Clinical and genetic studies of fatal familial insomnia

Abstract

We report a 42-year-old man who, for 8 months, had intermittent motor abnormalities and mild difficulty falling asleep. A diagnosis of fatal familial insomnia (FFI) became evident over the next 6 months when he developed progressive insomnia, myoclonus, sympathetic hyperactivity, and dementia. The amyloid or prion protein (PrP) genotype showed features typically seen in FFI, with a 178Asn mutation and a 129Met polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178Asn mutation with the 129Met polymorphism is not due to "founder effect." Western immunoblot showed a trace of protease-resistant PrP in the thalamus--which had the most significant neuronal loss and gliosis--a moderate amount of PrP in the fronto-temporal area, and no detectable protein elsewhere in the brain. Endocrine studies showed that a circadian modulation of hormonal levels could be maintained despite a near-total absence of sleep. Administration of gamma-hydroxybutyrate induced a remarkable increase in slow-wave sleep.

A case of fatal familial insomnia in Africa

“…Remarkably our patient carried a mutated allele that was identical with that reported by Bosque et al [1] and Reder et al [6]. In these cases a rare combination of the D178N mutation/M 129 haplotype with the 24-bp deletion R3/R4, a rare (1-3% in frequency in the normal population [2]) genetic polymorphism, was found on the same allele.…”

“…In these cases a rare combination of the D178N mutation/M 129 haplotype with the 24-bp deletion R3/R4, a rare (1-3% in frequency in the normal population [2]) genetic polymorphism, was found on the same allele. This could mean that the family described by Bosque et al [1] and Reder et al [6] and our patient's family all share a common, remote, ancestor. This is the first description of an African family with FFI, which supports the worldwide distribution of the disease and demonstrates that, despite differences, the clinical features of the disease are similar in subjects with different genetic background.…”

Novel twelve-generation kindred of fatal familial insomnia from Germany representing the entire spectrum of disease expression

“…Furthermore, homo-or heterozygosity of codon 129 is supposed to influence the age of disease onset, its duration, and phenotypic expression [Gambetti et al, 1995;Goldfarb et al, 1992a;Reder et al, 1995]. We report on an extensive German kindred of 12 generations comprising more than 800 individuals and approximately 200 living potential carriers with affected patients exhibiting the mutation D178N segregating with 129M at the polymorphic site.…”

“…However, familial CJD and FFI, show considerable phenotypic variation even within a family or a sibship. The D178N mutation of PRNP has been described in 9 families of CJD [Goldfarb et al, 1992a[Goldfarb et al, , 1992bBosque et al, 1992;Kretzschmar et al, 1995] and in about 20 families and one further possibly sporadic case with FFI phenotype [Lugaresi et al, 1986;Medori et al, 1992;Petersen et al, 1992;Medori and Tritschler, 1993;Reder et al, 1995;Silburn et al, 1996;Nagayama et al, 1996;Colombier et al, 1997;McLean et al, 1997;Rossi et al, 1998] in worldwide distribution. The clinical and neuropathological differences between fCJD and FFI both caused by the same D178N mutation have been attributed to the 129M/V polymorphism [Goldfarb et al, 1992a] which was found to be associated with different isoforms of proteinase resistant prion protein (PrP res ) in fCJD and FFI patients [Monari et al, 1994].…”

Sleep and Sleep Regulation in Normal and Prion Protein-Deficient Mice

“…In FFI, there is a severe reduction of sleep, a gradual disappearance of spindle activity in the sleep EEG Reder et al, 1995;Sforza et al, 1995), and a disruption of hormone rhythms (Portaluppi et al, 1994(Portaluppi et al, , 1995Montagna et al, 1995). The main neurological features include hypometabolism, loss of neurons, and astrogliosis, with the first and most severe neuropathology appearing in the thalamus .…”