THE D178N (CIS-129M) FATAL FAMILIAL INSOMNIA MUTATION ASSOCIATED WITHDIVERSE CLINICOPATHOLOGICAL PHENOTYPES IN AN AUSTRALIAN KINDRED

Fatal familial insomnia (FFI) is an inherited prion disease characteri zed by progressive insomnia and dysautonomia with only modest cognitiv e impairment early in the disease, associated with atrophy and gliosis in the medial thalamus, but without: spongiform change. FFI is associ ated with an aspartic acid to asparagine mutation at codon 178 of the PrP gene (D178N) in conjunction with methionine at the codon 129 polym orphic site on the mutant allele (cis-129M). We report a pedigree with this genotype in which marked clinicopathologic phenotypic heterogene ity occurred including typical Creutzfeldt-Jakob disease, FFI; and wha t was thought to be an autosomal dominant cerebellar ataxia (ADCA)-lik e illness, suggesting that the genotype-phenotype correlation is not a s tight for this mutation as is frequently supposed.