Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects
✍ Scribed by Piero Parchi; Armin Giese; Sabina Capellari; Paul Brown; Walter Schulz-Schaeffer; Otto Windl; Inga Zerr; Herbert Budka; Nicolas Kopp; Pedro Piccardo; Sigrid Poser; Amyn Rojiani; Nathalie Streichemberger; Jean Julien; Claude Vital; Bernardino Ghetti; Pierluigi Gambetti; Hans Kretzschmar
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 330 KB
- Volume
- 46
- Category
- Article
- ISSN
- 0364-5134
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✦ Synopsis
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.