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Prion disease update 2012


[With the continuing decline in the number of cases in the human population of variant Creutzfeldt-Jakob disease — abbreviated previously as vCJD or CJD (new var.) in ProMED-mail — the scope of the occasional ProMED-mail updates has been broadened to include other prion-related diseases. In addition to vCJD, data on other forms of CJD: sporadic, iatrogenic, familial, and GSS (Gerstmann-Straussler-Scheinker disease) are included also since they may have some relevance to the incidence and etiology of vCJD. – Mod.CP]

In this update:
[1] UK: National CJD Surveillance Unit – monthly statistics not updated as of Wed 4 Jan 2012 – no new vCJD cases.
[2] UK: caprine BSE, comment
[3] Bacterially expressed recombinant protein is infectious
[4] Evaluation of vCJD blood test
[5] Turkey: 1st probable vCJD case
[6] Prions in spleen
[7] Neurotoxic monomer

[1] UK: National CJD Surveillance Unit – monthly statistics not
updated as of Wed 4 Jan 2012 – no new vCJD cases.
Date: Thu 16 Feb 2012
Source: UK National CJD Surveillance Unit, monthly statistics [edited]
Refer to ProMED-mail Prion disease update 2012 (01), archive no 20120104.0027 for UK vCJD statistics up to 4 Jan 2012.

communicated by: ProMED-mail

[2] UK: caprine BSE, comment
Date: Wed 4 Jan 2012
From: David Thomson [edited]
re: Isolation of prion with BSE properties from farmed goat [ProMED-mail Prion disease update 2012 (01) 20120104.0027, part [2]
It may be relevant to consider the reported rare BSE cases in small ruminants (goats) from a slightly different perspective.

To my knowledge it has not yet been possible to definitively determine the precise origins of BSE affecting cattle, despite it being relatively widely accepted that feeding of inadequately processed, contaminated animal proteins (presumably derived from infected cattle)
to cattle resulted in spread, gross amplification, and the large scale outbreak that occurred in the UK after 1986.

Is it conceivable that rather than being a rare disease of goats acquired from exposure to cattle-origin proteins in feedstuffs, BSE might, in fact, have originated as a relatively ‘rare’ small ruminant TSE that jumped to cattle (via small ruminant origin animal proteins)
where it was then capable of much more aggressive spread than in its original source host species?

Given the information in the report that goats in the UK are inherently managed relatively intensively and that they will test positive to BSE if infected with BSE (whereas when sheep are co-infected with BSE and scrapie, they tend to test positive only to scrapie), it may perhaps be significant that there has not been more evidence of BSE infection detected amongst UK goats, especially those now aged animals likely exposed to contaminated feedstuffs during the period before the feed ban was implemented in the UK.

Further retrospective studies of scrapie cases amongst goats predating 1984 (if sufficient material is still available) may be helpful to clarify this issue.

David Thomson
DV Grafton, LHPA

[Can any reader provide information or comment on the presence of BSE in goats in the UK prior to 1984? – Mod.CP]

[3] Bacterially expressed recombinant protein is infectious

Date: Thu 12 Jan 2012
Source: Journal of Virology [edited]

[ref: Wang F et al: Genetic informational RNA is not required for recombinant prion infectivity. J Virol. 2012; 86(3): 1874-6]

Whether a genetic informational nucleic acid is required for the infectivity of transmissible spongiform encephalopathies is central to the debate about the infectious agent. Here we report that an infectious prion formed with bacterially expressed recombinant prion
protein plus synthetic polyriboadenylic acid and synthetic phospholipid 1-palmitoyl-2-oleoylphosphatidylglycerol is competent to infect cultured cells and cause prion disease in wild-type mice. Our results show that genetic informational RNA is not required for
recombinant prion infectivity.

communicated by: ProMED-mail

[Definitive proof that prions are infectious agents comprised of protein in a misfiled form and devoid of nucleic acid in contrast to all other known infectious pathogens. – Mod.CP]

[4] Evaluation of vCJD blood test
Date: Fri 13 Jan 2012
Source: Channel 4 News [edited]
A blood test for variant CJD is for the 1st time being offered to patients from around the United Kingdom and some from abroad who are suspected of having what was once known as mad cow disease. [A detailed description of this test was posted previously as part [5] of
ProMED-mail Prion disease update 2011 (08), archive no 20110905.2710. – Mod.CP]

Channel 4 News has learned that a notification has been sent to neurologists around the country from the NHS [National Health Service] National Prion Clinic and the Medical Research Council’s Prion Unit saying that the blood test is now available. Between 5 and 10 samples a week are now being sent in from here and other countries where there have been cases of vCJD.

