Sporadic Creutzfeldt-Jakob disease: discrete subtypes or a spectrum of disease?

Although the condition we now call sporadic Creutzfeldt–Jakob disease (sCJD) was the first human prion disease to be described, it remains in many important respects the least well understood. In the familial forms of CJD (fCJD) the close association with mutations in the prion protein gene ( PRNP ) limits speculation concerning their aetiology. For the acquired forms of human prion disease (kuru, iatrogenic CJD and variant CJD), we have a good understanding of aetiology in terms of the source of infection and the routes of exposure, and we can model these diseases in experimental animals with a degree of confidence. However, exactly upon what aetiological factors the apparently ‘sporadic’ nature of sCJD depends is open to a number of possible interpretations; and these points of view tend to reflect deep-seated assumptions in the minds of those working on prion diseases or, as they have also been known, the transmissible spongiform encephalopathies.A traditional view of sCJD (often informed by analogies with animal transmissible spongiform encephalopathies and their modelling in mice) tends towards viewing all of these diseases as acquired. In this scenario, sCJD represents cases of human transmissible spongiform encephalopathy for which the human (or animal) source of infection is yet to be determined. By extension, the PRNP mutations associated with familial forms of CJD are proposed to represent susceptibility factors that make infection (presumably by an ubiquitous agent in the environment) and consequent disease almost certain within an individual's lifetime.An alternative view, often favoured by those who subscribe to the prion hypothesis, regards prion protein metabolism as an error prone process. Rarely (and if the incidence of sCJD is a reliable indication, it is a very rare event indeed), the normally benign or positively beneficial cellular prion protein acquires a self-perpetuating abnormal folding state, which ultimately leads to neuronal …