Kuru is the prototype human prion disease first reported in publications by Dr. D. Carleton Gajdusek and Vincent Zigas in 1957 in the Fore tribes of Papua New Guinea. The word “Kuru” means to tremble due to fever or cold. It is a non-inflammatory neurodegenerative disease and is a form of transmissible spongiform encephalopathy transmitted through the act of cannibalism.
The symptoms of Kuru progress rapidly with cerebellar and extrapyramidal signs and symptoms, with death occurring within one to two years of onset of symptoms. The disease is now extinct, but its discovery in the 20th century was pivotal for understanding the other prion diseases. Other prion diseases include Creutzfeldt-Jakob disease(CJD), fatal familial insomnia (FFI),variant CJD(vCJD), and Gerstmann-Straussler-Scheinker(GSS) disease.
Kuru was prevalent in the Eastern Highlands of Papua New Guinea in the early 1900s. The disease was confined to the Fore tribe and their neighboring linguistic groups. The infectious prion becomes enriched in the victim’s brain.
At its peak in the 1940s to the 1950s, the mortality rate on the affected villages went as high as 35/1000 population. Children and women were usually more affected than men, probably because they consumed the brain as compared to the men who preferred muscles. With the decrease in the practice of ritualistic cannibalism, the cases decreased rapidly after the 1950s.
An active survey in Papua New Guinea from July 1996 to June 2004, identified only 11 new cases. In some of those cases, researchers noted an incubation period of more than 50 years. There are no new cases recorded recently, with the last case reported in 2005.
The prion proteins(PrP) are encoded by the prion protein gene (PRNP gene). PrPc is a normally folded protein, rich in alpha-helices, and undergoes complete proteolysis. The PrPSc isoform is the misfolded protein that gives rise to the disease; it is rich in beta sheets and is resistant to degradation by enzymes. Thus the PrPSc aggregates and further promotes the conversion of other PrPc to PrPSc. A chain reaction is set, which results in the pathogenesis of prion disease.
As a prion is a naturally occurring protein, no immunologic or inflammatory reactions are present against it; this is probably due to the negative selection of T and B cells that recognizes the misfolded PrPSc as a self protein since it is identical to the normal PrPc protein.
Individuals with homozygosity of methionine allele at codon 129 of prion protein gene (PRNP gene) were susceptible to short incubation period and early death. In contrast, ones with heterozygosity at this position were relatively resistant to the disease with longer incubation periods and delayed death. On the other hand, heterozygosity at codon 127 provides strong, and possibly complete, resistance to kuru.
Grossly no lesions are seen on the brain. Autopsy specimens of the brain did not show any perivascular scuffing or other signs of inflammatory brain pathology.
However, microscopic studies of the brain show astrocyte proliferation and hypertrophy due to neuronal damage. Gliosis and vacuolization extending throughout the gray matter of the brain are present. The neurons were shrunken and hyperchromatic, with the dispersion of Nissl substance within the intracytoplasmic vacuoles similar to those seen in scrapie. Vacuolated "moth-eaten" neurons (striatum) and Purkinje cells (cerebellum) are also a feature. Most affected structures involved the deeper layers of the cortex, the vermis and flocculonodular lobe in the cerebellum, and the corticospinal and spinocerebellar tracts in the spinal cord.
Amyloid plaques are known as "kuru plaques" are seen, which are numerous in the cerebellum, basal ganglia, thalamus, and cerebral cortex in descending order. These amyloid plaques stain with periodic acid-Schiff, Alcian blue, and Congo red stain. Anti PrP immunocytochemistry can be useful to demonstrate Prion protein accumulation in brain tissues as well.
Kuru is an invariably fatal neurodegenerative disease. It has a predictable history as compared to other prion diseases.
Once a victim is infected, an ill-defined prodromal phase may be present that lasts a few months. Symptoms include headaches and joint pains. The knee, ankle, elbow, and wrist joint are usually involved. Abdominal pain and weight loss can also be present. Although kuru was thought to have an infectious etiology, there are no classical signs of meningitis or encephalitis like fever, convulsions, or coma.
The three discernible phases in kuru include:
Evaluation is mainly through history and physical examination. The characteristic progression of symptoms in the vulnerable populations leads to high suspicion of the diagnosis. There are no laboratory and imaging tests available that give a definitive diagnosis of Kuru. The pathological evaluation of CNS tissue and distinct histopathological findings are diagnostic. EEG is abnormal, but no periodic sharp waves are present, as compared to other prion diseases.
Human prion diseases are universally fatal with no treatment other than supportive treatments to this date.
It is crucial to differentiate and rule out other forms of dementia that are treatable and reversible. Further dementia may be associated with cerebellar signs/symptoms, which can be differentiated with kuru disease by the brain and vascular imaging, appropriate blood workup, serological workup, pathological evaluation, and genetic studies. These differentials for kuru include:
Kuru is universally fatal, with death typically occurring within 24 months of the onset of symptoms. The quality of life is greatly diminished, and victims are mostly dependent on their relatives in the latter half of the disease stage.
As Kuru patients deteriorate, they develop severe cerebellar and extrapyramidal signs and symptoms. The patients become moribund and bedridden.
The care of the victim relies heavily on family members who act as caregivers once they reach the third stage of the disease. The patients are malnourished, can develop decubitus ulcers with secondary infections, and aspiration pneumonia, which causes death.
The end of cannibalism has put an end to Kuru disease. The last case recorded was in 2005. However, it remains the first described transmissible spongiform encephalopathy unraveling the mystery of other prion diseases. Although kuru has disappeared, it remains significant for the largest outbreak of human to human transmission of prion disease transmitted through the oral route in the Eastern Highlands of Papua New Guinea.
Although it has been a decade since the last report of kuru disease, other prevalent prion diseases are universally fatal. The kuru disease stands as a pioneer in the discovery of the infectious prion proteins, thus providing knowledge and clues to the other prion diseases.
The current data about the natural history and clinical progression of the disease, as well as its detrimental effects (death), and designing an effective therapeutic study, have all proved challenging. Researchers are studying different therapeutic approaches targeting the conversion of PrPc to PrPsc. However, no successful treatment exists to date. Thus, a collaboration for effective pooling of the therapeutic studies is necessary to unravel more about prion diseases. Establishing an early diagnosis can be the key to therapeutic success and improvement of quality of life.
Currently, the treatments focus on symptomatic improvements of the patients. This care should include multidisciplinary support teams, hospice care, and the family members of the victims.
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