Elsevier

The Lancet Neurology

Volume 2, Issue 3, March 2003, Pages 167-176
The Lancet Neurology

Review
Familial and sporadic fatal insomnia

https://doi.org/10.1016/S1474-4422(03)00323-5Get rights and content

Summary

Familial fatal insomnia (FFI)—a hereditary prion disease caused by a mutation at codon 178 of the prion-protein (PrP) gene (PRNP) that leads to a D178N substitution in the protein—and its sporadic form, sporadic fatal insomnia (SFI), have similar disease phenotypes. Both disorders have clinical features of disrupted sleep (loss of sleep spindles and slow-wave sleep and enacted dreams during rapid-eye-movement sleep), autonomic hyperactivation, and motor abnormalities (myoclonus, ataxia, dysarthria, dysphagia, and pyramidal signs). PET shows pronounced thalamic and limbic hypometabolism that becomes more widespread in later stages. Neuropathological assessment reveals severe neuronal loss and astrogliosis of the anterior medial thalamus and inferior olives, with later cerebral cortical and cerebellar involvement. Accumulation of an isoform of protease-resistant PrP fragment in FFI distinct from that found in a familial form of Creutzfeldt-Jakob disease with the same D178N mutation, shows the effect of the polymorphism at codon 129 of PRNP on phenotypic expression and the possibility of distinct prion “strains” with diverse pathological potential. Intriguing clinicopathological correlations in FFI and SFI suggest a role for the thalamolimbic system in the regulation of sleep and other circadian functions.

Section snippets

Clinical features of FFI

FFI affects both sexes equally in an autosomal dominant manner with (probable) high penetrance. Onset is between 36 years and 62 years of age (mean 51 years [SD 7·1]). FFI is uniformly fatal. The disease duration, defined from the onset of insomnia, varies from 8 months to 72 months (mean 18·4 months [SD 17·3]). Patients in the original pedigrees died after either a short (8–11 months; mean 9·1 months [SD 1·1]) or a long (11–72 months; mean 30·8 months [SD 21·3]) disease course.14 Most patients

Pathophysiology of FFI

FFI has led to interesting speculations and opened new avenues in clinical science because, as a disease, it lies at the intersection of two areas of scientific research: the complex and still unclear pathophysiology of the prion diseases and the mechanisms of regulation of sleep and circadian rhythms. These special characteristics have made FFI an intriguing and even controversial issue.

Unsolved issues in FFI

The study of FFI has yielded important insights into several areas of neurological investigation including the relevance of the thalamus and related limbic cortical areas in the control of autonomic and circadian rhythms and the concept of agrypnia excitata. This research has further widened the clinical and pathological range of prion diseases and introduced a novel molecular mechanism of disease inheritance and phenotypic variability of a genetic disease with the first identification of human

Search strategy and selection criteria

Data for this review were obtained from our personal files and searches of Medline, Current Contents, and references from relevant articles. Search terms were “fatal familial insomnia”, “prion” and “Creutzfeldt-Jakob disease (CJD)”. All abstracts and full papers related to the topic were assessed. We included data from 1986, when FFI was first described, to the present. Papers published in English and French were reviewed.

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