CLINICAL AND GENETIC-STUDIES OF FATAL FAMILIAL INSOMNIA

We report a 42-year-old man who, for 8 months, had intermittent motor abnormalities and mild difficulty falling asleep. A diagnosis of fatal familial insomnia (FFI) became evident over the next 6 months when he developed progressive insomnia, myoclonus, sympathetic hyperactivity, and dementia. The amyloid or prion protein (PrP) genotype showed features typically seen in FFI, with a 178(Asn) mutation and a 129(Met) polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178(Asn) mutation with the 129(Met) polymorphism is not due to a ''founder effect.'' Western immunoblot showed a trace of protease-resistant PrP in the thalamus-which had the most significant neuronal loss and gliosis-a moderate amount of PrP in the fronto-temporal area, and no detectable protein elsewhere in the brain. Endocrine studies showed that a circadian modulation of hormonal levels could be maintained despite a near-total absence of sleep. Administration of gamma-hydroxybutyrate induced a remarkable increase in slow-wave sleep.