Professor John Collinge, who has been part of the team developing the blood test, said that so far the test had not produced any false positive results — that is, where a test shows there is infection when there is none. This is a significant step forward in the fight against the disease.

Channel 4 News has also learned that funding from the Medical Research Council has meant the team has now been able to begin a crucial new phase in assessing the blood test. This involves testing 5000 anonymous samples from the US, supplied from the American Red Cross. America [had] low levels of exposure to BSE and the tests will enable
the scientists to assess the false positive rate. This is a significant step forward in the fight against the disease. [However]
Prof Collinge said if they find there are a significant number of
false positives then “it will be back to the drawing board.”

If, on the other hand, the test works [that is, finds no false
positives], then the next step will be to screen 50 000 anonymous UK
blood donors which would allow the 1st accurate assessment of how many
people in this country are carrying the disease.

Recent studies from tonsil samples show that possibly one in 4000
people in the UK or 15 000 in total may be infected with the [prion
associated with] the disease, although some tests have put the numbers
slightly higher.

The latest figures from the Health Protection Agency show that there
have so far been 176 definite or probable cases of vCJD since it was
first detected in humans in 1995 until the end of 2011. Channel 4 News
understands that there was a [single] “cluster” of deaths at the end
of a year in which 4 people died.

Variant CJD [vCJD] is a human form of bovine spongiform encephalopathy
(BSE) which first emerged in Britain in 1986 as a result of beef offal
being fed to cattle. The prions which are responsible for BSE and vCJD
were found in the brains, spinal cords, and spleens of cows. When the
meat was mechanically recovered, and turned into the likes of
hamburgers and baby food, the prions entered the human [food] chain.

Variant CJD is a cruel disease which causes a form of dementia,
affecting both the brain and nervous system. It has a long incubation
period and mainly affects young people. The majority of deaths have
been in those in their 20s, although there have been exceptions.

The development of a possible blood test was announced last February
2011 in a scientific paper published in The Lancet. Permission has now
been given by UCLH [University College London Hospitals], the hospital
trust to which Prof Collinge and his team are attached, to start a
clinical evaluation in patients in whom a diagnosis of vCJD is

Currently blood undergoes leucodepletion, which involves the removal
of the white blood cells. But this does not remove all the prions

[cells carrying prions]

and there have been several cases of people
infected with vCJD after receiving blood products. There have also
been cases of people being infected through the use of surgical

It is understood that a 50 year old woman died from vCJD within the
past few weeks after she received a blood transfusion in 2002 — 4
years after leucodepletion was introduced.

Professor Collinge told Channel 4 News said that the blood test was
“extremely good news”. “In principle, it may allow us to find how many
people in the population are infected so we can target risk management
strategies and ensure the safety of our blood supply,” he said. “It
could also enable us to make an earlier diagnosis and as treatments
become available it is going to be desperately important to get to
patients early before there is extensive damage to the brain.”

Frank Dobson, who was the health secretary who introduced
leucodepletion, urged the government to provide any necessary future
funding. “Up to now we have been flying blind, applying the
precautionary principle. We now need to have extensive trials because
we do not know who is carrying it and who is donating blood,” he

But apart from the government backing needed if they are able to go to
the next phase and start testing UK blood samples, professor Collinge
said they would also need a commercial company to step in and take
over because his laboratory is simply not capable of dealing with such
large scale samples.

