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 (FFI) is genotypically and phenotypically distinct and, likely, the third most common inherited prion disease. The genotype, characterized by the D178N mutation on the prion protein (PrP) gene coupled with the methionine codon at position 129 has been demonstrated in all cases. The immunoblot pattern of the PrPres associated with FFI shows a molecular mass of approximately 19kDa for the core protein and a marked underrepresentation of the unglycosylated form. The histopathology, characterized by marked thalamic and inferior olivary atrophy with a variable degree of cerebral cortical spongiosis has been observed in all but two cases. The disease duration was found to be significantly shorter in the FFI subjects homozygous at codon 129 than in the heterozygous subjects. The FFI sleep disorder is characterized by lack of spindle activity and disruption of the wake-sleep cycle which can only be established , or excluded, by polysomnography. Autonomic, endocrine and cognitive impairments also require careful assessment in each case. A condition lacking the D178N mutation and pathologically identical to FFI has been reported. Presence of sleep, autonomic and endocrine abnormalities needs to be demonstrated to identify this condition as a sporadic form of FFI. The pathophysiology of the sleep disorder, the pathogenic mechanisms, fine and early structural changes, including the role of apoptosis, and disease penetrance are the major unresolved issues in FFI.
Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
P
P
Gambetti
E
E
Lugaresi
D001342:Autonomic Nervous System Diseases / Q000503:physiopathology; D001921:Brain / Q000473:pathology; D006801:Humans; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000635:transmission; D011328:Prions / Q000235:genetics / Q000472:pathogenicity; D012893:Sleep Wake Disorders / Q000503:physiopathology
D011328:Prions