Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.)
This article includes discussion of fatal familial insomnia and sporadic fatal insomnia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
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 diplopia, pyramidal signs, myoclonus, dysarthria or dysphagia, and ataxia. PET shows marked thalamic hypometabolism, and neuropathology invariably 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.
• The pathological hallmark of fatal familial insomnia is severe loss of thalamic neurons and gliosis, especially marked in the mediodorsal and anterior nuclei, and inferior olivary atrophy.
• 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.
• 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 (Lugaresi et al 1986). In 1992 fatal familial insomnia was proven to be a prion disease linked to a mutation at codon 178 of the prion protein gene (Medori et al 1992). 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 2 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 (Goldfarb et al 1992). 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 (Gambetti et al 1995; Montagna et al 1998). Fatal familial insomnia and CJD178 also differ in the size and shape of the PRNP (PrPSc) (Monari et al 1994). First recognized in an Italian family, fatal familial insomnia has been shown to have a worldwide distribution (Padovani et al 1998; Harder et al 1999; Tabernero et al 2000; Spacey et al 2004; Baldin et al 2009; Shi et al 2010; Jansen et al 2011; Pedroso et al 2013). 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 (Rodriguez-Martinez et al 2008). The sporadic form of fatal familial insomnia, or sporadic fatal insomnia, also has been described (Mastrianni et al 1999; Parchi et al 1999; Scaravilli et al 2000). 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 (Capellari et al 2008).
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