[byline: Victoria Macdonald]

communicated by:

[5] Turkey: 1st probable vCJD case
Date: Sat 24 Dec 2011
Source: Dementia and Geriatric Cognitive Disorders Extra [edited]

[ref: Adapınar DO et al: The first report of a patient with probable
variant Creutzfeldt-Jakob disease in Turkey. Dement Geriatr Cogn Dis
Extra. 2011; 1(1): 429-32]

[Interested readers should access the original paper via the source
URL to view the full text, the figures, and the references cited. –

Variant Creutzfeldt-Jakob disease (vCJD) was first reported in the UK
in 1996. Here, we report the 1st Turkish case of vCJD. A 47 year old
man, who has never lived outside of Turkey and had had no transfusion,
was admitted to the University Hospital with speech disorder,
cognitive decline, and ataxia following depression, irritability, and
personality change. The immunoassay of the 14-3-3 protein in the
cerebrospinal fluid (CSF) was negative. [The presence of 14-3-3
protein in CSF has been shown to be highly sensitive and specific for
the diagnosis of Creutzfeldt-Jakob disease. – Mod.CP]. Brain magnetic
resonance imaging revealed high-signal lesions involving the bilateral
caudate and lentiform nucleus on T2- and diffusion-weighted imaging.
The patient developed akinetic mutism 10 months after disease onset.
The clinical presentation and neuroimaging findings were compatible
with the vCJD cases reported since 1996 and met the World Health
Organization’s case definition for probable vCJD.

Creutzfeldt-Jakob disease (CJD), which is characterized by progressive
dementia with a fatal and incurable course, is the most common human
prion disease. There are 4 types of this disease: the sporadic (85 per
cent), familial (10-15 per cent), iatrogenic (1 per cent), and variant
types [1]. Variant Creutzfeldt-Jakob disease (vCJD) was first reported
in 1996 in the United Kingdom and has been causally linked to the
consumption of cattle products contaminated with the bovine spongiform
encephalopathy (BSE) agent [2]. To date, more than 215 cases of vCJD
have been identified worldwide, including in the UK, France, Ireland,
Italy, the USA, Canada, Saudi Arabia, Japan, The Netherlands,
Portugal, Spain, and Taiwan. In the present paper, we report the
clinical and radiological data of the 1st Turkish case of vCJD.

Case report
A 47 year old man, who was previously healthy and had no history of
psychiatric or neurological disorders before the onset of this
disease, presented with a 6 month history of progressive behavioural
and personality changes, depression, and cognitive decline. His
relatives reported that personality changes were his 1st symptoms. He
had been a rigorous, disciplined, and frugal person, who was
dependable at work and a valued member of his family; however, he
became aggressive, extravagant, foul-mouthed, sexually disinhibited,
and angry. His wife reported that the patient would have sudden
outbursts of agitation, and 2 months later, these outbursts were
followed by paranoid behaviours and possessiveness. Due to the
psychiatric nature of his complaints, he was admitted to a psychiatry
clinic, where he was diagnosed as having a manic disorder and was
given atypical antipsychotic drugs. 3 months later, the patient
exhibited gait changes, ataxia, and dysarthria, severe forgetfulness,
difficulties in swallowing and eating, and incontinence. The patient
developed involuntary movements in both of his feet, with dystonic
aversion-inversion posturing and occasional erratic movements. He
became dependent and apathetic and exhibited regressive behaviours.
The patient also exhibited visual hallucinations, during which he
reported seeing animals. Some of these complaints may have been side
effects from his medication and, consequently, several of the
patient’s medications were stopped or changed.

As a result of the progressive deterioration of the patient’s general
status, his relatives transferred him to the Psychiatry Department of
our University Hospital. After the neurological examination conducted
at the Psychiatry Clinic, he was diagnosed as having rapid progressive
dementia with early onset and was hospitalized at the Neurology
Clinic. As reported in the patient’s medical history, he had never
been exposed to cadaveric pituitary hormones, had never undergone a
neurosurgical procedure, organ or tissue grafts, or a blood
transfusion, and had never travelled to the UK or to any country with
reported incidences of BSE.

