Sporadic fatal insomnia in a fatal familial insomnia pedigree.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of neurodegenerative disorders which uniquely comprise sporadic, genetic, and acquired forms.1 According to the leading theory, genetic TSEs are caused by mutations in the prion protein gene (PRNP), the acquired forms derive from an exogenous prion infection, while the sporadic forms arise spontaneously, as a consequence of a somatic mutation or a stochastic metabolic event. At least six phenotypic subtypes of sporadic human TSEs exist, which has been shown to correlate with both the genotype at polymorphic PRNP codon 129 and either one of two types of abnormal prion protein (PrPSc) with distinct physicochemical properties.2 The phenotypic variability of genetic TSEs broadly reproduces that of the sporadic form, although the relative incidence of each subtype varies considerably in the two forms. The fatal insomnia (FI) phenotype, for example, is the third most frequent genetic prion disease but the rarest of the sporadic TSE subtypes, with only 15 cases diagnosed worldwide.1,3 Given their rarity and supposedly distinct etiology, the occurrence of distinct TSE forms among genetically related individuals is not expected. Here we describe the co-occurrence of both sporadic and genetic forms of FI within the same family