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From: TSS ()
Subject: Prion disease and gene types
Date: June 3, 2008 at 12:48 pm PST

Prion disease and gene types

Dr Simon Mead and Professor John Collinge, NHS National Prion Clinic

Readers will be well aware that by eating contaminated food in the 1980s and early 1990s, much of the UK population has been potentially exposed to Bovine Spongiform Encephalopathy (BSE, commonly known as ‘mad cow disease’). For over a decade we have known that the infectious agent or prion that causes BSE may also infect humans, causing the fatal brain illness variant Creutzfeldt-Jakob disease (vCJD). While, fortunately, numbers of patients developing vCJD have been relatively small so far, and indeed numbers of patients seen have been falling in recent years, we do not know how many people might be silently infected with BSE prions. It is known that it may take several decades for signs of the disease to show and that our genetic make up is important in determining this. From research in laboratory mice, we also know that some may become ‘carriers’ of the infection but do not themselves develop the disease. People with such a ‘subclinical’ infection would still pose a potential risk to others by blood donation or contamination of surgical instruments for example.

the importance of gene types

We have known for many years that a common variation in a gene, known as the prion protein gene, is very important in determining the risk of developing prion diseases and how long it takes for the disease to develop when someone becomes infected. There are three genetic types in the UK population known as MM, VV and MV. So far, vCJD has only affected people with MM genetic type. Around 40% of healthy people in the UK are MM, about 50% are MV and around 10% are VV. It is likely that BSE prions will infect people of the VV and MV types also, but they may have much longer incubation periods (the time taken from being infected with prions until the brain disease becomes apparent) and may also develop a pattern of disease which may be different to vCJD. We suspect this again as result of research in laboratory mice wher e those that had the VV and MV genes had a different type of disease and different types or ‘strains’ of prions developed. Kuru was an epidemic prion disease which affected the Fore people living in the Eastern Highlands of Papua New Guinea. It was the practice in these communities before 1960 to consume their dead at mortuary feasts as a mark of respect and mourning and this led to the prion infection passing between people. Kuru has now largely disappeared but from studies over the past decade we have learned that the incubation periods can be over 50 years and that the MM, VV and MV people have different incubation periods, MV individuals having the longest. A similar effect was seen in people accidentally infected with prions when they were treated with growth hormone injections before 1985 (so called iatrogenic CJD).

an unusual diagnosis

Some years ago at the National Prion Clinic we looked after a young woman with a severe dementia and loss of balance. Her examination and other tests such as her MRI brain scan suggested that her diagnosis was sporadic CJD. Most patients with sporadic CJD are MM, but the disease also occurs in VV and MV patients. Her genetic type was VV. After she died we investigated the cause of death further by microscopic examination of the brain, and by testing the abnormal prion protein deposits in the brain. Sporadic CJD is usually a disease of late adult life while vCJD has largely occurred in young adults. Because she was young, we obviously wished to consider the possibility that her illness was related to BSE rather than being a sporadic case. The autopsy findings were not typical of sporadic CJD, with a lot of prion protein deposited in the brain. However, these changes were not similar to vCJD either. Also in vCJD, prions are deposited at high levels in certain tissues outside the brain and spinal cord known as lymphoreticular tissues (lymph nodes, tonsil and spleen for example) but these samples were not available for analysis from this patient.

prion strains

Prions occur in different forms or strains. These can be distinguished by looking at the rogue prion protein (known as PrPSc) from brain tissue. In this patient we found a molecular strain different from any of the types we have seen in sporadic CJD and similar to that which we see in vCJD (which we call type 4 PrPSc). Although quite similar to type 4, we showed that the new type was different because it could be distinguished from the typical vCJD pattern by additional special tests.


