-eye-movement sleep), autonomic hyperactivation, and motor abnormalities (myoclonus, ataxia, dysarthria, dysphagia, and pyramidal signs). PET shows pronounced thalamic and limbic hypometabolism that becomes more widespread in later stages. Neuropathological assessment reveals severe neuronal loss and astrogliosis of the anterior medial thalamus and inferior olives, with later cerebral cortical and cerebellar involvement. Accumulation of an isoform of protease-resistant PrP fragment in FFI distinct from that found in a familial form of Creutzfeldt-Jakob disease with the same D178N mutation, shows the effect of the polymorphism at codon 129 of PRNP on phenotypic expression and the possibility of distinct prion "strains" with diverse pathological potential. Intriguing clinicopathological correlations in FFI and SFI suggest a role for the thalamolimbic system in the regulation of sleep and other circadian functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyloid / genetics
  • Brain / pathology
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Diagnostic Imaging
  • Electroencephalography
  • Humans
  • Insomnia, Fatal Familial / diagnosis
  • Insomnia, Fatal Familial / genetics*
  • Nerve Degeneration / diagnosis
  • Nerve Degeneration / genetics
  • Prion Proteins
  • Prions
  • Protein Precursors / genetics
  • Thalamus / pathology


  • Amyloid
  • PRNP protein, human
  • Prion Proteins
  • Prions
  • Protein Precursors