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Research paper
Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene
  1. Anna Poleggi1,
  2. Sven van der Lee2,
  3. Sabina Capellari3,4,
  4. Maria Puopolo1,
  5. Anna Ladogana1,
  6. Eleonora De Pascali1,
  7. Debora Lia1,
  8. Alessia Formato1,
  9. Anna Bartoletti-Stella3,4,
  10. Piero Parchi3,5,
  11. Cornelia van Duijn2,6,
  12. Maurizio Pocchiari1
  1. 1 Department of Neuroscience, Istituto Superiore di Sanità, Roma, Italy
  2. 2 Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3 IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
  4. 4 Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
  5. 5 Department of Diagnostic Experimental and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
  6. 6 Translational Epidemiology, Faculty Science, Leiden University, Leiden, The Netherlands
  1. Correspondence to Professor Maurizio Pocchiari, Department of Neuroscience, Istituto Superiore di Sanità, Roma 00161, Italy; maurizio.pocchiari{at}


Objectives The Glu to Lys change at codon 200 (E200K) of the PRNP gene is the most frequent mutation associated to genetic Creutzfeldt-Jakob disease (CJD) and the only one responsible for geographical clusters. Patients carrying this mutation develop disease at different ages and show variable clinical phenotypes that are not affected by the methione/valine polymorphism at codon 129 of the PRNP gene suggesting the influence of other factors. The objective of this study is to look for genes other than PRNP that might be responsible of this variability.

Methods We searched for other genes by performing genome-wide analyses (GWA) on 19 patients with genetic CJD and 18 healthy subjects carrying the E200K mutation of PRNP and belonging to the Calabrian cluster in Italy. We then validate this result in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD referred to the Italian CJD national registry.

Results and conclusions We identified two single nucleotide polymorphisms on the CYP4X1 gene locus as candidate disease modifiers in patients with E200K CJD of the cluster area and confirmed this finding in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD. Our results indicate that the CYP4X1 gene modulates the onset of disease in patients with E200K genetic and sporadic CJD. This finding improves our understanding on the pathogenesis of CJD, suggests new targets for developing novel therapeutic strategies and might be useful for the stratification of patients in future preventive treatment trials.

  • Creutzfeldt-Jakob disease
  • GWA study

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  • Contributors AP and MPo contributed to the planning, conduct and reporting of the work; SvdL and EDP to conduct the genome-wide study; DL and AF to conduct the validation study; SC and ABS to conduct expression studies; AL to collect clinical data, blood samples and interpret the results; MPu to conduct statistical analyses; PP, to conduct PrPsc glycotyping; CvD and PP to critically revised the manuscript. MPo is responsible for the overall content as guarantor.

  • Funding This work was partially supported by the Ministero della Salute, Italy, for the national surveillance of Creutzfeldt-Jakob disease.

  • Competing interests None declared.

  • Patient consent Next of kin consent obtained.

  • Ethics approval Ethic Committee, Istituto Superiore di Sanità, Rome, Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data are in the submitted paper.

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