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| Fatal Familian Insomnia | In both sporadic and familial fatal insomnia, the molecular mass of the Prp(Sc) fragment was 19 kD in these mice. On the contrary, these characteristics were different in the mice inoculated with homogenate from patients with typical sporadic or familial Creutzfeldt-Jakob disease, and the molecular mass of their PrP(Sc) was 21 kD.
These results indicated that fatal familial insomnia can be generated in the absence of the D178N mutation.
Gambetti and Parchi suggested that the repertoire of conformational changes of PrP(Sc) may be relatively limited--a factor that may facilitate the discovery of treatments.
Scaravilli in 2000 reported another case of sporadic fatal insomnia, confirmed by polysomnography and neuropathologic findings, in which there was no mutation detected in the prion gene. His patient was homozygous for methionine at codon 129.
Molecular Genetics
It was demonstrated that an asp178-to-asn (D178N) substitution in the PRNP gene in conjunction with the met129 polymorphism on the same allele was responsible for FFI.
Creutzfeldt-Jakob syndrome was associated with val129 in all 15 affected members of 6 kindreds, whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.
Medori identified the D178N mutation in all 4 affected persons and 11 of 29 unaffected persons from kindred with FFI.
Genotype/Phenotype Correlations
In an analysis of 14 patients with FFI from 5 unrelated families, Montagna in 1998 found that patients who were homozygous for the met129 polymorphism had more prominent oneiric episodes, insomnia, and dysautonomia at disease onset, whereas patients heterozygous for met/val129 showed ataxia and dysarthria at disease onset, earlier sphincter loss, and seizures.
Dauvilliers in 2004 stated that FFI patients with met129 homozygosity tended to have a clinical course of less than 1 year, severe insomnia, recurrent oneiric episodes, continuous motor overactivity, and severe dysautonomia.
Quite the opposite, FFI patients with met/val129 heterozygosity tended to have a clinical course of greater than 2 years, insomnia or pseudohypersomnia, severe ataxia and dysarthria at disease onset, normal rest activity, and mild dysautonomia.
Animal Model
Tobler in 1996 reported alterations in circadian rhythm and sleep in PrP null mice. The changes in these mice show intriguing similarities with the sleep alterations in FFI.
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