Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon
178 of the Prion Protein Gene
R. Medori, H-J. Tritschler, A. LeBlanc, F. Villare,
V. Manetto, H.Y. Chen, R. Xue, S. Leal, P. Montagna,
P. Cortelli, P. Tinuper, P. Avoni, M. Mochi, A. Baruzzi, J.J. Hauw,
J. Ott, E. Lugaresi, L. Autilio-Gambetti, P. Gambetti
New England Journal of Medicine 326(7), 444--449 (1992 Feb 13)
Abstract
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 family 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 theta 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.
Comment in: N Engl J Med 1992 Feb 13;326(7):486-7
