Genetic Risk Factors of Creutzfeldt-Jakob Disease in the Population of Newborns in Slovakia.

Dana Kosorinova,Martin Stelzer,Eva Mitrova,Dana Zakova,Girma Belay

doi:10.3390/pathogens10040435

Abstract

The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of gCJD was confirmed in Orava region. The most common point mutation of the prion protein gene (PRNP) is E200K. CJD has a long asymptomatic phase and it is not known when the carriers of the mutation E200K become infectious. Precautions to prevent iCJD are focused especially on clinical CJD cases, but asymptomatic CJD-specific mutation carriers cannot be excluded, and represent a potential genetic CJD-risk group. The aim of this study was to determine the occurrence, frequency and geographic distribution of the E200K mutation among the newborns, comparing the areas of focal accumulation of gCJD with extra-focal ones, as well as distribution of the polymorphism M129V of the PRNP gene. A total of 2915 samples of dry blood spots from anonymous newborns were analyzed. We used RealTime PCR method to determine the presence of the E200K mutation and the M129V polymorphism. Genetic testing revealed 13 carriers of the E200K mutation. Investigation of the M129V polymorphism affirmed higher representation of methionine homozygotes (48% MM, 44% MV, 8% VV). Achieved results fully confirmed our previous observations concerning both the specific and nonspecific genetic CJD risk among the Slovak general population. The 48% of methionine homozygotes and 4 carriers of the E200K mutation among 1000 live-born children in Slovakia underline the benefits of genetic testing.

Highlights

While in most of countries the genetic form represents about 10–15% of all Creutzfeldt–Jakob disease (CJD) cases, in Slovakia it is characterized by considerably higher incidence of gCJD (65–75% of all confirmed cases), mainly in the north of Slovakia, in the Orava region [1]
DNA was isolated by paramagnetic particles method (ZyGem Corporation Ltd., Hamilton, New Zealand) and subsequently the presence of the point mutation of the E200K on the prion protein gene (PRNP) gene was determined by Real Time PCR using TaqMan hybridization probes (Applied Biosystems, Foster City, CA, USA)
The findings correlate with the incidence of genetic CJD in Slovakia and despite the fact that the tested Orava cohort was significantly smaller than the number of samples from the other Slovak regions, asymptomatic carriers of the mutation E200K in the gCJDE200K focal area significantly exceeded (p = 0.00089789) the findings in extra-focal ones

Summary

Introduction

CJD occurs in three forms: sporadic (sCJD) whose origin is unknown; genetic (gCJD), caused by specific mutations of the prion protein gene (PRNP); and iatrogenic (iCJD); which is acquired by therapeutic or invasive diagnostic measures. The most common mutation associated with gCJD is a point mutation E200K (gCJDE200K ) and in Slovakia it represents almost all gCJD cases [2], except the cases with R208H mutation [3] and P238S (not published yet). It influences formation and clinical course of the disease.

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