Increased incidence of sporadic Creutzfeldt‐Jakob disease on the island of Crete associated with a high rate of PRNP 129‐methionine homozygosity in the local population

Abstract

Since the spring of 1997, when the Neurology Department of the University Hospital of Crete admitted its first patient, nine cases (eight neuropathologically confirmed and one probable) of sporadic Creutzfeldt-Jakob disease (sCJD) have been recorded. This represents an annual incidence five-fold higher than expected based on the island's population (0.54 million). Molecular analysis of the prion-protein gene (PRNP) showed no mutations in any of the seven CJD cases studied. Five patients (ages 64-88 years) were homozygous for methionine-129 of PRNP and showed the classic sCJD triad (subacute dementia, myoclonus, periodic electroencephalogram). Brains contained type 1 (unglycosylated 21.5 kDa band) protease-resistant prion protein (PrPres). Two patients (ages 56 and 57 years), both homozygous for valine-129, showed cerebellar ataxia and later dementia not associated with periodic electroencephalogram; brain PrPres was type 2. Genotyping of 205 Cretan controls showed that methionine-129 homozygosity, a susceptibility factor for sCJD, was significantly higher in this population than in other Caucasian populations (57.0% n = 205 vs. 41.5% n = 859, p < 0.0001). These data are the first to relate a high regional incidence rate for sCJD to the distribution of PRNP 129 genotypes in the local population; however, additional factors may be operational.

The M129V polymorphism of codon 129 in the prion gene (PRNP) in the Danish population

“…The observation may reflect the higher incidence of the Met allele in the population, since 54% of the population in Crete are homozygous for Met [21]. Homozygosity of Met on codon 129 has been reported to be a predisposing factor also for sCJD [29].…”

“…This putative East-West gradient seems to be confirmed by our analysis. Not only have Japan and Turkey a higher Met-allele prevalence than Denmark, also countries in the Eastern part of Europe like Greece, Finland, Poland and Slovakia [19][20][21][22][23] tend to exhibit a higher occurrence of the Met allele than countries situated in the Western part i.e. France, UK, Iceland, Austria and Denmark [24][25][26][27].…”

Prion susceptibility and protective alleles exhibit marked geographic differences

“…If the heterozygotes have a lower probability to develop CJD, then the native Americans will be less susceptible than other populations as they have the highest rate of heterozygotes M/V (46.9%). And according a recent study, where a high frequency of M homozygotes in Crete island was associated with an increased number of sporadic CJD patients [Plaitakis et al, 2001], the high frequency observed in CE Asia (88.1%) for Met homozygotes could result in a very high risk for prion diseases in that group. Variation at the codon 129 (and thus, variation in the whole PRNP) is highly structured by continent as shown from AMOVA results, suggesting that natural selection may have acted as a diversification factor among human groups.…”

Genotype frequencies at codon 129 of the Prion Protein Gene in Brazil: implications in susceptibility to variant Creutzfeldt--Jakob disease compared to European and Asian populations

“…[7]. Clear differences in the distribution of this genetic trait exist between Europeans and Asian populations [8][9][10][11][12][13][14][15][16][17][18][19][20]. In the present work we estimated the distribution of M129V in a Brazilian population and compared genotype and allele frequencies with previously published data.…”