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Surveillance of Human Prion Diseases

1st Italian Family Day on Prion Diseases. Milan, October 3, 2009. Surveillance of Human Prion Diseases. Maurizio Pocchiari Dpt. Cell Biology and Neurosciences E-mail:maurizio.pocchiari@iss.it. Surveillance of Human Prion Diseases.

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Surveillance of Human Prion Diseases

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  1. 1st Italian Family Day on Prion Diseases Milan, October 3, 2009 Surveillance of Human Prion Diseases Maurizio Pocchiari Dpt. Cell Biology and Neurosciences E-mail:maurizio.pocchiari@iss.it

  2. Surveillance of Human Prion Diseases

  3. Overall distribution of TSE diseases in humans(Data from the EuroCJD and NeuroCJD Surveillance)

  4. Sporadic CJD is • is not related to any recognizable risk factor , • is evenly distributed, with no significant temporal or spatial cluster, • is not linked to any strong genetic background. • In other words, we have no clue as to how and why some people develop sporadic CJD • The only two identified weak risk factors are • the presence of methionine homozygosity at codon 129 of the prion protein gene (PRNP) , • age greater than 60 years

  5. Identified risk factors for sporadic CJD Codon 129 polymorphism Age-specific mortality rates in Italy Accidental transmission of sporadic CJD might occur during surgery, with an incubation period exceeding 10 years.

  6. Sporadic CJD and prevention • Prevention of sporadic CJD will be difficult to achieve. • But, it is not linked to any professional activity and is not transmissible from person to person during care of patients, laboratory testing, or social or sexual contact. • The observed increase in cases occasionally reported in some regions is difficult to explain, but it likely represents better case identification by local neurologists.

  7. Iatrogenic CJD in EUROCJD To date, >400 patients with iatrogenic CJD (dura mater grafts, hGH, corneal transplants, contaminated neurosurgical instruments, or i.c. EEG electrodes ) have been reported worldwide

  8. Genetic TSE diseases gCJD FFI GSS From: Wadsworth et al., 2003

  9. Genetic TSE diseases in theEUROCJD contries

  10. Frequency of genetic TSE in the EUROCJD countries gCJD FFI GSS

  11. Frequency of positive family history for genetic TSE gCJD FFI GSS

  12. No familial cases of CJD were found in our series

  13. PRNP genotype in all suspected cases

  14. TSE in Italy(1993-2008) °18.5% of total cases (No.=1087)

  15. PRNP Mutations Identified in Italy Glu --> Lys at codon 200 CJD Glu --> Lys at codon 196 CJD Val --> Ile at codon 203 CJD Arg --> His at codon 208 CJD Val --> Ile at codon 210 CJD Glu --> Gln at codon 211 CJD Asp --> Asn at codon 178/val CJD Asp --> Asn at codon 178/met FFI Pro --> Leu at codon 102 GSS Inserts (1,4,7,8) in the octapeptide repeat region

  16. E200K and V210I genetic CJD • Cluster • Originof the E200K and V210I mutation • Penetrance and factorsinfluencing the age at onset • Anticipation

  17. Regional distribution of E200K and V210I cases by place of birth E200K V210I 1-3 cases 1-3 cases 4-10 cases 4-9 cases 26 cases 10-20 cases December 2008

  18. CLUSTERS OF GENETIC E200K CJD CASES

  19. E200K gCJD Ancestral Origin Lee et al., 1999

  20. V210I gCJD

  21. E200K and V210I genetic CJD • Cluster • Originof the E200K and V210I mutation • Penetrance and factorsinfluencing the age at onset • Anticipation

  22. 1 Italian Slovak 0.8 Lybian Jews 0.6 Cumulative penetrance 0.4 0.2 0 100 0 20 40 60 80 Age at onset CLUSTERS OF FAMILIAL Glu200Lys CJD CASES

  23. Cumulative age-dependent probability of developing CJD for V210I carriers CJD cases CJD +neurological cases 1 0.9 0.8 0.7 0.6 Cumulative penetrance 0.5 0.4 0.3 0.2 0.1 0 <30 30-39 40-49 50-59 60-69 70-79 80 Age (years)

  24. E200K and V210I genetic CJD • Cluster • Originof the E200K and V210I mutation • Penetrance and factorsinfluencing the age at onset • Anticipation

  25. 95 Unaffected parent carrier Offspring with CJD 85 Parent with CJD 75 Age (years) 65 55 45 35 0 5 10 15 20 25 Number of pedigrees Analysis of genetic anticipation in E200K CJD (Calabria cluster)

  26. Unaffected parent carrier Offspring with CJD Parent with CJD Analysis of genetic anticipationin V210I CJD

  27. Anticipation in genetic E200K and V210I Creutzfeldt-Jakob disease Evidence or confounding factors?

  28. Origin of the D178N/129M mutation: Regional distribution of cases by place of birth or residence Birth Residence 1-3 cases 1 case 4 cases 2 cases December 2008

  29. Residence Origin of the P102L mutation: Regional distribution of cases by place of birth or residence Birth 1-2 cases 1-2 cases 3-6 cases 3-5 cases 7-9 cases 6 cases *December 2008

  30. Phenotype Variability in P102L GSS Italiancases: Clinical patterns in GSS families Progressive Dementia Cerebellar Syndrome Percentage GSS Italian Families

  31. Families of patients Neurologists and Pathologists in the EuroCJD and NeuroCJD participating countries The EuroCJD Surveillance: Australia (S Collins, C Masters), Austria (H Budka, E Gelpi), Canada (GH Jansen), France (A Alperovitch, J-P Brandel), Germany (I Zerr, H Kretszchmar), Italy (S Almonti, A Ladogana, V Mellina, M Puopolo), Netherlands (C van Duijn, P Sanchez-Juan), Slovakia (E Mitrova), Spain (J de Pedro Cuesta), Switzerland (A Aguzzi), UK (R Knight, R Will) N ISS c Maria Puopolo, Anna Ladogana, Anna Poleggi Acknowledgments

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