Abstract
Kuru, also referred to as the “laughing disease,” is a human prion disease first reported in publications by Carleton Gajdusek among the Fore tribes in Papua New Guinea. It is a non-inflammatory neurodegenerative disease in nature. It presents a form of transmissible spongiform encephalopathy, which is transmitted through the act of cannibalism.
It is also the first human prion disease successfully transmitted to non-human primates. Its discovery in the 20th century and successful transition were key to understanding other prion diseases. The pathology and transmission of prion diseases are attributed to the misfolding of the prion protein. Diagnostic evaluation is mainly conducted through the patient’s history and physical examination.
The kuru symptoms progress rapidly, accompanied by various cerebellar and extrapyramidal signs and symptoms. The death occurs within one to two years of the symptoms’ onset. The disease is universally fatal and is currently considered extinct.
Introduction
Human prion diseases (HPD) are progressive and fatal neurodegenerative diseases that are caused by abnormal, misfolded prion protein (PrPSc). They can be sporadic, genetic, or acquired; the latter group includes kuru, a non-inflammatory neurodegenerative disease representing transmissible spongiform encephalopathy (Mahat & Asuncion, 2021). The discovery of kuru opened new perspectives on human medicine. It played a key role in the subsequent transmission of Creutzfeldt–Jakob disease.
In contrast, kuru’s transmission to non-human primates belongs among the most significant contributions to biomedicine of the 20th century (Mahat & Asuncion, 2021). In this context, the current paper provides a comprehensive overview of kuru’s transmission, pathophysiology, histopathology, symptomatology, diagnostic evaluation, prognosis, and complications, highlighting the disease’s influence, effects, and outcomes.
Transmission
Kuru’s transmission mechanism was the subject of a long discussion. The disease is primarily localized to the Fore people of Papua New Guinea and those with whom they intermarried. Michael Alpers, an Australian medical researcher, conducted extensive studies, including one in 1961, accompanied by anthropologist Shirley Lindenbaum (Liberski et al., 2019).
Their research suggested the epidemic onset may have originated in 1900 from a single individual from the Fore territory who is thought to have developed some form of Creutzfeldt–Jakob disease (Hasbun et al., 2021). Consequent research successfully demonstrated that the disease spread rapidly due to Fore’s endocannibalistic funeral practices. Corpses of tribe members were often buried for several days, then exhumed, dismembered, and served with the larvae.
The elimination of cannibalism because of Australian colonial law enforcement and the local Christian missionaries’ efforts significantly contributed to the decline in the occurrence. According to research by Liberski et al. (2019), kuru had already declined among the Fore by the mid-1960s. However, the mean incubation period of the disease is 14 years, and 7 cases were reported with latencies of 40 years or more for those most genetically resilient, with continued appearances for several more decades (Hasbun et al., 2021). Therefore, there is still a probability of newly registered kuru cases.
Clinical Transmission
Kuru can be considered unique in its own disease group. According to Hasbun et al. (2021), it was the first human prion disease to be transmitted to non-human primates. The transmission of kuru to chimpanzees earned Carleton Gajdusek a Nobel Prize in 1976. Non-human primates include rhesus monkeys, marmosets, gibbons, and sooty mangabey monkeys (Liberski et al., 2019).
A detailed account of experimental kuru in 41 chimpanzees was published in 1973. The incubation period varied from 11 to 39 months, with the average being 23 months for the first passage, 12 months for the second, 13 months for the third, and 14 months for the fourth passage (Liberski et al., 2019). The clinical course was divided into three stages: prodromal, intermediate, and late.
The prodromal period, or stage I, is defined by the earliest behavioral alterations. In particular, animals become inactive, often extremely dirty, and submissive. Vicious and aggressive animals become passive and withdraw from competition with their normal cagemates, allowing smaller chimpanzees to tease and take food from them.
Periods of sullen apathy are often interrupted by outbursts of furious screaming. Apart from that, stage I is characterized by a period of minimal disabilities, such as minor motor dysfunction. Animals do not leave their cages; they slowly fall, their movements involuntary.
The beginning of an intermediate stage (II) is defined by difficulties when a chimp raises from a supine position; gait is ataxic; however, sitting is still possible. The gait of chimpanzees is quadrupedal, where they put their hands on the ground with their knuckles instead of their palms. Truncal titubation, a characteristic of human kuru, is also observed in stage II (Liberski et al., 2019). Muscle tone is increased, followed by flexion contractures. Choreiform movements are observed in conjunction with severe tremors, lateral nystagmus, visual difficulties, and intermittent left strabismus; however, Babinski signs are observed only occasionally.
