Prion Disease: Genetic and Infectious
Prion Disease: Genetic and Infectious
Abstracts & Commentary
Sources: Prusiner SB. N Engl J Med. 2001;344:1516-1526; Roos RP. N Engl J Med. 2001;344:1548-1551; Lloyd SE, et al. Proc Natl Acad Sci U S A. 2001;98:6279-6283.
The normal human PrP gene (PrPc) maps to the short arm of chromosome 20 and is designated PRNP. Presently, 5 different pathological mutations of PRNP (PrPSc) have been linked to fatal familial prion diseases. Prion diseases need be not only poor genetics, however, they also can come in the form of infectious proteins transferred from the nervous systems of other animals. Prusiner points out that prion diseases naturally fall genetically into the category of one of the major, late life neurodegenerative illnesses. As is well known, genetic variability affects a number of the neurodegenerative disorders (eg, Alzheimer’s, Parkinson’s, Huntington’s, ALS, etc), and, in many instances, reflects the abnormal effect of more than a single genetic abnormality. None of these more widespread illnesses, however, share the rapidly disastrous, functional abnormalities caused by pathological prions. What’s different about pathological prions from other genetic diseases? The answer is that no other genetic abnormality can produce an infectious killer protein that is infectious. Nor can any family member, other than an identical twin, be likely to obtain the rare human killer protein unless they randomly cannibalize dying members of an infected tribe. The genetically inherited dominant genes that cause Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) disease, and fatal familial insomnia are all rare, progress rapidly, and reflect inborn mutations in PrP proteins. They’re not ordinarily infectious from person to person, but see below.
Abnormal (variant) PrPSc prions act as infections, but as noted above, unlike all other infectious agents, they fail to contain the nucleic acids DNA or RNA. Nevertheless, they possess infectious capacity. Once infected, the production of abnormal prions may be transferred from one animal to another of the same species as well as to other nonprimate mammals or even humans. This infectious aspect of the abnormal prion was first identified a little more than 40 years ago when an aboriginal, isolated New Guinea Kuru tribe was found to be indulging in cannibalism. A high, remarkable death rate in the tribe had developed gradually preceded by 14 advancing illnesses consisting of ataxia, tremor, dementia, and death. Death was followed by cannibalistic eating of the dead persons’ brains and muscles. A few years later, extracts from Kuru brains injected into the brains of chimpanzees induced a behavioral disintegration as well as autopsied brain that resembled the sufferings of prion disease in New Guinea. Since that time, abnormal PrP prions have unfortunately been transferred into human brain from undiagnosed, contaminated brain electrodes, from application of similarly infected dura mater of patients dying from prion deaths, too close surgical operations, and from cadaveric growth hormone taken from women dying from prion disease.
PrPSc diseases can affect a variety of species: human (Kuru, variant CJD, FFI); sheep (scrapie); cattle, (Mad cow disease), bovine spongiform encephalopathy (BSE); mink (transmissible mink encephalopathy); mules, deer, and elk (chronic wasting disease); feline spongiform encephalopathy (FSE); and exotic ungulate encephalopathy (Kudu, nyala, oryx). The most dramatic disaster, however, relates to the tragedy that followed the rapid infection by pathological prions in English cattle that started early in 1980 and rose to a peak of danger in 1992.
Roos adds an important supplement to Prusiner’s reports. Evidence indicates that from 1980 through 1982, cattle in South England were exposed in their diet to slaughtered feed of neural tissue taken from sheep or goats that died from scrapie, a well known disorder for centuries, but also a prion disease. Shortly after, for economic reasons, material from both cattle and sheep’s nervous systems was ground up and used for cattle feed. The result was horrifying with an incidence of identified BSE in UK cattle in more than 37,000 cases in 1992. Stringent attention stopped the dangerous feedings and by 2000, English BSE incidence dropped to 1537. Much smaller numbers have turned up in Germany, Ireland, and France.
Mad cow disease due to transferred abnormal prions into humans was categorized as new variant CJD (vCJD) with the incident age of its human sufferers varying from 13 to 22 years at onset. At this writing, no explanation has been forthcoming of the age of this young cohort. As to the total incidence of new vCJD in the United Kingdom thus far, approximately 100 human cases have appeared. Presently, only 4 vCJD cases have been identified outside of England, 3 in France and 1 in Ireland.
Roos emphasizes that safety of the blood supply for medical use has received special attention here in the United States. Up to the present, no human blood or blood fractions have given any evidence of carrying the new vCJD. No blood transfusion carrying vCJD has been found or mentioned in this country. Nevertheless, federal regulatory agents are making strong efforts to apply every possible prevention to keep blood free from CJD.
Commentary
Despite the tragic epidemic of vCJD in the United Kingdom, France, and Ireland, Neurology Alert finds no record of vCJD disease appearing in the United States. Weekly Report, a contemporary American newsletter on blood collection and transfusion, indicates that no patient anywhere in the world has as yet received vCJD from blood, whether it be sporadic or from a human donor who later developed vCJD. The US Department of Agriculture has had a screening program for BSE and scrapie and stringent prophylactic attention has prevented any evidence carriers.
Just within the past month, Lloyd and colleagues report that in mice the first possible step in identifying genetic susceptibility to prion diseases may be "where a methionine (NM) or Valine (v) may be encoded in the prion protein." All diagnosed cases of vCJD to date have contained the NM genotype.
A final point to consider: despite the enormous biomedical research that has been given to the normal and variant prions, until recently no one has discovered the normal function of cellular prion protein (PrPC). Without great shouting, a French group led by Mouillet-Richard has perhaps found the solution (Mouillet-Richard S, et al. Science. 2000;289:1925-1928). PrPC is normally found on nerve cell surfaces and apparently may be a signal transduction protein. —Fred Plum
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.