Kuru is an incurable degenerative neurological disorder, found exclusively among the Fore linguistic group, natives of Estern Highlands of Papua Nuova Guinea. Kuru was a human prion disease that was the result of the practice of ritualistic cannibalism among the Fore, in which relatives prepared and ate the tissues (including brain) of deceased family members, as a mark of respect and mourning ( transumption ). Brain tissue from individuals with kuru was highly infectious, and the disease was transmitted either through eating or by contact with open sores or wounds.
The illness was marked by the subacute onset of tremor (the term Kuru derives from the Fore word "kuria/guria" which means "to shake") and ataxia followed by motor weakness and incontinence.
Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified and it causes brain and nervous system changes similar to Creutzfeldt-Jakob disease, Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia, variant CJD (vCJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. The common central feature of these diseases is the post-translational conversion of host-encoded, cellular prion protein ( PrpC ), encoded by the PRNP gene, to an abnormal isoform, named PrpSC.
Kuru was first noted in 1952-1953 by anthropologists Ronald Berndt and Catherine Berndt among the Fore and to a lesser extent neighboring groups with whom the Fore intermarried: Yate, and Usanufa people. The disease was researched by Daniel Carleton Gajdusek as part of an international collaboration with Australian doctor Michael Alpers and in 1975 a complete bibliography of Kuru was published by Alpers et al. In the mid-1960s, Alpers collected post-mortem brain tissue samples from an 11-year-old Fore girl, Kigea, who had died of kuru. He took these samples in the USA to Gajdusek who then injected two chimpanzees with the infected material. Within two years, one of the chimps, Daisy, developed kuru, demonstrating that this human neurodegenerative disease can be transmitted to chimpanzees and subsequently classified as a transmissible spongiform encephalopathy (TSE), or slow unconventional virus disease.
The origins of kuru have remained obscure.
When first investigated in 1957, kuru was found to be present in epidemic proportions, with approximately 1000 deaths in the first 5 years of observation (1957-19 61). The total number of kuru cases from 1957-2004 exceeded 2700, with more than 200 people 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. More recently, kuru-related deaths declined to only 2 from 2003-2008.
The prohibition of the practice of endocannibalism in the 1960s clearly led to the decline in the epidemic, but a few cases are still occurring because of kuru’s long potential incubation period, which can exceed 50 years.
In the initial years of kuru investigation, the disease occurred principally in women, children and adolescents of both sexes, with only 3% in adult males. 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, the most infectious organ responsible for kuru.
Other references: The Epidemiology of Kuru
(Australian Government, The department of Health)
Gadjusek (1973) reported three main stages in the progression of symptoms.
- First stage: the "ambulant stage": it includes unsteadiness of stance, gait, voice, hands, and eyes; deterioration of speech; tremor; shivering; in-coordination in lower extremities and dysarthria.
- Second stage: the "sedentary stage": patient can no longer walk without support, more severe tremors and cerebellar ataxia, shock-like muscle jerks, emotional lability (there may be euphoria with inappropriate laughter, which has led to the disease being referred to as the laughing death), depression, and mental slowing.
- Third stage: the "terminal stage": patient’s inability to sit up without support; more severe cerebellar ataxia, tremor; urinary and faecal incontinence; dysphagia (the patient may be unable to feed oneself, this can lead to malnutrition or starvation).The patient is also unresponsive to his surrounding, and acquires ulcerations.
The average time from exposure to symptoms (incubation period) is 10 to 13 years, but incubation periods of 50 years or even longer have been reported.
Death usually occurs within 1 year after the first sign of symptoms, often because of pneumonia or pressure sores infection.
(Kuru, the dynamics of a Prion Disease)
Prion diseases are difficult to diagnose using conventional methods such as PCR, serology or cell culture assays since the infectious agent or prion lacks nucleic acid components and consists of an abnormally folded conformer of the protein PrPSC, that the infected organism does not recognise as foreign, so that neither inflammatory nor immunological responses are observed.
In detail, for kuru diagnosis the specific assessments are:
- Clinical diagnosis: neurological examination of the patient: dominant clinical features include fatigue, insomnia, depression, weight loss, headaches, general malaise, and ill-defined pain sensations. In addition, neurological features including extrapyramidal signs, cerebellar ataxia, pyramidal signs, cortical blindness and psychiatric features are frequent.
- No laboratory and imaging studies are helpful in diagnosing kuru.
- Histologic findings: post-mortem histopathological examination of brain tissue:
- Primary changes include vacuoles in nerve cell bodies, dendrites, and axons and reactive swelling, widespread spongiform change and astrocytosis, as well as neuronal loss affecting the cerebral hemispheres and cerebellum.
