Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

TLDR

Phenotypic heterogeneity in sporadic Creutzfeldt‑Jakob disease is well documented, yet no systematic classification of its variants exists. The study aimed to define the full spectrum of sCJD variants by examining 300 patients. Clinical features, PRNP genotype, PrP(Sc) properties, neuropathology, and immunohistochemistry were assessed in all subjects. Six phenotypic variants were identified: 70 % classic CJD (PrP(Sc) type 1, methionine allele), 25 % ataxic/kuru‑plaque (PrP(Sc) type 2, valine homo/hetero), two additional thalamic and dementia‑cortical variants (PrP(Sc) type 2, methionine homo), and a rare progressive‑dementia variant (PrP(Sc) type 1, valine homo), showing that PrP(Sc) physicochemical properties combined with PRNP codon 129 genotype largely determine phenotypic variability and enable molecular classification.

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.