title: A novel PRNP Y218N mutation in Gerstmann-Sträussler-Scheinker disease with neurofibrillary degeneration.
abstract: Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrP(res)), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrP deposits, and expression of mutant ubiquitin (UBB(+1)) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.
authors.affiliation: Instituto de Investigación Sanitaria BioDonostia, Hospital Donostia, San Sebastian, Spain. ainhoa.alzualdezuloaga@osakidetza.net
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Alzualde
authors.forename: Begoña
authors.initials: B
authors.lastname: Indakoetxea
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Fermin
authors.initials: F
authors.lastname: Moreno
authors.forename: Myriam
authors.initials: M
authors.lastname: Barandiaran
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.forename: Ainara
authors.initials: A
authors.lastname: Estanga
authors.forename: Irune
authors.initials: I
authors.lastname: Ruiz
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
authors.forename: Begoña
authors.initials: B
authors.lastname: Atares
authors.forename: Ramón
authors.initials: R
authors.lastname: Juste
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Rodriguez-Martínez
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
mesh_terms: D001216:Asparagine / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005192:Family Health; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications / Q000235:genetics*; D016098:Gerstmann-Straussler-Scheinker Disease / Q000150:complications / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D025801:Ubiquitin; D050994:Voltage-Dependent Anion Channels; D014443:Tyrosine; D001216:Asparagine