Goldfarb, Lev G.
From the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Address correspondence to: Lev G. Goldfarb, National Institutes of Health, Building 10, Room 4B37, 10 Center Dr, MSC 1361, Bethesda, Maryland 20892-1361; firstname.lastname@example.org
Variant Creutzfeldt-Jakob disease (vCJD) is a fearsome illness that has been linked to consumption of contaminated meat products of animals incubating mad cow disease. 1 The only other orally transmitted human prion disease is kuru, for which vCJD is the closest analog. Because of their similar modes of transmission, kuru and vCJD may share other pathogenic mechanisms. For this reason, the kuru epidemic that occurred in the later part of the 20th century is coming under renewed scrutiny. A report by Huillard d’Aignaux and his colleagues on the evolution of this epidemic appears in this issue. 2
Kuru presents with limb ataxia, dysarthria, and a shivering tremor, and typically progresses to complete motor and mental incapacity and death within 6–12 months. 3 The origin of the kuru epidemic remains unknown; it may have started with a case of sporadic CJD, 4 or it may have originated from a disease in domestic or wild animals. The epidemic developed in the 1940s–1950s in the Eastern Highlands of Papua New Guinea, and spread through ritual cannibalism. More than 2500 cases (about 80% of all kuru deaths) occurred among the 12,000 persons living in the Fore region. Over three-quarters of the kuru victims were adult women; most of the rest were children. The youngest was a boy 4 1/2 years of age. 4
The cannibalistic mourning rituals that had been carried out in the Fore region for many decades were abandoned as of the late 1950s. Exposure to kuru infectivity ceased. No one born after 1960 has ever developed kuru, 4 although it took another 40 years for the epidemic finally to subside. We have supporting evidence from clusters of kuru cases that have been linked with known cannibalistic feasts, establishing the incubation period as being at least 30 years.
Early investigators of the kuru epidemic were misled about the basic nature of the disease. With transmission occurring predominantly within a circle of close relatives, most kuru patients had a family history of the disease, which caused investigators to hypothesize that the disease was inherited. Large kuru pedigrees were compiled and analyzed. Genetic models were developed suggesting that kuru was controlled by a single
“Prion diseases break down the usual boundaries: these diseases may be infectious or hereditary. . .”
autosomal dominant gene with high penetrance in females, and an early-onset form in the homozygous state. 5 It was not until much later that investigators realized all aspects of kuru epidemiology could be explained by transmissibility of an infectious agent. 4
Although the early hypotheses on kuru genetics have been roundly disproved, it has turned out that genetics play a unique role in this disease. This rests on the role of an unusual protein known as a prion—a particle that can self-replicate, but is not “alive” by any usual definition. This prion protein (PrP) is encoded by the human gene PRNP. 6
Prions are responsible for a whole set of neurodegenerative disorders, including kuru and vCJD, that constitute the transmissible spongiform encephalopathies (TSE). Prion diseases break down the usual boundaries: these diseases may be infectious or hereditary, or they may arise sporadically. The familial forms (inherited TSE, familial Creutzfeldt-Jakob disease, and fatal familial insomnia) are all associated with multiple missense, insertional, and deletion mutations in the PRNP gene. 7
“. . .prion—a particle that can self-replicate, but is not ‘alive’ by any usual definition.”
The current view of TSE pathogenesis is based on the “protein only” hypothesis. According to this hypothesis, the critical event in TSE pathogenesis is the change of conformation in the normal host-encoded protein to an isoform that is linked to infectivity. 8 In other words, PRNP mutations alter the secondary structure of the encoded protein, which—remarkably—makes it infectious. 8 TSE results from the accumulation in the brain of the abnormal isoform of the prion protein. Because this form is partially resistant to proteases, its toxic fragments gradually accumulate in neurons. This accumulation produces the rapid progression of symptoms that characterizes the TSE phenotypes.
In addition to the mutations that lead to frank disease, there is a polymorphism of the gene that affects susceptibility. This sequence (at codon 129 of the PRNP gene) codes alternatively for methionine (M) or valine (V). The M substitution makes a person more susceptible to developing infectious and sporadic TSE. Homozygous carriers of the 129 M allele are over-represented among patients with sporadic CJD 9 and iatrogenic CJD. 10 The MM/MV/VV genotype frequencies in populations vary from 0.32/0.43/0.24 in New Guineans 11 to 0.37/0.51/0.12 in the British 9 to 0.92/0.08/0 in the Japanese. 12
No germ line mutations have been found in the PRNP coding sequence of kuru patients. 11 However, there is abundant evidence that allelic variation may affect susceptibility to the ingested prions. Using archival tissues and well documented medical observations, it became possible to find links between the genotype of kuru patients and the course of their disease. 13 Individuals homozygous for the 129 M allele had an earlier age of disease onset and a shorter duration of illness. 13 This genetic susceptibility led to depletion of the 129 MM genotype as the epidemic progressed.
The question of genetic susceptibility to prion disease is relevant to one of the most urgent questions about the recent outbreak of vCJD, namely its incubation time (and thus the likely trajectory of the epidemic). Although the kuru experience offers some clues, there is no direct way to evaluate incubation time in kuru patients. We can make rough estimates based on the age of disease onset, whether groups of individuals were exposed to the infectious agent during certain limited periods in their lives. The role of genetic susceptibility may be useful in refining these estimates. Fore males were exposed to kuru between 1 and 10 years of age, when they accompanied their mothers in mourning rituals. Most men had no additional exposure later in life. 4 Of the male kuru patients with disease onset between ages 5 and 14 years, 53% were 129 MM. Only 27% of patients with disease onset after age 15 carried the same genotype, suggesting a shorter incubation time for 129 MM individuals. 11
Apparently, the decline of kuru incidence has been determined by two independent events: discontinuation of exposure, and exhaustion of the susceptible genotype. Carriers of the alternative genotypes, MV and VV, developed kuru at a later age, after a much longer incubation, and many have survived. Indeed, six of eight recently published cases of kuru 14–16 and five of eight of our latest cases were homozygous for the 129 V allele.
What does the situation in the Fore villages 40 years ago tell us about the current outbreak of vCJD in the U.K.? The 129 MM genotype has been found in every victim to date. If the analogy between kuru and vCJD can be extended to the increased but not exclusive susceptibility of the 129 MM genotype, we would expect additional cases of vCJD to show longer incubation periods and to occur in older individuals with alternative codon 129 genotypes, signaling a maturing evolution of the vCJD epidemic.
Recent models for predicting the course of the vCJD epidemic have assumed that carriers of the 129 MM genotype are the only susceptible group, and that the incubation time has a uniform distribution. 17–18 If non-MM individuals develop vCJD after longer incubation times (with an independent distribution), the length of the epidemic and the overall number of projected cases will be higher than currently estimated.
The possibility of genetic susceptibility is being explored in many areas of epidemiology. In the example of vCJD, susceptibility of the carriers of non-129 MM genotypes may well be crucial for accurately projecting the course of the epidemic. This possibility is under discussion, 19 although an appropriate model has not yet been formulated. The role of genetic susceptibility is still uncertain in many other areas of human health, but it is likely to be a major factor in the spread of infectious diseases.
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