The BSE epidemic has resulted in over 180 human deaths, many less than was forecasted after the first discovery of the connection between Mad Cow Disease and Human Prion Disease. Diagnosed clinical variant Creutzfeldt-Jakob disease (vCJD) cases until now all carried the same genotype of the prion protein gene. Now a case of CJD with many characteristics of vCJD in a young British woman with a genotype previously unassociated with vCJD has been discovered and reported in a recent scientific paper. If this case is indeed linked to BSE, many more people may be at risk of developing vCJD.
In the December 2007 issue of Archives of Neurology, British researchers reported on the case of a woman who died of Creutzfeldt-Jakob Disease (CJD) at the age of 40. The clinical picture and overall pathology of the deceased woman shared many of the same characteristics as that of variant Creutzfeldt-Jakob Disease (vCJD), the human prion disease which is linked to Bovine Spongiform Encephalopathy (BSE). Interestingly, the genetic make-up of the prion protein (PrP) gene of the woman has never before been identified in clinical vCJD cases. Before this discovery, all vCJD clinical cases were known to carry the Methionine/Methionine (MM) genotype of the prion protein gene. The Valine/Valine (VV) PrP genotype found in the deceased woman has never been reported before to be associated with clinical vCJD. Predictions of the likelihood of future vCJD casualties vary, based on the inclusion of only the MM genotype or all three occurring PrP protein genotypes MM, MV and VV. If this new case is indeed vCJD, then the worst-case casualty predictions may be realistic. In future, close monitoring of Human Prion Disease cases in countries affected with BSE is essential.
Variant or sporadic CJD?
A genetic cause for prion disease in the case of the British woman can be excluded since the prion protein gene was normal; there were no mutations, no deletions or duplications. Therefore, it is possible that this case represents a new type of sporadic CJD, a Human Prion Disease that arises spontaneously with approximately equal incidence in individuals with all three PrP genotypes and the most common subtype of CJD. The differential diagnosis of sCJD and vCJD is based on several criteria including the properties of the PrPSc protein, the pathological phenotype and clinical presentation. Many of these criteria point in the direction of vCJD, such as the relatively long duration of the disease (the woman died 14 months after diagnosis) and her young age. Further, the widespread PrPSc deposition pattern found at the autopsy was atypical of sCJD and was similar to vCJD. However, the biochemical properties of the prion protein differed from that of vCJD, and also from that of the known sCJD types. This prompted the authors to define a new prion type (type 7). The presence of PrPSc deposits in lymporeticular tissues is otherwise an important discriminating factor between sCJD and vCJD. Unfortunately, in this case lymphoreticular tissue was not available for examination. Therefore the question whether this case is vCJD or sCJD can not be answered conclusively. Detailed transmission studies of prions in mice will give more clues as to the nature of the prion protein from this patient.
New prion strain?
If the British woman actually died from the human form of Mad Cow Disease, why do these differences to other known mad cow vCJD cases occur? The authors postulate that infection of VV or MV individuals with BSE or vCJD may result in the propagation of distinct prion strains, i.e. the BSE prion strain may be altered upon transmission to humans with a different background. This hypothesis is supported by results of experimental transmissions in mice carrying the Valine variant of the human prion protein (V129-mice). These mice could become infected with a novel form of prion disease, not yet identified in humans. The unsettling conclusion is that there may be types of sporadic CJD in the human population that are still unrecognized as being associated with BSE.
