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

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

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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.

Original languageEnglish (US)
Pages (from-to)224-233
Number of pages10
JournalAnnals of Neurology
Volume46
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

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Codon
Valine
Phenotype
Methionine
Dementia
Kuru
PrPSc Proteins
Genotype
Genes
Creutzfeldt-Jakob Syndrome
Peptide Hydrolases
Alleles
Pathology
Sporadic Creutzfeldt-Jakob Disease
Prion Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. / Parchi, Piero; Giese, Armin; Capellari, Sabina; Brown, Paul; Schulz-Schaeffer, Walter; Windl, Otto; Zerr, Inga; Budka, Herbert; Kopp, Nicolas; Piccardo, Pedro; Poser, Sigrid; Rojiani, Amyn; Streichemberger, Nathalie; Julien, Jean; Vital, Claude; Ghetti, Bernardino; Gambetti, Pierluigi; Kretzschmar, Hans.

In: Annals of Neurology, Vol. 46, No. 2, 1999, p. 224-233.

Research output: Contribution to journalArticle

Parchi, P, Giese, A, Capellari, S, Brown, P, Schulz-Schaeffer, W, Windl, O, Zerr, I, Budka, H, Kopp, N, Piccardo, P, Poser, S, Rojiani, A, Streichemberger, N, Julien, J, Vital, C, Ghetti, B, Gambetti, P & Kretzschmar, H 1999, 'Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects', Annals of Neurology, vol. 46, no. 2, pp. 224-233. https://doi.org/10.1002/1531-8249(199908)46:2<224::AID-ANA12>3.0.CO;2-W
Parchi, Piero ; Giese, Armin ; Capellari, Sabina ; Brown, Paul ; Schulz-Schaeffer, Walter ; Windl, Otto ; Zerr, Inga ; Budka, Herbert ; Kopp, Nicolas ; Piccardo, Pedro ; Poser, Sigrid ; Rojiani, Amyn ; Streichemberger, Nathalie ; Julien, Jean ; Vital, Claude ; Ghetti, Bernardino ; Gambetti, Pierluigi ; Kretzschmar, Hans. / Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. In: Annals of Neurology. 1999 ; Vol. 46, No. 2. pp. 224-233.
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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.",
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T1 - Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

AU - Parchi, Piero

AU - Giese, Armin

AU - Capellari, Sabina

AU - Brown, Paul

AU - Schulz-Schaeffer, Walter

AU - Windl, Otto

AU - Zerr, Inga

AU - Budka, Herbert

AU - Kopp, Nicolas

AU - Piccardo, Pedro

AU - Poser, Sigrid

AU - Rojiani, Amyn

AU - Streichemberger, Nathalie

AU - Julien, Jean

AU - Vital, Claude

AU - Ghetti, Bernardino

AU - Gambetti, Pierluigi

AU - Kretzschmar, Hans

PY - 1999

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N2 - 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.

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