A total of 10–15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt–Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann–Sträussler–Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12–88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt–Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term “gTSE” is preferable to “familial TSE”. Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.
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This study was funded through an EU Concerted Action (BIOMED2 Contract No. BMH4-CT97-2216). Australia: The Australian National CJD Registry is funded by the Commonwealth Department of Health and Ageing. We are grateful to the following people involved in the Australian National CJD Registry: C.L. Masters, A. Boyd, G. Klug, and J. Lee. Austria: The Austrian Reference Centre for Human Prion Diseases (ÖERPE, Head: Prof. Herbert Budka) acknowledges the help of Drs Christa Jarius, Ellen Gelpi, Christine Haberler, Thomas Ströbel, and Till Voigtländer; DI Dita Drobna; and Ms. Helga Flicker, Brigitte Millan-Ruiz, and Monika Richter. Canada: The Canadian Surveillance System is funded by Health Canada. Other collaborators on the project are Dr C Bergeron, neuropathologist (University of Toronto), Dr N Cashman, neurologist and one of the principal investigators for CJD-SS, Dr D Westaway, consulting scientist (University of Toronto). France: We would like to acknowledge all reporting physicians and the members of the Reseau National de surveillance de maladies de Creutzfeldt-Jakob et maladies apparentees. Germany: The German surveillance system is funded by the Federal Ministry of Health 9BMG, 325-4471-02/15. We are grateful to all reporting physicians throughout Germany who contributed to the German surveillance system and especially to Maja Schneider-Dominico for her excellent support in the co-ordination of surveillance. We also acknowledge the help of Drs Otto Windl and Walter Sculz-Schaeffer. Italy: We would like to acknowledge the Ministry of Health and the Istituto Superiore di Sanità for supporting the surveillance of CJD in Italy and S. Almonti, V. Mellina, and L. Ingrosso for help in collecting data and advice. The Netherlands: CJD surveillance in the Netherlands is funded by the Dutch Ministry of Health, Welfare, and Sports. We acknowledge the help of colleagues at the Department of Neurology at the Academic Medical Centre, Amsterdam and the Department of Pathology at the University Medical Centre, Utrecht. Slovakia: The Slovak Surveillance System was supported by the Slovak Ministry of Health and by grants from the European Union. We would like to acknowledge the help of Dr. Dana Slivarichová, Dr. Vladimíra Verchovodková, all reporting physicians and collaborating pathologists. Spain: We are grateful to all reporting physicians and to members of the Spanish TSE study group at Consejo Interterritorial and co-workers at CNE and ISCIII and laboratories, particularly to N. Cuadrado and J.Yague. Switzerland: This work was supported by the Kanton of Zurich and by grants from the European Union. The Swiss Reference Center for Prion Diseases is being funded by the Swiss Federal Office of Public Health. UK: The UK CJD Surveillance System is funded by the Department of Health and the Scottish Executive Health Department. We are grateful to all the members of staff at the National CJD Surveillance Unit and in particular to James Ironside for neuropathological expertise and to clinicians throughout the UK for their co-operation with the study.
Gábor G. Kovács and Maria Propolo Contributed equally
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Kovács, G.G., Puopolo, M., Ladogana, A. et al. Genetic prion disease: the EUROCJD experience. Hum Genet 118, 166–174 (2005). https://doi.org/10.1007/s00439-005-0020-1
- Prion protein gene
- Creutzfeldt-Jakob disease
- Fatal familial insomnia
- Gerstmann-Sträussler-Scheinker disease
- Point mutation
- Insertional mutation