Abstract
Differentiating iatrogenic Creutzfeldt-Jakob disease (iCJD) from sporadic CJD (sCJD) would be useful for the identification and prevention of human-to-human prion transmission. Currently, the diagnosis of iCJD depends on identification of a recognized source of contamination to which patients have been exposed, in addition to fulfilling basic requirements for the establishment of diagnosis of CJD. Attempts to identify differences in clinical manifestations, neuropathological changes and pathological prion protein (PrPSc) between iCJD and sCJD have been unsuccessful. In the present study, using a variety of more sophisticated methods including sucrose step gradient sedimentation, conformational stability immunoassay, protein misfolding cyclic amplification (PMCA), fragment-mapping, and transmission study, we show no significant differences in gel profiles, oligomeric state, conformational stability and infectivity of PrPSc between iCJD and sCJD. However, using PMCA, we find that convertibility and amplification efficiency of PrPSc is greater in iCJD than in sCJD in a polymorphism-dependent manner. Moreover, two protease-resistant PrP C-terminal fragments (termed PrP-CTF12/13) were detected in all 9 cases of sCJD but not in 6 of 8 cases of iCJD tested in this study. The use of fragment mapping- and PMCA-based assays thus provides a means to distinguish most cases of iCJD from sCJD.
Highlights
Human prion diseases are highly heterogeneous and can be classified as sporadic, hereditary or acquired
In the present study, using a variety of more sophisticated methods including sucrose step gradient sedimentation, conformational stability immunoassay, protein misfolding cyclic amplification (PMCA), fragment-mapping, and transmission study, we show no significant differences in gel profiles, oligomeric state, conformational stability and infectivity of PrPSc between iatrogenic Creutzfeldt-Jakob disease (iCJD) and sporadic CJD (sCJD)
No significant differences in gel mobility of proteinase K (PK)-resistant PrPSc were observed between the two diseases (Figure 1A)
Summary
Human prion diseases are highly heterogeneous and can be classified as sporadic, hereditary or acquired. All of them are associated with a pathological prion protein (PrPSc) that assimilates its cellular form (PrPC) by a conformational transition, the PrPSc origin in acquired prion disease is apparently different from that of sporadic and hereditary forms in which PrPSc is formed spontaneously. Variant CJD results from the consumption of beef products contaminated by bovine spongiform encephalopathy (BSE) and is characterized by the deposition in the affected brain of an exclusive single type of BSE-derived PrPSc. Iatrogenic infections have been associated with corneal transplant (n=2), stereotactic EEG (n=2), neurosurgery (n=4), dura mater graft (n=228), growth hormone (n=226), gonadotropin (n=4) and blood transfusion (n=4) [1,2]. The clinical presentations of iCJD may differ from those of sCJD due to mode and route of infection. As in sCJD, homozygotes at codon 129 of PRNP seem to be predisposed to the disease [3,4]. 102 of iCJD cases were homozygous at codon (~80%): 73/128 for methionine/methionine (MM) homozygosity (~60%) and 29/128 for valine/valine (VV) homozygosity (~20%), while only 26/128 were MV heterozygous (~20%) [3,4]
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