A NOVEL MECHANISM OF PHENOTYPIC HETEROGENEITY DEMONSTRATED BY THE EFFECT OF A POLYMORPHISM ON A PATHOGENIC MUTATION IN THE PRNP (PRION PROTEIN GENE)

Fatal familial insomnia (FFI) is a subacute dementing illness original ly described in 1986. The phenotypic characteristics of this disease i nclude progressive untreatable insomnia, dysautonomia, endocrine and m otor disorders, preferential hypometabolism in the thalamus as determi ned by PET scanning, and selective thalamic atrophy. These characteris tics readily distinguish FFI from other previously described neurodege nerative conditions. Recently, FFI was shown to be linked to a mutatio n in the prion protein gene (PRNP) at codon 178, which results in the substitution of asparagine for aspartic acid. As such, FFI represents the most recent addition to the growing family of prion protein-relate d diseases. The mutation that results in FFI had previously been linke d to a subtype of familial Creutzfeld-Jakob disease (178(Asn) CJD). Th e genotypic basis for the difference between FFI and 178(Asn)CJD lies in a polymorphism at codon 129 of the mutant prion protein gene: 129(M et) 178(Asn) results in FFI, 129(Val) 178(Asn) in CJD, The finding tha t the combination of a polymorphism and a single pathogenic mutation r esult in two distinct conditions represents a significant advance in o ur understanding of phenotypic variability.