Current Molecular Medicine 2004, 4, 375-384 375 Genetic Studies in Relation to Kuru: An Overview L.G. Goldfarb*, L. Cervenakova and D.C. Gajdusek National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA American Red Cross J .H . Holland Laboratory , Rockville, MD 20855, USA Centre National de la Recharche Scientifique, Institut Alfred Fessard, Gif-sur-Yvette, France Abstract: Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic “kuru-type” amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or “prion” diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena. INTRODUCTION to isolate an infectious agent continued [3]. Systematic research on kuru started in March Simultaneously, genetic patterns of disease 1957 when D. Carleton Gajdusek and Vincent Zigas distribution were also under study. The investigators studied 36 kuru cases and identified at least 300 were impressed by the fact that the illness was deaths from kuru that had occurred in the preceding restricted to Fore natives and their immediate 5 years [1]. These investigators first suspected that neighbors with whom Fore regularly intermarried, and kuru was a viral meningo-encephalitis leading to a that all known cases occurred in genetically related subacute or chronic disease with a pattern individuals [4]. reminiscent of Economo’s encephalitis and directly During a 1959 visit to D.C. Gajdusek’s Laboratory referred to it as a syndrome similar to paralysis at the National Institutes of Health in Bethesda, agitans [1, 2]. The association between kuru and veterinary neuropathologist James R. M. Innes noted cannibalism was considered during the first months similarities between neuropathology findings in kuru of studies, but rejected as unlikely when cases were and scrapie of sheep, a slow virus infection in which encountered in young children who were not susceptibility is genetically determined. Reflecting on believed to have engaged in the ritual cannibalistic published reports and an exhibit on kuru studies that consumption of deceased relatives [3]. Failure to find was set up by D.C. Gajdusek at the Wellcome any febrile response, cerebrospinal fluid pleocytosis, Medical Museum in London [5, 6], William J. Hadlow increased cellularity or perivascular cuffing in the wrote a letter to Lancet that suggested a possible neuropathologic images led to exclusion of an acute relationship between kuru and scrapie and infection as the cause of disease, although attempts recommended testing transmissibility of kuru in laboratory primates [7]. These observations stimulated enormously the ongoing attempts to find *Address correspondence to this author at the National Institutes of a microbial etiological agent since scrapie was the Health, Bldg 10, Room 4B37, 10 Center Dr., MSC 1361, Bethesda, only known example of non-inflammatory fatal CNS Maryland 20892-1361, USA; Tel: 301 402 1480; Fax: 301 496 6341; E- disease that was nonetheless shown to be mail: [email protected] transmissible. With the help of Carlton Herman and J. 1566-5240/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. 376 Current Molecular Medicine, 2004, Vol. 4, No. 4 Goldfarb et al. Anthony Morris, D.C. Gajdusek started intracerebral two groups, North and South. The administrative inoculation of many species of animals including boundary coincides with a minor cultural and monkeys, and later chimpanzees, anticipating linguistic division [15, 17]. unusually long incubation periods. In 1966, In the early years of the Administration frequent Gajdusek, Gibbs and Alpers reported transmission of fighting that claimed many lives was suppressed kuru to chimpanzee [8]. allowing the population to freely cultivate sweet Kuru, the prototype human TSE, was until potato in their gardens and breed pigs and chickens recently the only example of oral transmission without fear of attack [17, 18]. Unrelated to kuru, occurring in humans. Although the incidence of kuru among other measures directed at regulating the has markedly declined, further kuru studies are local’s social life and making it healthier, the Christian important not only from a historical perspective. The missionaries and the new Administration discouraged latest TSE member, vCJD, linked to consumption of the cannibalistic rituals [19], and cannibalism contaminated beef from animals incubating BSE [9] completely ceased between 1957 and 1962 [3]. has phenotypic similarity to kuru [10], therefore these During anthropological investigations conducted in disorders are expected to share basic disease 1951-1952 and 1952-1953, the presence of kuru mechanisms. The third infectious form of TSE, was noted among the Fore, Iate and Usurufa people iatrogenic Creutzfeldt-Jakob disease (iCJD), is a [18]. Fore always believed that kuru was a kind of disease associated with the use in modern medicine sorcery (among 34 other variants of sorcery) [18]. To of human tissues and extracts such as cadaveric induce kuru, the sorcerer had to obtain some object dura matter, corneal transplants, or growth hormone intimately associated with the victim, clothing, extracted from human pituitaries that may be excreta, hair or discarded food. He then packaged contaminated with the CJD agent [11]. the object in bark and leaves making a bundle, and Genetic studies of TSEs during the past decade half-buried it in a swamp. The sorcerer would return resulted in discoveries indicating that each hereditary daily to shake the bundle until his victim developed form of TSE, familial CJD, Gerstmann-Sträussler- “shaking disease” [2, 18]. Scheinker disease (GSS) and familial fatal insomnia Cannibalism was practiced in most Eastern (FFI) is associated with mutations in the PRNP gene Highlands populations before the Australian coding for the prion protein [12]. In addition, strong administrative control took over [18, 20, 21]. It evidence was presented for the existence of consisted primarily of the ceremonial consumption of genetically determined susceptibility to infectious and close-of-kin as an act of respect. Meat and viscera sporadic forms. Methionine/valine (Met/Val) coding were taken from the corpse and cooked in a steam variation at codon 129 of the PRNP gene has been oven wrapped in leaves or stuffed into bamboo extensively studied. Accumulated evidence has cylinders. The whole body was eaten. The shown that although this substitution does not by cannibalistic mourning rituals were attended and itself cause disease, it dramatically influences the performed almost exclusively by women and their phenotype produced by other PRNP mutations [13] young children, usually the closest relatives of the and is responsible for susceptibility/resistance to deceased, preferentially exposing them to the kuru, iatrogenic and sporadic forms of CJD [11, 14]. infectious agents. Men ate only the meat. Infants were contaminated by their mothers through rubbing their skin and eyes, and cleaning noses [3]. THE POPULATION OF THE KURU-AFFECTED REGION Kuru incidence grew dramatically in the 1940s and 1950s to reach a level of more than 200 new The Eastern Highlands Province of Papua New cases per year in 1957-1959 [22, 23]. More than Guinea is located at the beginning of the Highlands 80% of kuru cases ever recorded, of a total of about valleys at an average height of 1600m. It occupies 3,000, occurred in the Fore cultural and linguistic the valleys of Lamari, Asaro, Wahgi, Tua, Dunatina group, consisting of about 12,000 people. The and Ramu rivers. Common feature of this province is mortality rate of kuru in some Fore villages reached the steep