Fatal familial insomnia is a prion disease characterized by loss of sleep, oneiric stupors with dream enactment, autonomic activation, and somatomotor abnormalities. The latter may include oculomotor abnormalities, pyramidal signs, myoclonus, dysarthria or dysphagia, and ataxia. PET shows marked thalamic hypometabolism, and neuropathology typically reveals a moderate to severe neuronal loss and gliosis in the anteromedial thalamic and inferior olivary nuclei. The disease is usually linked to the D178N mutation in the PRNP gene co-segregating with methionine at the polymorphic codon 129. However, sporadic cases of fatal insomnia, lacking the PRNP mutation, may also occur. Fatal familial insomnia represents a model disease for the study of sleep, emphasizing the role of the thalamo-limbic circuits in sleep regulation.
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• Fatal familial insomnia is a hereditary prion disease characterized by progressive loss of deep sleep, abnormal REM sleep, dysautonomia, and motor signs.
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• The pathological hallmark of fatal familial insomnia is typically severe loss of thalamic neurons and gliosis, especially marked in the mediodorsal and anterior nuclei, and inferior olivary atrophy.
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• Fatal familial insomnia patients carry a mutation at codon 178 of the prion protein gene, coupled with methionine at the polymorphic codon 129 in the mutated allele.
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• Rare patients with sporadic fatal insomnia display the same clinicopathological features of fatal familial insomnia in the absence of the prion protein gene mutation.
Historical note and terminology
Fatal familial insomnia is an autosomal dominant neurodegenerative disease that was originally described in 1986. It is clinically characterized by progressive impairment of the ability to sleep, dysautonomia, and motor signs, whereas its pathological hallmark is the preferential thalamic and olivary degeneration, which invariably involves the anteroventral and mediodorsal thalamic nuclei (45). In 1992 fatal familial insomnia was proven to be a prion disease linked to a mutation at codon 178 of the prion protein gene (52). The same 178 mutation is also linked to a familial prion disease with a phenotype similar to that of Creutzfeldt-Jakob disease (CJD178). The common methionine/valine polymorphism at codon 129 of PRNP determines the phenotypes associated with the two diseases. Indeed, although fatal familial insomnia is invariably linked to the presence of the methionine codon at position 129 of the mutant allele, CJD178 is linked to the presence of the valine codon at that position (26). Fatal familial insomnia is characterized by slightly different clinical and pathological features also according to the codon 129 genotype in the normal wild-type allele that determines whether patients are methionine homozygous or methionine and valine heterozygous (25; 56). Fatal familial insomnia and CJD178 also differ in the size and shape of the PRNP (PrPSc) (55). First recognized in an Italian family, fatal familial insomnia has been shown to have a worldwide distribution (58; 31; 79; 77; 05; 76; 36; 62). Two distinct haplotypes have been shown to be potentially associated with the D178N mutation in European families, suggesting the occurrence of at least 2 independent D178N-129M mutational events in Europe, preserved and transmitted from one generation to the next until now (69). The sporadic form of fatal familial insomnia, or sporadic fatal insomnia, also has been described (51; 59; 73; 01). Remarkably, sporadic fatal insomnia has also been reported in a fatal familial insomnia pedigree, a rather unlikely occurrence and one that highlights the questions still existent about the pathophysiology of the prion diseases (10).