Identification of new molecular alterations in fatal familial insomnia

Hum Mol Genet. 2016 Jun 15;25(12):2417-2436. doi: 10.1093/hmg/ddw108. Epub 2016 Apr 7.


Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. This study describes new neuropathological and biochemical observations in a series of eight patients with FFI. The mediodorsal and anterior nuclei of the thalamus have severe neuronal loss and marked astrocytic gliosis in every case, whereas the entorhinal cortex is variably affected. Spongiform degeneration only occurs in the entorhinal cortex. Synaptic and fine granular proteinase K digestion (PrPres) immunoreactivity is found in the entorhinal cortex but not in the thalamus. Interleukin 6, interleukin 10 receptor alpha subunit, colony stimulating factor 3 receptor and toll-like receptor 7 mRNA expression increases in the thalamus in FFI. PrPc levels are significantly decreased in the thalamus, entorhinal cortex and cerebellum in FFI. This is accompanied by a particular PrPc and PrPres band profile. Altered PrP solubility consistent with significantly reduced PrP levels in the cytoplasmic fraction and increased PrP levels in the insoluble fraction are identified in FFI cases. Amyloid-like deposits are only seen in the entorhinal cortex. The RT-QuIC assay reveals that all the FFI samples of the entorhinal cortex are positive, whereas the thalamus is positive only in three cases and the cerebellum in two cases. The present findings unveil particular neuropathological and neuroinflammatory profiles in FFI and novel characteristics of natural prion protein in FFI, altered PrPres and Scrapie PrP (abnormal and pathogenic PrP) patterns and region-dependent putative capacity of PrP seeding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Entorhinal Cortex / metabolism
  • Entorhinal Cortex / physiopathology
  • Female
  • Gliosis / genetics
  • Gliosis / physiopathology
  • Humans
  • Insomnia, Fatal Familial / genetics*
  • Insomnia, Fatal Familial / physiopathology
  • Interleukin-10 Receptor alpha Subunit / genetics*
  • Interleukin-6 / genetics*
  • Male
  • Neurons / metabolism
  • Neurons / pathology
  • Prion Diseases / genetics*
  • Prion Diseases / physiopathology
  • Prion Proteins / genetics*
  • Receptors, Colony-Stimulating Factor / genetics*
  • Thalamus / metabolism
  • Thalamus / physiopathology
  • Toll-Like Receptor 7 / genetics*


  • CSF3R protein, human
  • Interleukin-10 Receptor alpha Subunit
  • Interleukin-6
  • PRNP protein, human
  • Prion Proteins
  • Receptors, Colony-Stimulating Factor
  • TLR7 protein, human
  • Toll-Like Receptor 7