Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges
ANNALS OF NEUROLOGY
Authors: Abu-Rumeileh, Samir; Redaelli, Veronica; Baiardi, Simone; Mackenzie, Graeme; Windl, Otto; Ritchie, Diane L.; Didato, Giuseppe; Hernandez-Vara, Jorge; Rossi, Marcello; Capellari, Sabina; Imperiale, Daniele; Rizzone, Mario Giorgio; Belotti, Alessia; Sorbi, Sandro; Rozemuller, Annemieke J. M.; Cortelli, Pietro; Gelpi, Ellen; Will, Robert G.; Zerr, Inga; Giaccone, Giorgio; Parchi, Piero
ObjectiveComprehensively describe the phenotypic spectrum of sporadic fatal insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder. MethodsA survey among major prion disease reference centers in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features and the results of diagnostic investigations. ResultsMean age at onset was 43 years, and mean disease duration 30 months. Early clinical findings included psychiatric, sleep, and oculomotor disturbances, followed by cognitive decline and postural instability. In all tested patients, video-polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. Cerebrospinal fluid (CSF) levels of proteins 14-3-3 and t-tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real-time quaking-induced conversion assay (RT-QuIC) revealed a positive prion seeding activity in 60% of cases. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases. InterpretationsFI is a disease of young or middle-aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age-related PrP misfolding. The combination of psychiatric and/or sleep-related symptoms with oculomotor abnormalities represents an early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video-polysomnography, FDG-PET, and especially CSF prion RT-QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. Ann Neurol 2018;84:347-360
Genotypes of prion protein gene in sheep with atypical scrapie in Slovenia
SLOVENIAN VETERINARY RESEARCH
Authors: Piano, Jelka Zabavnik; Cotman, Marko; Ambrozic, Ivan; Juntes, Polona
Atypical scrapie is a form of transmissible spongiform encephalopathy (TSE). It is observed in most European countries and represents a growing proportion of detected scrapie cases in sheep. Ovine atypical scrapie was established in Slovenia for the first time in 2010 after introduction of the test that was sensitive enough to detect the form of prions characteristic for atypical scrapie. From the beginning of 2010 to the end of March 2016 we tested for scrapie 8633 sheep and confirmed 10 cases of atypical scrapie. Susceptibility to classical and atypical form of scrapie is at least partly genetically determined. It is known that sheep with the prion protein gene (Prnp) genotype ARR/ARR are the most resistant to the development of classical form of scrapie, the sheep with the genotype VRQ/VRQ are the most susceptible. Conversely, atypical scrapie often occurs in sheep with ARR allele and rarely in sheep carrying the VRQ allele. In addition, development of the disease is significantly affected by the amino acid at position 141 of the prion protein (fenilalanin or leucin). Comparison of Prnp genotypes of sheep with atypical scrapie to genotypes of 1,680 randomly selected dead sheep showed that atypical scrapie does not occur in sheep carrying alleles VLRQ and ALRH. It was detected in sheep with allele AFRQ, although in Slovenia proportion of ewes with this allele is small (1.14% of the sample of sheep) and in animals with allele ALHQ. Only a small proportion of diseased sheep had allele ALRR and ALRQ. Allele ALHQ in Slovenia occurs in 6.5% of sheep, so we can expect that the atypical scrapie would occur in our sheep population.