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Clinical and genetic studies of fatal familial insomnia

From the Departments of Neurology (Drs. Reder, Mednick, Spire, Garay, and Roos), Pathology (Dr. Wollmann), Medicine (Dr. Van Cauter), and Psychia. try (Dr. Ovsiew), University of Chicago School of Medicine, Chicago, IL, and the Laboratory of Central Nervous System Studies (Drs. Brown, Cer venàkovà, Goldfarb, and Gajdusek), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Article abstract—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 12g^Met polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178^Asn mutation with the 12g^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.

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