Finally, at stage III, animals are unable to raise themselves from a supine position and cannot sit (Liberski et al., 2019). A severe startled response of flexion of all extremities develops, accompanied by the violent, coarse trembling of all limbs. Overall, the neuropathological picture is almost identical to that of natural kuru except for the absence of amyloid plaques. In the cerebral cortex, the spongiform change and intraneuronal vacuoles, similar to those encountered in scrapie, are the most prominent, accompanied by severe astrocytic gliosis (Liberski et al., 2019). Binucleated neurons are prominent; the same type of neuronal lesions can also be observed in the spider monkey.
Pathophysiology
The development and spread of prion diseases result from the abnormal folding of prion proteins. In kuru, the prion proteins (PrP) are encoded by the prion protein gene (PRNP gene) (Connor et al., 2019). PrPc is a customarily folded protein rich in alpha-helices and can undergo complete proteolysis. In turn, the PrPSc isoform is the form of a misfolded protein rich in beta sheets and resistant to enzyme degradation (Mahat & Asuncion, 2021). The PrPSc aggregates and promotes the conversion of other PrPc proteins to PrPSc (WHO, n.d.).
Consequently, a chain reaction is initiated, leading to the pathogenesis of prion disease. Since prions are naturally occurring proteins, no inflammatory or immunologic reactions are present against them (CDC, n.d.). It is likely due to the negative selection of B and T cells that recognize the misfolded PrPSc as a self-protein because it is identical to the normal PrPc.
The disease resistance varies depending on an individual’s homozygosity. Individuals with homozygosity of the methionine allele at the prion protein gene’s codon 129 are susceptible to a short incubation period and early death. Conversely, individuals with heterozygosity at this position are relatively resistant to the disease, exhibiting longer incubation periods and delayed mortality (Mahat & Asuncion, 2021). Finally, heterozygosity at codon 127 provides strong and possibly complete resistance to kuru.
Histopathology
Autopsy brain specimens show neither perivascular scuffing nor other signs of inflammatory brain pathology. No lesions are visible on the brain; however, microscopic brain studies reveal astrocyte proliferation and hypertrophy resulting from neuronal damage. Gliosis and vacuolization are present throughout the brain’s gray matter. The neurons are hyperchromatic and shrunken, with the Nissl substance dispersion within the intracytoplasmic vacuoles similar to that seen in scrapie (Mahat & Asuncion, 2021). Purkinje cells (cerebellum) and Vacuolated neurons (striatum) also appear.
The most affected structures include the deeper layers of the cortex, the flocculonodular lobe in the cerebellum, the vermis, and the corticospinal and spinocerebellar tracts of the spinal cord. Amyloid plaques are also seen in the cortex, thalamus, basal ganglia, and cerebellum, in ascending order (Mahat & Asuncion, 2021). These plaques stain with periodic Alcian blue, acid-Schiff, and Congo red stains. Anti-PrP immunocytochemistry can also demonstrate the accumulation of prion protein in brain tissues.
Symptomatology
After a patient is infected, a prodromal phase may occur, lasting several months. Symptoms include headaches and joint pain, with the knee, elbow, ankle, and wrist joints typically involved (Liberski et al., 2019). Weight loss and abdominal pain can also be present. Despite kuru resembling an infectious etiology, it does not exhibit the classical signs of meningitis or encephalitis, such as fever, convulsions, or coma. The three discernible phases in kuru include ambulatory, sedentary, and terminal.
The ambulatory phase usually presents with features of cerebellar ataxia. There is a slight gait unsteadiness that progresses to ataxia and incoordination of the trunk and lower limb muscles (Mahat & Asuncion, 2021). The body shivers, which is exacerbated by lower temperatures. Titubation and other abnormal body movements are presenting signs.
Curling of feet and clawing of toes are observable for maintaining balance. Patellar clonus and ankle clonus are the hallmark clinical picture. As the disease progresses, the Romberg sign may be present (Mahat & Asuncion, 2021). Cerebellar signs such as nystagmus, dysarthria, dysmetria, and intention tremor are also reported. Individuals are also emotionally labile and may exhibit sporadic, uncontrolled laughter. This is the reason why the disease is also referred to as the “laughing disease.”
