Background
Kuru is among the fatal neurodegenerative prion protein (PrP) diseases in humans. Others include Creutzfeldt–Jakob disease (CJD), Gerstmann–Straüssler–Scheinker (GSS) disease, fatal familial insomnia (FFI), and variant CJD (vCJD). [1, 2] PrP diseases in nonhuman animals include bovine spongiform encephalopathy (BSE) also known as, mad cow disease, chronic wasting disease (CWD), scrapie, transmissible mink encephalopathy, feline spongiform encephalopathy, and ungulate spongiform encephalopathy. Although cross-species transmission of prion diseases seems to be limited by an apparent species barrier, the epidemic of BSE in the United Kingdom, which began in 1986, and its transmission to humans indicated that animal prion diseases could pose a significant public health risk. [3, 4, 5]
Human prion diseases can be divided etiologically into inherited, sporadic, and acquired forms. [2, 6, 7, 8] Kuru is the focus of discussion in this article. The pathological and clinical characteristics of kuru that distinguish it from other PrP diseases in humans are also discussed.
The solution of the kuru riddle, which was initially considered a slow conventional viral disease, [9] opened a novel field of biomedical sciences and initiated more than a quarter century of research. This research has resulted in two Nobel prizes (D. Carleton Gajdusek in 1976 and Stanley B. Prusiner in 1997) and is linked to a third prize (Kurt Wüthrich, who determined the structure of the PrP). [10] Kuru research has affected the concepts of nucleation-polymerization protein cancers and conformational disorders. [10, 11]
Kuru affected the Fore (pronounced for-ay) linguistic group of the Eastern Highlands of Papua New Guinea and, to a lesser extent, neighboring groups with whom the Fore intermarried. [12] The word kuru is derived from a term in the Fore language that means “to shake from fear” and stems from trembling as a conspicuous symptom of the disease. [13] Local verbal history, recorded when the disease was first studied by Western medicine in the 1950s, dated the onset of the first case of kuru to the 1920s. During the epidemic, this disease predominantly affected women and children of both sexes, but only rarely affected men. [14]
Kuru was spread by the endocannibalistic funeral practices of the Fore. Family members were ritualistically cooked and eaten following their death, with the female relatives usually consuming the brain, which was the most infectious organ. [15] The brain of the deceased was usually removed by one of the older women from the community whose hand would be wrapped in ferns. [15] The prohibition of endocannibalism in the 1950s led to the decline in the epidemic; however, the disease has persisted into the present century because of an incubation period that may exceed 50 years. Only two kuru-related deaths were reported from 2003-2008, indicating that the epidemic is approaching its end. [16]
Pathophysiology
The prion is a naturally occurring protein found in the CNS and elsewhere. Prion diseases are associated with an accumulation of a disease-related isoform of host-encoded PrP through a posttranslational process involving conformational change and aggregation. According to the protein-only hypothesis, an abnormal PrP isoform is the principal, and possibly sole, constituent of the transmissible agent or prion. [17] A common coding polymorphism at codon 129 of the PrP gene (PRNP), where either methionine (M) or valine (V) may be encoded, is a strong susceptibility factor for human prion diseases. Codon 129 heterozygosity protects against the development of iatrogenic and sporadic CJD and kuru. [18, 19, 2]
Protease-resistant glycoprotein, designated PrP, was isolated as a result of work done by Prusiner and coworkers in 1982 by progressive enrichment of brain homogenates for infectivity. The central feature of this protein was a posttranslational conversion of the host-encoded cellular prion protein (PrPC) to an abnormal isoform, termed PrPSc, that consists of ‘‘small proteinaceous infectious particles that resist inactivation by procedures which modify nucleic acids,” ie, radiation, heat, or enzymatic degradation. [20, 21]
A possible mechanism for prion propagation involves the largely alpha-helical isoform (PrPC) refolding into a beta-sheet isoform (beta-PrP). Beta-PrP is prone to aggregation in physiological salt concentrations. The process of recruitment of beta-PrP monomers is essentially thermodynamically irreversible and driven by intermolecular interactions. [20, 22] Any immunologic or inflammatory response to this infection is absent, [11] as prions are naturally occurring proteins.
Based on etiological classification, human prion diseases can be divided into inherited, sporadic, and acquired forms.
