Complete Penetrance of Creutzfeldt-Jakob Disease in Libyan Jews Carrying the E200K Mutation in the Prion Protein Gene

Serena Spudich, James A. Mastrianni, Margaret Wrensch, Ruth Gabizon, Zeev Meiner, Irit Kahana, Hana Rosenmann, Esther Kahana, Stanley B. Prusiner

Creutzfeldt-Jakob disease (CJD) is a prion disease which is manifest as a sporadic, inherited, and transmissible neurodegenerative disorder. The mean age at onset of CJD is approximately 60 years, and as such, many people destined to succumb undoubtedly die of other illnesses first. The delayed onset of CJD has complicated the analysis of inherited forms of the illness and led to the suggestion that mutations in the prion protein (PrP) gene are necessary but not sufficient for prion disease despite genetic linkage; indeed, an environmental factor such as a ubiquitous virus has been proposed as a second necessary factor. To examine what appeared to be incomplete penetrance, we applied a life-table analysis to clinical and pedigree data from a cluster population of Libyan Jews in which the E200K mutation is prevalent. The study population included 42 affected and 44 unaffected members of 13 Libyan Jewish families, all of whom possessed the E200K mutation. The calculated value using life table analysis is 0.77 at age 70 which increases to 0.89 if a mutation carrier survives to age 80 and 0.96 if age 80 is surpassed. These data argue that the E200K mutation alone is sufficient to cause prion disease and does so in an age-dependent manner.