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How Long is the Incubation Period for Prion Diseases?
Abstract & Commentary
By Joseph E. Safdieh, MD, Assistant Professor of Neurology, Weill Medical College, Cornell University. Dr. Safdieh reports no financial relationship relevant to this field of study.
Synopsis: The incubation period for the prion disease Kuru can be very long in some cases and suggests that the risk for development of new cases of variant Creutzfeldt-Jakob disease will continue for quite some time.
Source: Collinge J, et al. Kuru in the 21st Century—An Acquired Human Prion Disease with Very Long Incubation Periods. Lancet. 2006;367:2068-2074.
Prion diseases are caused by the accumulation in the brain of an abnormally configured isoform of an intrinsic protein, termed prion protein (PrP). Much attention has been devoted to the variant form of Creutzfeldt-Jakob disease (vCJD), which is caused by dietary exposure to meat from cattle infected with bovine spongiform encephalopathy (BSE), known to the general public as Mad Cow Disease. The first human prion disease to be described was Kuru, an epidemic which occurred in a defined population from Papua, New Guinea, who contracted the disease via human-to-human transmission through ritual cannibalism. Kuru is a progressive cerebellar syndrome that is invariably fatal. Collinge and colleagues attempted to characterize the incubation period of Kuru by studying cases identified between 1996 and 2004. They argue that the ritual of cannibalism was virtually eliminated by 1960, so that cases appearing in the study period would have a prolonged minimum incubation period. Eleven cases were identified in the study period, all born well before 1960. The minimum incubation period for these cases ranged from 34-41 years, with a likely incubation period of 39-55 years. Of the 10 cases tested, 8 were heterozygous at polymorphic codon 129 of the PrP gene. Heterozygosity at this codon is known to protect against development of Kuru and prolong the incubation period in cases that eventually occur. All documented cases of vCJD in humans are homozygous for methionine at this codon, which is known to increase susceptibility to Kuru as well. Collinge et al conclude that the incubation period of Kuru is very long in some cases, and is partially explained by genetics. They suggest that the incubation period of human BSE infection may also be quite prolonged in some cases, especially due to the less efficient cross-species transmission of BSE compared to the intra-species transmission of Kuru.
vCJD was first identified in the United Kingdom in 1996, raising serious public concerns about the safety of the cattle supply. Cattle most certainly acquired BSE through dietary consumption of infected tissue and, in response to the BSE and vCJD epidemic, this practice was stopped. This is analogous to the history of Kuru, where the ritual cannibalism was stopped over a brief, defined period of time. Despite the fact that the cannibalism was stopped, cases of Kuru continued to appear many decades later. The majority of these cases were heterozygous at codon 129 of the PrP gene, which is protective against prion disease. Considering that all cases of vCJD up to this time are homozygous for methionine at this codon, there may be a later peak of cases of vCJD in the heterozygous population. Fifty-one percent of Europeans are heterozygous at this codon. Although the source of human BSE infection has been almost completely eliminated, the burden of vCJD will likely persist for decades, as new cases present with a prolonged incubation period. Neurologists should, therefore, continue to be trained to recognize the presenting signs of vCJD, and realize that the demographics of the disease onset may shift to an older population.