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.

Creutzfeldt-Jakob disease in a young person with valine homozygosity at codon 129: sporadic or variant?

“…Neuropathological review of these two earlier cases has found changes in the brain consistent with sporadic CJD; full clinical and genetic data are not available on these cases, but neither showed evidence of PrP RES accumulation in lymphoid tissues. The lack of characteristic neuropathology of vCJD in the brain, the absence of detectable PrP in the tonsil appendix and spleen, together with a PrP RES type 1 pattern in the cerebral cortex all provide supportive evidence for this being a case of sporadic CJD, similar to the other rare cases occurring in valine homozygotes with a type 1 PrP RES 3. A less likely explanation is that this case may represent bovine spongioform encephalopathy (BSE) infection in a valine homozygous person without the characteristic pattern of PrP glycosylation occurring in BSE and related disorders in animals and humans 5.…”

Patients with Alzheimer's disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease

“…According to Parchi et al ,35 in sporadic CJD disease different subtypes exist. As described in detail by Zerr et al ,36 the typical clinical phenotype with rapidly progressive dementia, myoclonus and typical EEG and CSF findings is present in about 70% of patients with CJD.…”

“…As described in detail by Zerr et al ,36 the typical clinical phenotype with rapidly progressive dementia, myoclonus and typical EEG and CSF findings is present in about 70% of patients with CJD. In 10% of cases of CJD, disease duration is longer and patients often show extrapyramidal signs (MV2 subtype35 37). In these patients EEG does not show CJD typical PSWCs and testing for protein 14–3–3 yields inconsistant results 36.…”

The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype

“…Based on the size of the protease-resistant core fragment, several isoforms of PrP Sc can be recognised by immunoblotting,4 most commonly a type 1 (21 kDa) or a type 2 isoform (19 kDa). The currently accepted classification for sporadic Creutzfeldt-Jakob disease (sCJD) combines the PrP Sc isotype with the presence of either methionine or valine at codon 129 of the prion protein to define six molecular subtypes that correspond to distinct clinical and neuropathological phenotypes 5. A smaller fragment of protease-resistant PrP Sc (7–8 kDa) is found in patients with Gerstmann-Sträussler-Scheinker disease (GSS), a genetic form of prion disease 6…”