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.