TSEs IN HUMANS

Different types of prion diseases in humans include Creutzfeldt-Jakob disease (CJD): variant CJD, sporadic CJD, iatrogenic CJD, and familial CJD, kuru, Gerstmann-Straussler-Scheinker Syndrome, and fatal familial insomnia. Transmission can occur from person to person or animal to person. However, it is important to realize that not all TSEs can cross the species barrier, and some can only cross the species barrier in one direction. It is not known why some can and others cannot. Finally, prion diseases can be hereditary with two different tranmission pathways. If a mother has a TSE, the misfolded protein may be in the cytosol of her egg and may be passed in this way to her child through maternal inheritance (sperm has so little cytoplasm that it is much less likely to transmit). In addition, there is a mutant gene in which a one base-pair change may lead to an amino-acid substitution which changes the conformation to primarily beta-sheets, as in the PrPSc conformation. This genetically-altered protein is heritable by regular genetic inheritance patterns (Prusiner, 2004).




This is a photo of the different brain regions affected by TSEs. Photo courtesy of nobelprize.org

Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob (CJD) is the most common prion-related disease in humans, with approximately one case per million people worldwide per year (almost seven thousand people will contract this disease in 2010). The first cases were reported by two neurologists, Hanz Gerhard Creutzfeldt and Alfonz Maria Jakob, in Germany in the early 1920s. Its origins are genetic in only as many as 10 percent of cases and sporadic in approximately 85 percent of cases. It has been suggested that CJD may be acquired through blood transfusions or contact with infected blood.

Creutzfeldt-Jakob is certainly transmissible person-to-person; iatrogenic transmission has been documented after corneal transplants, through use of human growth hormones, dura mater transplants, and intra-venous immunoglobins associated with infected individuals, ingestion of infected tissue or significant contact with infected fluid or tissue. The Centers for Disease Control found no evidence that individuals who receive blood transfusions regularly or come into contact with possibly infected blood (nurses, doctors etc.) show any greater incidence of Creutzfeldt-Jakob disease than the rest of the population.

The first symptoms of CJD are dementia, which progresses rapidly and involves memory problems, personality changes and hallucinations, poor coordination of movement, and abnormal gait and speech. As the disorder progresses and the sponge-like damage moves from the cerebellum down through the medulla and brain stem the patient starts to have tremors or myoclonus, move rigidly and spastically, and their reflexes may fail. These are all symptoms of spongiform neural damage.
CJD is ultimately fatal and, once symptoms appear an individual can expect anywhere from a few weeks to years left to live. A new variant of CJD (vCJD) was discovered recently in concurrence with rising incidence of bovine spongiform encephalopathy (BSE). vCJD was determined to be a human expression of BSE. Like kuru, vCJD is also transmitted through ingested neural tissue. It is possible that vCJD may have a similar incubation period to kuru, which may be as long as forty years. Another theory is that some individuals with kuru and CJD may have a genetic mutation that makes the incubation period longer, while those who do not have the gene will have a shorter incubation period of a few years.



photo courtesy of http://nobelprize.org


Kuru

Kuru is a particularly interesting disease because of its shocking history and origins found in the cannibalistic Fore tribe in Papua New Guinea. Kuru is an unnatural proliferation of prion diseases through cannibalistic ingestion of infected tissue from individuals who suffered from sporadic or genetic Creutzfeldt-Jakob disease . Kuru is also called the laughing sickness, a reference to uncontrollable laugher that accompanies the dementia, and the word "kuru" is taken from the Fore verb "to shake," a reference to the uncontrollable twitching the accompanies the disease. The men who discovered kuru, Baruch S. Blumberg and Daniel Carleton Gadusek earned the 1976 Nobel Prize in Medicine. Kuru may have a very long incubation period, perhaps up to forty years, although the average incubation period is fourteen years. The difference in incubation period depends on genetic factors and researchers have found that inheritance of a particular genetic variant of a prion protein made some members of the Fore tribe and their ancestors immune to the kuru epidemic.


Gestmann-Straussler-Scheinker Syndrome

Gestmann-Straussler-Scheinker (GSS) is so called because it was first reported in 1936 by Josef Gerstmann, Ernst Straussler and Ilya Scheinker. GSS is a thought of as a variant of familial Creutzfeldt-Jakob , though it is related to a different set of mutations of the prion protein gene. GSS is defined by genetic origins, neurodegeneration, occasional myoclonus, and common symptoms which include dementia, poor articulation due to difficulty controlling movements of tongue or mouth, difficulty controlling eye movements, poor reflexes, and abnormal gait and difficulty controlling movement in general. The first symptom is often memory loss. An individual can live with GSS from anywhere from a few years to a decade, though on average, individuals with GSS die after about five years. Approximately five out of every hundred million people a year are diagnosed with GSS.


Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is much less common than even Gestmann-Straussler-Scheinker syndrome. The scientific community is still unsure of how many people have ever died from or had this disease. Only fifty families in the world, however, have been found to possess the FFI prion protein gene mutation.

Fatal Familial Insomnia is a genetic disorder similar to Creutzfeldt-Jakob disease, but is distinct because the infectious prion proteins are primarily located in the thalamus, and thus spongiform neurodegeneration occurs here. Since the thalamus is involved greatly in the facilitation of sleep and wake states, the distinguishing symptom of FFI is the inability to sleep. FFI was discovered in 1974 by an Italian doctor, Ignazio Roiter upon observing two sisters who seemed to have died from insomnia. In the late 1990s, when prions were being heavily research, FFI was found to be a variant form of familial CJD that involved a different mutated prion gene.

There are four phases of FFI, and patients usually die between seven months and three years after onset. In first stage (four months on average,) increasing insomnia leads to paranoia, phobias and panic attacks. In the second stage (five months on average,) panic and hallucinations are readily observable. In the third stage (three months on average,) the patient is completely incapable of sleep and loses weight quickly. In the final stage the patient loses cognitive ability completely, is consumed by dementia and becomes mute and unresponsive before dying.









 
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