- Hematoxylin and eosin–stained sections show amyloid plaques.
- Gliosis and vacuolization are found throughout the gray matter and involve the cerebellum, thalamus, basal ganglia, and the anterior horns of the spinal cord.
Pathological changes in several kuru forebrain regions
(Central and peripheral pathology of kuru )
The PRNP gene encodes the prion protein, which has been implicated in various types of transmissible neurodegenerative spongiform encephalopathies. The human prion diseases occur in inherited, acquired, and sporadic forms. Acquired human prion diseases account for only 5% of cases of human prion disease, they include kuru, iatrogenic CJD and a new variant form of CJD that is transmitted to humans from affected cattle via meat consumption especially brain. Kuru is the most well-known example of acquired prion disease that results from exposure to human prions during endocannibalism.
The disease arise through horizontal infection and accumulation of aberrant prion protein in the brains of affected individuals that results from consumption of an individual dying of sporadic CJD. There is no evidence for vertical transmission of kuru.
THE PRNP GENE
The protein encoded by this gene, which is found on chromosome 20, is a membrane glycosylphosphatidylinositol-anchored glycoprotein ( PrpC ), expressed on the surface of all nucleated cells, especially on neurons, it is resistant to proteinase K and tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats; insertions or deletions of octapeptide repeat units are associated to prion disease.
PrpC may play a role in neuronal development and synaptic plasticity, may be required for neuronal myelin sheath maintenance and may play a role in iron uptake and iron homeostasis. There are also evidences of its role in copper homeostasis (the octapeptide repeat region contains a high-affinity binding site for copper ions), anti-oxidant and anti-apoptosis action. A review of evidence in 2005 suggested that PrpC may also have a normal function in maintenance of long-term memory.
The alterated PrpC isoform, PrpSC, consists of small proteinaceous infectious particle (prion) that resist inactivation by procedures which modify nucleic acids (radiation, heat, or enzymatic degradation) and is able to convert normal PrpC proteins into the infectious isoform by changing their conformation.
The difference between the two forms is conformational: the normal protein consists of mainly alpha helices with a spiral backbone, but in the mutated protein, PrpSC, a portion of its α-helical and coil structure is refolded into β-sheet: this high beta-sheet content correlates with PrpSC resistance to enzymatic digestion and infectivity.
Mutated prion protein is, therefore, predominately formed by beta sheets with a fully extended backbone. This alteration in tertiary structure provides evidence for post-translational modification of the protein.
The disease-associated protease-resistant peptide forms amyloid fibrils, formed by a steric zipper of superposed beta-strands, which tend to create plaques.
Scientists believe that the replication of a prion particle occurs almost exactly as the duplication of a virus: prions replicate by recruiting normal proteins, convert them into a prion-like shape that can go on to infect other cells. This change starts a chain reaction, and the new converted prions convert other proteins, this chain reaction occurrs especially inside neurons.
Before reaching the CNS, the first stage of prion desease involves lymphoid organs, in particular the spleen and lymph nodes; these are the first sites of PrpSC replication after infection by peripheral routes. Than, there are two routes for neuroinvasion: the hematogenous spread, or via the parasympathetic vagus nerve. Which of these two routes is most important remains still unclear, but a more complete understanding of the stages of prions spread from the periphery may allow to develope new pharmacological ways to stop the infection.
PATIENT RISK FACTORS
GENETIC RISK FACTORS
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: susceptibility is associated with homozygosity for methionine at PRNP codon 129.
Recent studies have demonstrated that heterozygosity at codon 129 of the human prion protein gene (PRNP) confers relative resistance to both sporadic and acquired prion diseases. This genotype is most marked in elderly women, but is also significant in a slightly younger cohort of men, consistent with their exposure to kuru as boys.
Analysis of the PRNP 129 methionine (M)/valine (V) polymorphism in 80 patients and 95 unaffected controls demonstrated that the kuru epidemic preferentially affected individuals with the M/M genotype. A higher representation of M/M carriers was observed among the affected young Fore males entering the age of risk, whereas a lower frequency of M/M homozygotes was found among the survivors. M/V and V/V genotypes predisposed to a lower risk of disease development and also to longer incubation times.
Distribution of PRNP codon 129 genotypes according to age at onset of illness in 92 kuru patients
This particular genotype seems to offer high or even complete protection against the development of kuru and has become frequent in this area through natural selection over recent history, in direct response to the epidemic: the surviving Fore population that had never developed kuru through the end of the epidemic showed evidence of an M/M genotype depletion caused by the kuru fatalities. This is thought to be perhaps the strongest example of recent natural selection in humans.
