People make terrible jokes about “mad cow” disease. (“Why is PMS called PMS? Because mad cow was already taken.”) Pundits use it as an example of an over-hyped disease (and to be fair, estimates of total cases due to the consumption of contaminated beef in the UK have varied widely, ranging from a few thousand up to well over 100,000). Vegetarians note it as one benefit that comes from their soyburgers. Everyone, it seems, has an opinion.
So-called “mad cow” disease, in humans, is a progressive neurological disorder more correctly called variant Creuzfield-Jacob disease (vCJD). This is due to infection with an agent called a prion. Additional background can be found here, but briefly, the prion is actually a misfolded form of a normal host protein (called PrPc, standing for “prion protein, cellular form”). Its a concern to human health largely because the disease swept through cattle herds in the UK in the 1980s, and it is uncertain just how many humans unknowingly consumed contaminated beef–and therefore, how many may eventually develop vCJD.
vCJD is one of a family of transmissible spongiform encephalopathies (TSEs); others in this family include scrapie (which affects sheep), chronic wasting disease (which affects deer, elk, and moose, among others), and another human TSE called kuru (discussed further below).
Kuru was first recognized a half-century ago among the Fore group in the highlands of Papua New Guinea. Investigations showed that the disease was spread by cannibalism (though, at the time, the causative prion had not yet been identified). Women and children became infected during ritual consumption of the bodies of deceased relatives. Men did not participate in this, and were largely spared from development of kuru. This practice was outlawed in 1954, and ceased by 1960. Around this time, extensive surveillance for kuru in this area was instituted, initially identifying a relatively large number of cases (approximately 200 deaths per year in the late 1950s). And while incident disease cases dropped dramatically over the decades (the average incubation period was found to be ~12 years, similar to one form of vCJD), surveillance has continued.
A new Lancet paper reports on recent results of this surveillance, detailing cases of kuru diagnosed over the last decade–at least 36 years removed from the end of cannibalism in this group, and likely over 50 years from the time of exposure. From 1996 to 2004, 11 cases were identified.
The kuru cases they found during this period were unique for several reasons. First and most striking, because most of them were in men. As I mentioned earlier, men make up a small percentage of kuru cases–of the 2700 total cases diagnosed during the course of the epidemic, only ~2% were in men (versus 64% in this study). This is likely because their only exposure comes during childhood, when they participated in the ritual feasting, while women were exposed throughout their lives. After about the age of 6, boys were taken from their mothers and brought up in the mens’ house, where, the paper notes, “they participated little in feasts and did not eat the brain, by far the most infectious organ in kuru.” The male cases in this study ranged in age from 46 to 63 years old, suggesting an incubation period of over 50 years if most of their exposure occurred before the age of 6.
DNA was available for 10 of these cases. A genetic analysis of the several loci was undertaken, as genetic susceptibility to prion disease has been documented both in humans (in the case of vCJD) and in animals (to various TSEs). In humans, for example, a polymorphism in PrPc appears to increase susceptibility to both the acquired CJD as well as what’s known as “sporadic” CJD (in which the prion is not acquired exogenously). People who carry two copies of this particular allele (with a methionine at codon 129 of the PrPc gene rather than a valine) represent about 38% of the European population, but thus far, have accounted for almost all clinical CJD cases. When this gene was examined in those 10 fatal kuru cases, 8 were found to be heterozygotes, with one each homozygous for valine and methionine at codon 129.
What this suggests is that, perhaps, those with a particular genetic makeup (such as those homozygous for the methionine129 allele) may be the most susceptible to TSEs, making them the first wave of TSE cases in an epidemic. Therefore, what we are seeing now in the UK and elsewhere in Europe may be just the beginning of the epidemic; heterozygotes (like those in the current study) may have a longer incubation period for the disease. The authors suggest that:
Mean incubation periods of human BSE [bovine spongioform encephalopathy] infection of 30 years or more should therefore be regarded as possible, if not probable, with the longest incubation periods approaching (and perhaps exceeding) the typical human lifespan.
This conclusion is reached by extrapolating from kuru to human exposure to BSE, but it should be noted that there are some problems with this. First, kuru represents a human-to-human transmission event (dubbed “intraspecies recycling” in the paper). Studies of prions in a laboratory setting using animal models have shown that there is a species barrier to transmission, and that prions that have been adapted to a particular species–for example, prions that have been passaged once in a mouse, and are then harvested and inoculated into a second mouse–result in a decreased incubation period and a higher lethality when compared to the primary passage (which would have come from another animal species, such as a cow or human). Therefore, kuru may have a shorter incubation period and higher virulence than BSE transmitted to humans. Additionally, the concentration of prions varies by animal tissue. Kuru has been especially associated with handling or consumption of the host brain (high in prion concentration), whereas individuals exposed to BSE have been so via contaminated animal muscle (theoretically, with minimal nervous tissue involvement). Therefore, the infectious dose of the prion should be much lower for BSE than that in kuru, which may either extend the incubation period beyond even 30 years, or may mean that the theoretical “mad cow” epidemic will never materialize. Unfortunately, only time will tell.
Collinge et al. 2006. Kuru in the 21st century–an acquired human prion disease with very long incubation periods. Lancet. 367:2068-74.
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