In summary, although this young woman clearly died of a prion disease, we could not conclude she had vCJD, but also we could not be sure this was sporadic CJD either. Although we were not able to make definite conclusions on the basis of a single patient, we felt it important to report this tragic death and these findings in the medical literature so as to bring this to the attention of other doctors who might see similar patients in the future. This unusual finding reminds us of the importance of keeping alert to the possibility that BSE prions will cause disease in individuals with different genetic types, who may develop a disease that may resemble sporadic CJD, or vCJD, or have a new pattern of disease. This work emphasises the importance of continuing to study the rogue prion protein type in patients and we thank all patients and families who have kindly consented to use their, or their loved one’s, tissues for this medical research.

Reference: Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman Simon Mead; Susan Joiner; Melanie Desbruslais; Jonathan A. Beck; Michael O’ Donoghue; Peter Lantos; Jonathan D. F. Wadsworth; John Collinge Arch Neurol. 2007;64(12):1780-1784. Newsletter issue 17 april 2008

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc ype in a Young British Woman


The Italian cases (11 and 15 years of age) originally named bovine amyloidotic spongiform encephalopathy (BASE) were characterized by an unglycosylated protein band with a lower molecular mass (thus named L cases) and the predominance of the monoglycosylated band. In addition, immunohistochemical detection of PrPres in these cases found greater deposits in the cerebral cortex and thalamus versus the brain stem. The French cases found a higher molecular mass associated with the unglycosylated protein band and were called H cases (see figure 1). *** The different “strains” are now called atypical BSE. ...

full text, skroll down to page 6 ;

MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE

***Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.***

Progress Report from the National Prion Disease Pathology Surveillance Center

An Update from Stephen M. Sergay, MB, BCh & Pierluigi Gambetti, MD

April 3, 2008

AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.


NOT to forget the 5 cases of the NOR-98 atypical scrapie documented in the USA in 2007, in five different states. WHICH pathologically looks like some sub-types of sporadic CJD, of which Stanely Prusiner warns of a public health risk ;

***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)

Chronic Wasting Disease


Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.

Communicated by: Terry S. Singeltary Sr.

[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP],F2400_P1001_PUB_MAIL_ID:1010,39963

There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey b y intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

Journal of American Medical Association

Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT

2 January 2000 British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999 British Medical Journal vCJD in the USA * BSE in U.S.


Why Americans, As Well as Koreans, Should Be Worried About Mad Cow Tainted USA Beef

By Terry S. Singeltary Sr. May 15, 2008

Straight to the Source

Web Note: This is an important commentary by Terry S. Singeltary Sr., on a recent Business Week story on the controversy in South Korea over their government's lifting on the ban on conventional (non-organic) beef, despite the fact that the USDA is still allowing slaughterhouse waste and blood and manure to be fed to cows, and refusing to test all cows at slaughter. See the Mad Cow section of the OCA website for in-depth information. Terry is a regular blogger on the OCA website on Mad Cow issues.

Ronnie Cummins

One Korean official says the probability of a human being catching a mad cow disease by eating U.S. beef is like the one of a golf player scoring a hole-in-one and then being killed by lightning.

this is typical BSe. you here industry groups comment 'your more likely to get hit by a car than die from CJD'. well, maybe so, but my mother and many more did not die from getting hit by a car, they died from CJD, my mothers being the hvCJD (confirmed), and my neighbors mother died from CJD (confirmed). the UKBSEnvCJD _only_ theory is incorrect. there are more strains of mad cow than the UK BSE in beef to nvCJD in humans in the UK. The deception by the USDA, FDA, and the Bush administration about mad cow disease, CJD, and all Transmissible Spongiform Encephalopathy over the past 8 years have been outrageous, to a point of being criminal. I am vested in nothing, but the truth.

snip...see full text ;

Tuesday, May 13, 2008

Concerned Americans against Mad Cow Disease STATEMENT OF SOLIDARITY with Koreans May 13, 2008


Tuesday, May 27, 2008

FDA BSE/Ruminant Feed Inspections Firms Inventory Report Texas Legend Ranch OAI 05/10/2008


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