The second, or sedentary, phase begins when the patient can no longer stand without support and ends when the patient can no longer sit without support. The ataxia, dysarthria, and tremor worsen during this phase. Hyperreflexia is more pronounced, and the plantar response remains flexor (Mahat & Asuncion, 2021). Other symptoms include jerky eye movements, opsoclonus, and dystonia.
During the final, or terminal, stage, the patient is bedridden and may develop dysphagia and incontinence. Victims are unresponsive to their surroundings, although conscious. Exaggeration of deep and primitive reflexes is present, but the Babinski response is negative. A fixed dystonic posture with athetosis and chorea is noted. Terminally moribund patients usually die of pneumonia or infection of the ulcerated wounds within 9 to 24 months of the onset of the disease (Mahat & Asuncion, 2021). Features of dementia may also be present, but not as prominently, compared to other prion diseases.
Diagnostic Evaluation
Assessment primarily involves reviewing the patient’s medical history and performing a physical examination. The World Health Organization’s clinical diagnostic criteria for HPDs include clinical findings, cerebrospinal fluid protein markers, and electroencephalography (WHO, n.d). In the meantime, according to the Centers for Disease Control and Prevention, the gold standard for definitive diagnosis of prion disease is the histology of autopsy specimens (Connor et al., 2019).
The typical progression of symptoms in vulnerable populations leads to high suspicion of the diagnosis. No laboratory or imaging tests are available to definitively diagnose kuru (Connor et al., 2019). The pathological evaluation of CNS tissue, along with distinct histopathological findings, is diagnostic. The electroencephalogram is abnormal, but no periodic sharp waves are present, unlike in other prion diseases.
It is vital to differentiate and rule out other forms of dementia that are treatable and reversible. Other dementias are associated with cerebellar signs and symptoms, which can be differentiated from kuru disease by brain and vascular imaging, appropriate blood and serological workup, pathological evaluation, and genetic studies (Satoh & Nakamura, 2022). These differentials for kuru include other diseases of a prion group, autoimmune or antibody-mediated disorders, Alzheimer’s disease, frontal and temporal dementias, encephalitis, infections, neoplasms and paraneoplastic syndromes, metabolic disorders, and toxins or metal poisoning.
Prognosis and Complications
Human prion diseases, including kuru, are universally fatal, with no treatment other than support. The quality of life is greatly diminished, and victims mainly depend on their relatives in the latter half of the disease stage. As patients with kuru deteriorate, they develop severe cerebellar and extrapyramidal signs and symptoms.
As mentioned earlier, the patients become moribund and bedridden. Therefore, the patient’s care relies heavily on family members who act as caregivers once they reach the third stage of the disease. The patients are malnourished and can develop decubitus ulcers with secondary infections and aspiration pneumonia, which typically causes death.
Conclusion
Although kuru disease is now considered extinct, other prevalent prion diseases continue to threaten society. The kuru disease is a pioneer in the discovery of infectious prion proteins, providing clues and knowledge to other prion counterparts. Researchers are investigating various therapeutic approaches that target the conversion of PrPc to PrPsc. Nevertheless, no successful treatment has been found to date. Therefore, collaboration is necessary for the development of compelling therapeutic studies to gain a deeper understanding of this disease group and achieve success, ultimately improving the quality of life.
References
Centers for Disease Control and Prevention (CDC). (n.d.). Prion diseases. Web.
Connor, A., Wang, H., Appleby, B. S., & Rhoads, D. D. (2019). Clinical laboratory tests used to aid in diagnosis of human prion disease. Journal of Clinical Microbiology, 57(10), e00769-19. Web.
Hasbun, R., Bloch, K. C., & Bhimraj, A. (Eds.). (2021). Neurological Complications of Infectious Diseases. Springer International Publishing.
Liberski, P. P., Gajos, A., Sikorska, B., & Lindenbaum, S. (2019). Kuru, the first human prion disease. Viruses, 11(3), 232. Web.
Mahat, S., & Asuncion, R. M. D. (2021). Kuru. StatPearls [Internet]. StatPearls Publishing. Web.
Satoh, K., & Nakamura, T. (2022). Human prion disease. Clinical and Experimental Neuroimmunology, 13(1), 24-33. Web.
World Health Organization (WHO). (n.d.). Transmissible spongiform encephalopathies. Web.