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Fatal familial insomnia (FFI) is a rare prionopathy with unusually high incidence in the Basque Country. We report detailed data on clinical, diagnostic, histopathological, and biochemical characteristics of a recent FFI case series. The Basque Brain Bank database was screened for patients diagnosed from 2010 to 2021 with standard genetic and/or neuropathological criteria. This series includes 16 patients, 25% without family history, with 12 cases from 9 unrelated (but geographically-linked, Basque country) kindreds, onset ranging from 36 to 70 years, and disease course from 7 to 11.5 months. Insomnia was the initial symptom in most cases, with consistent polysomnography in 92% of the cases. In contrast, 14-3-3 and RT-QuIC from cerebrospinal fluid were negative. Most patients were homozygous for methionine. Gliosis and neuronal loss in basal ganglia and thalamus were the main histopathological findings; Western blotting identified preferentially the protease-resistant prion protein (PrPres) type 2, although detection of the scrapie isoform of the prion protein (PrPSc) identified using brain tissue RT-QuIC was more successful. This is one of the largest current studies on FFI patients performed to provide improvements in diagnostic reliability. Among the analyzed tests, polysomnography and the genetic study show the highest diagnostic value in FFI.

Background: Sporadic Creutzfedlt-Jakob disease is a rapidly progressing and highly variable neurodegenerative disease with heterogeneous clinical presentation and with median survival times from diagnosis to death of four to six months. Methods: We report a rare case of a 61-year-old woman with a history of initially rapidly progressive dementia, with subsequent development of pyramidal and extrapyramidal signs and with unusually long survival period of 14 years. Initial magnetic resonance imaging evaluation, single-photon emission computed tomography and electroencephalogram did not show relevant alterations. Results: The postmortem examination of the brain showed diffuse spongiform change, gliosis, and neuronal loss along with abnormal immunostaining of prion protein in the grey matter, especially in the cerebellum. Indirect PRNP genetic analysis was negative. Conclusions: This case is, to our knowledge, the sporadic Creutzfeldt-Jakob disease patient with the longest survival period ever documented. This surprisingly long duration highlights the importance of histopathological confirmation with brain autopsies for suspected cases, as the disease can be easily misdiagnosed when dealing with such slowly progressing cases.