The neurological examination revealed that the patient was
disorientated in place and time. In addition, he was mute. Nystagmus
and conjugate gaze dysfunction were present, as were cerebellar
ataxia, dysmetria, and dysdiadochokinesia. The patient’s tone was
slightly increased in his lower limbs, and his plantar responses were

The level of protein in his cerebrospinal fluid was increased, and no
14-3-3 protein was detected. An electroencephalogram showed a
generalized slowing of wave, which was more evident in the left
hemisphere, but did not have any periodic complexes. He was referred
to the Radiology Department for cerebral MRI. On T2-weighted images
and fluid-attenuated inversion recovery (FLAIR) images, hyperintense
signal changes in the bilateral caudate nuclei (white arrows) and the
lentiform nucleus (black arrows) were seen. In addition,
hyperintensity in the bilateral thalamic region was less prominent
than in the previously described areas. Cortical hyperintensity was
noted on diffusion-weighted imaging.

Genotyping of the prion protein gene (PRNP) identified a P102L
mutation and heterozygosity for methionine at codon 129. The patient
did not want to undergo a brain biopsy, and we continued to follow his
progress at his home. At the time this report was written, the patient
was alive, mute, and on bed rest.

The patient described in the present report was the 1st probable case
of vCJD in Turkey. The clinical features of this patient are
consistent with the vCJD cases that have been identified in the UK and
France, including psychiatric manifestations at the disease onset, a
delayed occurrence of neurological signs, ataxia, and dementia [3]. In
addition to the pulvinar sign that was present on the MRI and EEG, the
patient fulfilled the WHO case definition for probable vCJD, the
specificity of which is 100 per cent [4]. Of note, a tonsil biopsy is
not necessary if the clinical features and the MRI findings are
compatible with vCJD, as the pulvinar sign is highly characteristic

Sequencing analysis revealed that the patient had 2 different
nucleotide changes in the coding region of the PRNP gene. The 1st one
is the M129V polymorphism, and our patient was heterozygous for this
alteration. Interestingly, all the patients who have undergone
genotyping up to now have been homozygous for methionine at codon 129.
This polymorphism is associated with susceptibility to prion diseases
[6]. The 2nd one is the P102L mutation, which was first identified in
affected members of 2 unrelated families with Gerstmann-Straussler
disease. P102L is one of the most common PRNP mutations and also
related to CJD.

This case highlights the difficulties in achieving an early diagnosis
of vCJD. At the initial presentation, a variety of diagnoses were
proposed, but vCJD was not considered in this patient. Instead, he was
diagnosed as having an affective disorder at the psychiatry clinic.
The delayed neurological signs in this patient pointed to the
possibility of progressive dementia, which is not surprising given the
frequency of psychiatric features that are observed by primary care
physicians. These clinical features are often misleading. Almost half
of the cases of vCJD were reviewed by a psychiatrist prior to the
patients’ neurological referral [7]. A neurological etiology was
usually suspected promptly after the patients developed objective
neurological features, which resulted in a neurological referral in
all of the cases. The single most important determinant of early
diagnosis was the presence of objective neurological features. For
this reason, all physicians must be careful when diagnosing rapidly
progressing dementia that begins at a young age.

communicated by:
Terry S Singeltary Sr

[The results presented in this report, if confirmed, indicate that
patients with vCJD are still being detected by the medical community.
The 1st presumptive Turkish case of vCJD has made its appearance 15
years after the 1st case in the United Kingdom. The source of this
infection of a patient who had no contact with the UK or any of the
other countries previously reporting vCJD, remains to be established.
– Mod.CP]

[6] Prions in spleen
Date: Thu 26 Jan 2012
Source: Nature News [edited]

[ref: Marchant J: Prion diseases hide out in the spleen. Nature News

Prion diseases such as bovine spongiform encephalopathy (BSE) and
variant Creutzfeldt-Jakob disease (vCJD) are able to jump species much
more easily than previously thought. A study published in Science
today [26 Jan 2012] shows that in mice, prions introduced from other
species can replicate in the spleen without necessarily affecting the
brain. The study reinforces the concern that thousands of people in
the United Kingdom might be silent carriers of prion infection,
potentially able to pass a lethal form of the disease to others
through surgery or blood transfusions.

