The inherited forms of prion disease (or familial CJD) is remarkably variable in patients. The disease can start as early as late adolescence or even extremes of old age or in fact never showing as a disease in a normal lifespan. It seems self-evident to us to point out that these differences in age at which the illness can start are incredibly important to people at-risk in families. At present doctors counsel families that onsets are seemingly random over decades of life that we cannot control or predict accurately. So far, the only definitive factors that seem to have a role in the age of onset include the actual code for the mutation itself, and in some types, variation at a site in the prion protein gene called polymorphic codon 129. Other genetic modifying factors have been proposed but small samples sizes mean that definitive evidence is lacking.

The aim of this study is to identify genetic determinants of age at clinical onset in the inherited prion diseases (IPD, including genetic CJD, GSS). We propose to assemble a world collection of DNA samples in IPD. Together we can collect >1000 samples with associated information about age at clinical onset. This will be an unprecedented resource and collaborative group that builds on the recently successful genetic studies in sporadic CJD. DNA samples will be processed using “genome wide arrays” to generate genetic data from 100,000s of variable positions. We will test whether these genetic factors appear to determine the age at which the disease starts, considering the prion protein gene (PRNP) mutation, country, sex and genetic ancestry of the individual.

In particular, we are now aware of genetic factors close to PRNP that seem to control the amount of the prion protein made in the brain. Such factors would be good candidates to alter age at clinical onset and could be labelled for attention in the analysis. Indeed, this study might provide evidence to support the hypothesis that lowering prion protein expression might prevent or delay IPD onset that underpins our main treatment target and strategy in these disorders. We might also identify a completely unexpected mechanism.

Evidence from family studies suggests that the modifying factors we are seeking are probably weak, but until we look with the best resource available, we cannot be sure. If we are successful and identify new genetic factors, the potential benefits are: genetic tools to better predict onset in people at-risk, and suggestions of mechanisms that determine onset that could be altered by therapeutics, perhaps by lowering of PrP expression or binding PrP in the brain. The work is relatively inexpensive, the main issue is to assemble a collection of samples that is sufficiently powered.