title: Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.
abstract: Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.
authors.affiliation: Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: P
authors.initials: P
authors.lastname: Parchi
authors.forename: A
authors.initials: A
authors.lastname: Giese
authors.forename: S
authors.initials: S
authors.lastname: Capellari
authors.forename: P
authors.initials: P
authors.lastname: Brown
authors.forename: W
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: O
authors.initials: O
authors.lastname: Windl
authors.forename: I
authors.initials: I
authors.lastname: Zerr
authors.forename: H
authors.initials: H
authors.lastname: Budka
authors.forename: N
authors.initials: N
authors.lastname: Kopp
authors.forename: P
authors.initials: P
authors.lastname: Piccardo
authors.forename: S
authors.initials: S
authors.lastname: Poser
authors.forename: A
authors.initials: A
authors.lastname: Rojiani
authors.forename: N
authors.initials: N
authors.lastname: Streichemberger
authors.forename: J
authors.initials: J
authors.lastname: Julien
authors.forename: C
authors.initials: C
authors.lastname: Vital
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
authors.forename: P
authors.initials: P
authors.lastname: Gambetti
authors.forename: H
authors.initials: H
authors.lastname: Kretzschmar
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D007562:Creutzfeldt-Jakob Syndrome / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D004569:Electroencephalography; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010641:Phenotype