Prions are infectious pathogens, primarily composed of the misfolded
form of a protein called PrP. Normal PrP molecules that are converted
into the misshapen type then aggregate in the brain to form hard,
insoluble clumps — with fatal consequences. Previous studies have
judged the ease of cross-species transmission by looking for clinical
symptoms as well as the presence of prions in infected animals’
brains. Results from these studies suggested that in many cases there
is an effective ‘species barrier’, with most inoculated animals
seemingly free of prions at the end of their lives.

But prions don’t just replicate in the brain — they also affect
lymphoid tissue, such as the spleen, tonsils, and appendix. So Vincent
Beringue, a prion researcher at the French National Institute for
Agricultural Research in Jouy-en-Josas, France, and his colleagues
used mice that had been genetically engineered to express either the
sheep or human version of PrP to look beyond the brain. The
researchers injected prions from elk, hamsters, and cattle into the
brains of the engineered mice — all species barriers that are
supposedly very hard to cross — then looked for prions in the spleens
and brains of the mice at regular intervals after exposure. As
expected, few of the mice had detectable prions in their brains. When
those expressing human PrP were inoculated with the BSE prion, only 3
out of 43 had detectable prions in their brains at the end of their
lives. But in lymphoid tissue it was a different story, with 26 of 41
spleens testing positive for prions, even though the mice showed no
clinical symptoms of BSE.

The research shows that prions jump species into lymphoid tissue much
more easily than into brain tissue, says Beringue. “If you extrapolate
that to the human situation, you can imagine that there are more
people infected subclinically in lymphoid tissues such as the spleen,
who may never develop the disease.” That’s a concern because these
carriers could infect others, for example by blood transfusion, organ
donation, or contaminated surgical instruments. Once passed human to
human, the infection could in theory then affect the brain and cause
lethal vCJD, says John Collinge, director of the Medical Research
Council Prion Unit at University College London, who wrote an analysis
to accompany the Beringue paper. “The main adaptation — that the
incoming BSE proteins have triggered the formation of human prions –
has occurred,” he says.

An epidemic of BSE among cows, dubbed ‘mad cow disease’, in Britain in
the 1980s, led to stringent controls on meat production and the use of
surgical and dental instruments. Human cases of the disease, vCJD,
were first seen in the mid-1990s. That sparked fears of a devastating
human epidemic, but only around 200 people have died from the disease
since then, and cases have been tailing off. But 2 recent surveys of
tissue samples from removed appendixes suggest that as many as in 4000
people in the United Kingdom could be carriers.

Beringue’s findings could help to explain these results, says
Collinge. “These estimates suggest there may be 15 to 20 000 people in
the United Kingdom incubating the disease,” he says. “Maybe they
predominantly have an infection restricted to the lymphoreticular
system.” Collinge warns that “all efforts should be made” to assess
the prevalence of prion infection in the United Kingdom by analysing
surgical and autopsy tissues, and to investigate whether blood tests
for vCJD can detect the infection in silent carriers (see part [4]
above). “Maybe they will never develop the disease themselves,” he
says. “But it’s precisely those people who present a risk to others.”

communicated by:

[While interesting, these findings are not new. The spleen cleans the
blood of old and damaged blood cells and prions which are abnormal
proteins may be filtered out in the spleen. – Mod.TG]

[7] Neurotoxic monomer
Date: Tue 14 Feb 2012
Source: Drug Discovery & Development [edited]
New disease 10x deadlier than “mad cow”
Scientists from the Florida campus of The Scripps Research Institute
have identified a single prion protein that causes neuronal death
similar to that seen in “mad cow” [bovine spongiform encephalopathy]
disease, but is at least 10 times more lethal than larger prion

This toxic single molecule or “monomer” challenges the prevailing
concept that neuronal damage is linked to the toxicity of prion
protein aggregates called “oligomers.” The study was published this
week in an advance, online edition of the journal Proceedings of the
National Academy of Sciences. [The abstract of this publication is
reproduced below. – Mod.CP]

“By identifying a single molecule as the most toxic species of prion
proteins, we’ve opened a new chapter in understanding how
prion-induced neurodegeneration occurs,” said Scripps Florida
professor Corinne Lasmezas, who led the new study. “We didn’t think we
would find neuronal death from this toxic monomer so close to what
normally happens in the disease state. Now we have a powerful tool to
explore the mechanisms of neurodegeneration.”

