Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene

Rossella Medori, Hans Juergen Tritschler, Andréa Leblanc, Federico Villare, Valeria Manetto, Hsiao Ying Chen, Run Xue, Suzanne Leal, Pasquale Montagna, Pietro Cortelli, Paolo Tinuper, Patrizia Avoni, Mirella Mochi, Agostino Baruzzi, Jean Jaques Hauw, Jurg Ott, Elio Lugaresi, Lucila Autilio-Gambetti, Pierluigi Gambetti

Research output: Contribution to journalArticlepeer-review


Background. We previously described two members of a family affected by an apparently genetically determined fatal disease characterized clinically by progressive insomnia, dysautonomia, and motor signs and characterized pathologically by severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Five other family members who died of this disease, which we termed "fatal familial insomnia," had broader neuropathologic changes suggesting that fatal familial insomnia could be a prion disease. Methods. We used antibodies to prion protein (PrP) to perform dot and Western blot analyses, with and without proteinase K, on brain tissue obtained at autopsy from two patients with fatal familial insomnia, three patients with sporadic Creutzfeldt-Jakob disease, and six control subjects. The coding region of the PrP gene was amplified and sequenced in the samples from the two patients with fatal familial insomnia. Restriction-enzyme analysis was carried out with amplified PrP DNA from 33 members of the kindred. Results. Protease-resistant PrP was found in both patients with fatal familial insomnia, but the size and number of protease-resistant fragments differed from those in Creutzfeldt-Jakob disease. In the famity with fatal familial insomnia, all 4 affected members and 11 of the 29 unaffected members had a point mutation in PrP codon 178 that results in the substitution of asparagine for aspartic acid and elimination of the Tth111 I restriction site. Linkage analysis showed a close relation between the point mutation and the disease (maximal lod score, 3.4 when θ was zero). Conclusions. Fatal familial insomnia is a prion disease with a mutation in codon 178 of the PrP gene, but the disease phenotype seems to differ from that of previously described kindreds with the same point mutation.

Original languageEnglish
Pages (from-to)444-449
Number of pages6
JournalNew England Journal of Medicine
Issue number7
Publication statusPublished - Feb 13 1992

ASJC Scopus subject areas

  • Medicine(all)


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