CONCLUSIONS OF THE SYMPOSIUM

On the basis of twenty-one kindreds and three cases from uninformative families, the Symposium has confirmed that fatal familial insomnia (F FI) is genotypically and phenotypically distinct and, likely, the thir d most common inherited prion disease, The genotype, characterized by the D178N mutation on the prion protein (PrP) gene coupled with the me thionine codon at position 129 has been demonstrated in all cases. The immunoblot pattern of the PrPres associated with FFI shows a molecula r mass of approximately 19kDa for the core protein and a marked underr epresentation of the unglycosylated form. The histopathology, characte rized by marked thalamic and inferior olivary atrophy with a variable degree of cerebral cortical spongiosis has been observed in all but tw o cases, The disease duration was found to be significantly shorter in the FFI subjects homzygous at codon 129 than in the heterozygous subj ects. The FFI sleep disorder is characterized by lack of spindle activ ity and disruption of the wake-sleep cycle which can only be establish ed, or excluded, by polysomnography, Autonomic, endocrine and cognitiv e impairments also require careful assessment in each case, A conditio n lacking the D178N mutation and pathologically identical to FFI has b een reported, Presence of sleep, autonomic and endocrine abnormalities needs to be demonstrated to identify this condition as a sporadic for m of FFI, The pathophysiology of the sleep disorder, the pathogenic me chanisms, fine and early structural changes, including the role of apo ptosis, and disease penetrance are the major unresolved issues in FFI.