title: Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy.
abstract: The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, α-synuclein, and amyloid-β has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrP(res) detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-β in 53.8%, amyloid angiopathy (Aβ) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type α-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins.
authors.affiliation: Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, AKH 4J, Währinger Gürtel 18-20, 1097, Vienna, Austria. gabor.kovacs@meduniwien.ac.at
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Jérémie
authors.initials: J
authors.lastname: Seguin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quadrio
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.forename: István
authors.initials: I
authors.lastname: Kapás
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.forename: Anne Gaëlle
authors.initials: AG
authors.lastname: Biacabe
authors.forename: David
authors.initials: D
authors.lastname: Meyronet
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Katalin
authors.initials: K
authors.lastname: Majtenyi
authors.forename: Lajos
authors.initials: L
authors.lastname: László
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.forename: Armand
authors.initials: A
authors.lastname: Perret-Liaudet
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*
chemical_list: C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D018698:Glutamic Acid; D008239:Lysine