Another factor that confers protection against Kuru is a PRNP variant: 127GV polymorphism; this polymorfism is recognized as an acquired prion disease resistance factor selected during the kuru epidemic.
The 127GV genotype was not found in any patients with kuru, suggesting that it may provide complete resistance to the disease.
Recent studyes carried out by Mead at al. (2003) and confirmed by Hardy at al. (2006), demonstrated that, as kuru imposed in the Fore an exceptionally strong balancing selection on the prion locus, global patterns of diversity in the same gene indicate historical balancing selection.
Authors cited evidence suggesting that cannibalism was widespread in many prehistoric populations; they hypothesized that a devastating kuru-like epidemic may have occurred in most of the population in which cannibalism has been documented, such as several Central and South African populations and the Aztecs in the Americas. Thus, worldwide PRNP haplotype diversity suggest that strong balancing selection at this locus occurred during the evolution of modern humans which may have provided the setting for selection pressure as protection against prion disease.
Frequency of human PRNP polymorphisms (%) in various world populations. n = number of individuals genotyped for M129V:
(Brain disease 'resistance gene' evolves in Papua New Guinea community)
(Balancing Selection at the prion protein gene consistent with prehistoric kuru-like epidemics)
(OMIM: Susceptibility tu Kuru, Population Genetics)
IMPLICATIONS FOR NEW VARIANT CREUTZFELDT-JAKOB DESEASE
Kuru, the prototype human transmissible spongiform encephalopathy (TSE), has been till now the only example of oral transmission occurring in humans. The latest TSE member, variant Creutzfeldt-Jakob disease (vCJD), linked to the consumption of contaminated beef from animals incubating bovine spongiform encephalopathy, has phenotypic similarity to kuru and, because of a common mode of transmission, might also share other pathogenic mechanisms. Therefore, information about kuru may be helpful in predicting outcomes for the current outbreak of vCJD.
Recent genetic studies of vCJD demonstrated that most of the vCJD patients studied was homozygous for the 129 M allele. If susceptibility to kuru and vCJD is similarly influenced by the codon 129 genotype, these observations may be relevant to the current outbreak of vCJD.
"It's absolutely fascinating to see Darwinian principles at work here. This community of people has developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable. Kuru comes from the same disease family as CJD so the discovery of this powerful resistance factor opens up new areas for research taking us closer to understanding, treating and hopefully preventing a range of prion diseases."
Professor John Collinge, Director of the MRC Prion Unit
No treatments have proven efficacious for prion disease such as kuru, which is neurodegenerative and inexorably fatal.
Since the discovery of the kuru epidemic in New Guinea, a huge amount of knowledge concerning prion disease, has been obtained so far; the study of the specific dynamics of kuru has given the opportunity to better understand all prion diseases and try to find a cure.
Some of the new treatments that are being experimented are:
- Chemotherapeutic approaches: they are focused on blocking the conversion of the normal form of prion protein to its abnormal counterpart either by directly binding PrpC or PrpSC, or by redistributing, sequestering, or downregulating PrpC, in order to prevent its conversion.
- Medcations like Congo red, Anthracyclines, Amphotericin B and its analogs, Sulfated Polyanions, and tetrapyrroles: have shown to be effective at preventing prion propagation, but they have a lot of toxic effects.
- Pentosan Polysulphate: another drug which is being tested; it hasn't shown to have toxic effects during experimentations and it can slightly attenuate clinical symptoms.
- Beta-sheet Breaker Peptides: these peptides have an inhibitory activity on the conversion of PrpC to PrpSC and the amyloidlike fibril formation.
- Chelation Therapy: copper levels can influence the conformational state of PrP, enhancing its infectivity, and this effect can be attenuated by chelator-based therapy using D-penicillamine, which selectively chelates copper.
- Immunological approach: recent studies demonstrated that the use of mouse vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, leads to a significant prevention of prion disease in mice later exposed orally to the 139A scrapie strain. In fact this vaccine induced the production of antibody binding to PrpC and/or PrpSC, which interfere with PrpSC-mediated conversion of PrpC to PrpSC and delay the onset of the disease.
The hystory and epidemiology of kuru has been the subject of many films, science fictions, books and documentaries such as the documentary, winner of the Special Jury Prize of Pacific International Documentary Film Festival (2011), Kuru: The Science and the Sorcery.
This documentary recounts the work of Alpers, Gajdusek and their colleagues in uncovering the link between kuru and endocannibalism in the Fore, the discovery of prions as the cause of the disease and also the relations between the disease and black magic.