Acquired prion disease
Kuru is the most well-known example of acquired prion disease [2] that results from exposure to human prions during endocannibalism. Susceptibility to the disease is associated with homozygosity for methionine at PRNP codon 129. As stated above, heterozygosity on this codon is protective. A novel PRNP variant—G127V polymorphism—is recognized as an acquired prion disease resistance factor selected during the kuru epidemic. [18] There is no evidence for vertical transmission of kuru. [14]
Other examples of acquired prion disease include iatrogenic CJD and vCJD. Iatrogenic CJD has been caused by implantation of dura mater grafts, treatments using growth hormone derived from pituitary glands of human cadavers, corneal transplantation, contaminated electroencephalographic (EEG) electrodes, and surgical operations using contaminated instruments. [2] vCJD was recognized in the United Kingdom in 1995 and is caused by the same prion strain that causes BSE in cattle. [4, 2, 3] Concerns persist about the potential for transmission of prions via blood transfusion, nonnervous tissue organ donation, and other iatrogenic routes not involving consumption of central nervous system tissue from infected cattle. [23, 4]
Sporadic prion disease
Approximately 85% of cases of human prion disease occur sporadically as sporadic CJD at a rate of 1-2 cases per million population per year worldwide. It does not have a sexual predilection. The cause of sporadic CJD is unknown, although hypotheses include somatic PRNP mutation or spontaneous conversion of PrPC into PrPSc as a rare stochastic event. [24, 25]
Inherited prion disease
Approximately 15% of human prion diseases are associated with autosomal dominant pathogenic mutations in PRNP. [24] The three main diseases that fall in this category include GSS, familial CJD, and FFI. [2, 20] Over 30 autosomal dominant pathogenic PRNP mutations have been described, and PRNP analysis can be used for presymptomatic genetic testing in affected families. [2]
Epidemiology
Frequency
United States
Kuru does not occur in the United States.
Four cases of BSE, which is a prion disease in cattle, have been reported in the United States. The most recent was reported on April 24, 2012. [26]
Three cases of variant CJD in humans have been reported from the United States. By convention, variant CJD cases are ascribed to the country of initial symptom onset, regardless of where the exposure occurred. There is strong evidence that suggests 2 of the 3 cases were exposed to the BSE agent in the United Kingdom and that the third was exposed while living in Saudi Arabia. [27]
International
Kuru is restricted to the Fore, a people found in the New Guinea highlands, although there is a single report of a case of transmissible subacute spongiform encephalopathy occurring in a visitor to the eastern highlands of New Guinea. [11] Kuru was acquired during endocannibalistic funeral rituals.
When first investigated in 1957, kuru was found to be present in epidemic proportions, with approximately 1000 associated deaths in the first 5 years of observation, 1957-1961. [16] The total number of kuru cases from 1957-2004 exceeded 2700, with more than 200 dying of the disease every year in the late 1950s. This number fell to about 6 per year in the early 1990s and between one and two cases per year in late 1990s, with only 11 cases identified from July 1996 through June 2004. [14] More recently, kuru-related deaths declined to only two from 2003-2008. [16]
The prohibition of the practice of endocannibalism in the 1950s has clearly led to the decline in the epidemic, with a few cases still occurring because of kuru’s long potential incubation period, which can exceed 50 years. [16, 2] Only 9 cases of kuru have been reported among Fore people who were born after 1956, and no cases have been reported among those born after 1959. [14] The last fatality due to kuru was reported in 2005, and no known kuru cases have occurred since then.
However, zoonotic, not human, prion disease, that is BSE continues to be sporadically seen. The BSE epizootic in the United Kingdom peaked in January 1993. There exists strong epidemiologic and laboratory evidence for a causal association between a new human prion disease called variant CJD that was first reported from the United Kingdom in 1996 and the BSE outbreak in cattle. [28]
Mortality/Morbidity
There is no effective treatment for kuru. It is uniformly fatal within 4-24 months of symptom onset. [29] The incubation period may be as short as 5 years or as long as 50 years. [14]
Race
Kuru has affected only the people of the Fore linguistic group of the Eastern Highlands of Papua New Guinea and their neighbors with whom they intermarried. [14, 12, 30]
The practice of endocannibalism was important to the Fore people as a way of respecting their dead relatives. It was rigorously forbidden, however, by the Australian government following the establishment of the Okapa patrol post in 1954 as one of the first administrative controls following contact with the people. Public consumption of dead relatives ceased almost immediately, and compliance was ensured by local police responsible for the subdistrict. By 1956, endocannibalism was effectively eliminated. Surreptitious eating of dead relatives was reported in remote communities for some years afterward, but, by the end of the 1950s, the practice had effectively ended. Epidemiological surveillance for kuru began in 1957 and has continued since. [14]
Sex
During the New Guinea epidemic, kuru was found to predominantly affect women and children of both sexes. Only 2% of overall cases were found in men from 1957-1958. [14]
Age
The latest year of birth recorded for any patient with kuru was 1959; only 9 individuals with kuru are recorded as having been born since 1956. [14] During the peak of the epidemic, it was estimated that most of the affected individuals were young women, but a small number of children and postmenopausal women were found to be infected, as well as postpubertal males in rare cases. [29]
These findings can be explained by women cooking and handling a dead relative's organs and women most commonly consuming the cooked brains. After age 6–8 years, boys were taken from their mothers and raised in the houses of men. From this point on, their exposure risk was the same as that for men, who typically had little participation in these feasts and did not eat cooked brains, by far the most infectious organ responsible for kuru. These cultural practices most likely explain why so few men developed kuru. [14]