In the study, the newly identified toxic form of abnormal prion
protein, known as TPrP, caused several forms of neuronal damage
ranging from apoptosis (programmed cell death) to autophagy, the
self-eating of cellular components, as well as molecular signatures
remarkably similar to that observed in the brains of prion-infected
animals. The study found the most toxic form of prion protein was a
specific structure known as alpha-helical.

In addition to the insights it offers into prion diseases such as “mad
cow” and a rare human form Creutzfeldt-Jakob disease, the study opens
the possibility that similar neurotoxic proteins might be involved in
neurodegenerative disorders such as Alzheimer’s and Parkinson

In prion disease, infectious prions (short for proteinaceous
infectious particles), thought to be composed solely of protein, have
the ability to reproduce, despite the fact that they lack DNA and RNA.
Mammalian cells normally produce what is known as cellular prion
protein or PrP; during infection with a prion disease, the abnormal or
misfolded protein converts the normal host prion protein into its
disease form.

Lasmezas explains that prion diseases are similar to Alzheimer’s and
other protein misfolding diseases in that they are caused by the
toxicity of a misfolded host protein. Recent work, as reported in The
New York Times, also found that diseases such as Alzheimer’s resemble
prion diseases by spreading from cell to cell.

The new study adds another twist. “Until now, it was thought that
oligomers of proteins are toxic in all these diseases,” Lasmezas said.
“Since we found for the 1st time that an abnormally folded monomer is
highly toxic, it opens up the possibility that this might be true also
for some other protein misfolding diseases as well.”

[The following is the abstract from the PNAS article referred to in
the preceding report. – Mod.CP]

Zhou M, Ottenberg G, Sferrazza GF, Ida Lasmezas C: Highly neurotoxic
monomeric alpha-helical prion protein. Proc Natl Acad Sci USA. 2012
Feb 7. [Epub ahead of print], doi:10.1073/pnas.1118090109; available

“Prion diseases are infectious and belong to the group of protein
misfolding neurodegenerative diseases. In these diseases, neuronal
dysfunction and death are caused by the neuronal toxicity of a
particular misfolded form of their cognate protein. The ability to
specifically target the toxic protein conformer or the neuronal death
pathway would provide powerful therapeutic approaches to these
diseases. The neurotoxic forms of the prion protein (PrP) have yet to
be defined but there is evidence suggesting that at least some of them
differ from infectious PrP (PrPSc). Herein, without making an
assumption about size or conformation, we searched for toxic forms of
recombinant PrP after dilution refolding, size fractionation, and
systematic biological testing of all fractions. We found that the PrP
species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a
monomeric, highly alpha-helical form of PrP. TPrP caused autophagy,
apoptosis, and a molecular signature remarkably similar to that
observed in the brains of prion-infected animals. Interestingly,
highly alpha-helical intermediates have been described for other
amyloidogenic proteins but their biological significance remains to be
established. We provide unique experimental evidence that a monomeric
alpha-helical form of an amyloidogenic protein represents a cytotoxic
species. Although toxic PrP has yet to be purified from prion-infected
brains, TPrP might be the equivalent of one highly neurotoxic PrP
species generated during prion replication. Because TPrP is a
misfolded, highly neurotoxic form of PrP reproducing several features
of prion-induced neuronal death, it constitutes a useful model to
study PrP-induced neurodegenerative mechanisms.”

communicated by:

[By identifying a single molecule as the most toxic species of prion
proteins, a new advance has been made in the understanding of how
prion-induced neurodegeneration occurs. Professor Corinne Lasmezas and
colleagues commented that they had not expected to find death from
this toxic monomer so close to what normally happens in the disease
state. “Now we have a powerful tool to explore the mechanisms of
neurodegeneration.” – Mod.CP]

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