Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development

Creutzfeldt-Jakob disease (CJD), the most important human prion disease, occurs in sporadic, iatrogenic and familial form. Except Slovakia and Israel, the recorded familial cases have never exceeded 10-15%. In the Slovak CJD group 95 out of 136 CJD cases (74.2%) carried a CJD-specific mutation in the prion protein gene (PRNP) at codon 200 (mutation E200K). All CJD(E200K) patients carried a heterozygous E200K mutation within the alelle with methionine at codon 129. No more than 53.7% were typical familial cases. The penetrance of the E200K mutation in 1975-2000 was 59.5%. The distribution of codon 129 polymorphism showed 78.6% of methionine-homozygous and 21.4% of methionine/valine-heterozygous patients. Genetic analysis performed on 278 CJD patient relatives demonstrated the E200K mutation in 97 (34.8%) of healthy relatives tested. The E200K mutation carriers were methionine-homozygous in 64% and methionine/valine-heterozygous in 36%. The relatives without the mutation showed a 54.9% methionine homozygosity, 10.4% valine homozygosity and 34.7% methionine/valine heterozygosity. Analysis ofthe E200K carriers provided evidence that the methionine homozygosity is a CJD risk factor, more efficient in CJD patients than in asymptomatic relatives. Th influence of both the E200K mutation and methionine homozygosity at codon 129 was evident in the duration of the clinical stage of CJD and in the immunoreactivity pattern of PrP resistant to proteases (PrP(res)). In the CJD(E200K) methionine-homozygous patients the mean duration ofthe disease was significantly shorter (3.7 +/- 2.0 months) than in the methionine/valine-heterozygous patients (7.84 +/- 7.3 months). Comparison of the PrP(res) positivity in the cerebellum of familial and sporadic CJD using specific polyclonal and monoclonal antibodies (MAbs) to PrP showed less conspicuous immune reaction in CJD(E200K) cases. Methionine-homozygous CJD patients were characteristic mainly by synaptic pattern of staining, while methionine/valine-heterozygous patients by PrP(res) granules and plaque-like structures. Most of numerous plaque-like PrP(res) deposits were found in sporadic valine/valine-homozygous cases. Potential professional risk was excluded in health facility workers. The percentage of professions related to farming was significantly higher in CJD(E200K) (48%) and sporadic CJD (44%) cases as compared to the employed population (9%).