Ann Clin Transl Neurol. 2018 Jun; 5(6): 777–783.
Published online 2018 Apr 26. doi: 10.1002/acn3.568 PMCID: PMC5989776 PMID: 29928661
Two novel PRNP truncating mutations broaden the spectrum of prion amyloidosis
Sabina Capellari,corresponding author 1 , 2 , † Simone Baiardi, 1 , † Rita Rinaldi, 3 Anna Bartoletti‐Stella, 1 , 2 Claudio Graziano, 4Silvia Piras, 2 Giovanna Calandra‐Buonaura, 1 , 2 Roberto D'Angelo, 3 Camilla Terziotti, 3 Raffaele Lodi, 1 , 5Vincenzo Donadio, 2 Loris Pironi, 6 Pietro Cortelli, 1 , 2 and Piero Parchicorresponding author 2 , 7 Author information Article notes Copyright and License information Disclaimer
Introduction Human prion diseases are neurodegenerative disorders characterized by tissue accumulation of a misfolded form (PrPSc) of the cellular prion protein (PrPC). They comprise three major phenotypes, namely Creutzfeldt‐Jakob disease (CJD), by far the most common, fatal insomnia (FI) and Gerstmann‐Straüssler‐Scheinker syndrome (GSS).1, 2 At variance with CJD and FI, GSS manifests a much slower clinical course and is mainly characterized by amyloid deposition rather than spongiform change in the affected brain tissue.2, 3 This major phenotypic difference directly reflects the composition and topology of PrPScaggregates. While in CJD and FI PrPSc accumulates as a full‐length or N‐terminally truncated fragments retaining the glycophosphatidylinositol (GPI) membrane anchor attaching the protein to the cell membrane,4 in GSS PrPSc mainly deposits in the extracellular space as unglycosylated anchorless fragments.2, 3 GSS was originally described as a parenchymal brain amyloidosis linked to missense or insertional mutations in the prion protein gene (PRNP).2 More recently, however, the discovery of premature truncating mutations in PRNP has expanded the phenotypic spectrum of anchorless PrP amyloidosis. The description of a PRNP stop‐codon mutation (p.Y145X) in a Japanese with dementia and both parenchymal and vascular PrP‐amyloid,5, 6 was followed by the findings of similar mutations at codons 160 (p.Q160X),7, 8 226 (p.Y226X),9 and 227 (p.Y227X)9 in patients with progressive dementia and pure PrP‐cerebral amyloid angiopathy (PrP‐CAA), GSS or mixed GSS/PrP‐CAA pathology.7, 9, 10Most significantly, PRNP truncating mutations at codons 163 (p.Y163X) and 203 (p.D203X), have been recently found in patients with chronic diarrhea, progressive autonomic failure, and peripheral polyneuropathy in association with widespread abnormal PrP deposition in peripheral organs and the CNS.11, 12 Based on the multiple organ system PrP deposition and the amyloid properties of the protein aggregates in the brain, the term PrP systemic amyloidosis was introduced, irrespectively of the demonstration of the classical pathological hallmarks of systemic amyloidosis.11, 13, 14
Here, we describe two Italian families with several affected members carrying novel truncating mutations in PRNP associated with progressive autonomic failure and variable cognitive impairment.
A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy
Simon Mead, M.D., Sonia Gandhi, M.D., Jon Beck, B.Sc., Diana Caine, Ph.D., Dillip Gallujipali, M.D., Christopher Carswell, M.D., Harpreet Hyare, M.D., Susan Joiner, M.Sc., Hilary Ayling, B.Sc., Tammaryn Lashley, Ph.D., Jacqueline M. Linehan, B.Sc., Huda Al-Doujaily, M.Sc., Bernadette Sharps, B.Sc., Tamas Revesz, M.D., Malin K. Sandberg, Ph.D., Mary M. Reilly, M.D., Martin Koltzenburg, M.D., Alastair Forbes, M.D., Peter Rudge, M.D., Sebastian Brandner, M.D., Jason D. Warren, M.D., Jonathan D.F. Wadsworth, Ph.D., Nicholas W. Wood, M.D., Janice L. Holton, M.D., and John Collinge, M.D.
Background Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.
Methods We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.
Results We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.
Conclusions Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.)
snip...
Presentation with diarrhea led to invasive investigations or surgery in several patients, with concomitant potential for iatrogenic transmission of prions from the gut through contamination of medical or surgical instruments.28 It is reassuring, however, that murine studies did not show experimental transmissibility, although this finding does not completely rule out the presence of potentially infectious human prions. Although nonmutant prion protein was detected in the protein deposits in multiple tissues, Western blotting showed that the protein was not proteaseresistant. PRNP analysis should be considered in the investigation of unexplained chronic diarrhea associated with a neuropathy or an unexplained syndrome similar to familial amyloid polyneuropathy. The prevalence of systemic amyloidosis associated with prion protein is probably low but might be better characterized with more widespread testing of PRNP and histologic examination for prion protein in biopsy samples.
***> Presentation with diarrhea led to invasive investigations or surgery in several patients, with concomitant potential for iatrogenic transmission of prions from the gut through contamination of medical or surgical instruments.28
''In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison.
The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II)
EFSA Panel on Biological Hazards (BIOHAZ) Antonia Ricci Ana Allende Declan Bolton Marianne Chemaly Robert Davies Pablo Salvador Fernández Escámez ... See all authors
First published: 17 January 2018 https://doi.org/10.2903/j.efsa.2018.5132 ;
also, see;
8. Even though human TSE‐exposure risk through consumption of game from European cervids can be assumed to be minor, if at all existing, no final conclusion can be drawn due to the overall lack of scientific data. In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids. It might be prudent considering appropriate measures to reduce such a risk, e.g. excluding tissues such as CNS and lymphoid tissues from the human food chain, which would greatly reduce any potential risk for consumers.. However, it is stressed that currently, no data regarding a risk of TSE infections from cervid products are available.
snip...
The tissue distribution of infectivity in CWD‐infected cervids is now known to extend beyond CNS and lymphoid tissues. While the removal of these specific tissues from the food chain would reduce human dietary exposure to infectivity, exclusion from the food chain of the whole carcass of any infected animal would be required to eliminate human dietary exposure.
ZOONOTIC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE
here is the latest;
PRION 2018 CONFERENCE
Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice
Hermann M. Schatzl, Samia Hannaoui, Yo-Ching Cheng, Sabine Gilch (Calgary Prion Research Unit, University of Calgary, Calgary, Canada) Michael Beekes (RKI Berlin), Walter Schulz-Schaeffer (University of Homburg/Saar, Germany), Christiane Stahl-Hennig (German Primate Center) & Stefanie Czub (CFIA Lethbridge).
To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys. Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years.
After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were detected in spinal cord and brain of some euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and pre-clinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles.
Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate.
The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.
Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP.
The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD..
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
READING OVER THE PRION 2018 ABSTRACT BOOK, LOOKS LIKE THEY FOUND THAT from this study ;
P190 Human prion disease mortality rates by occurrence of chronic wasting disease in freeranging cervids, United States
Abrams JY (1), Maddox RA (1), Schonberger LB (1), Person MK (1), Appleby BS (2), Belay ED (1) (1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA..
SEEMS THAT THEY FOUND Highly endemic states had a higher rate of prion disease mortality compared to non-CWD states.
AND ANOTHER STUDY;
P172 Peripheral Neuropathy in Patients with Prion Disease
Wang H(1), Cohen M(1), Appleby BS(1,2) (1) University Hospitals Cleveland Medical Center, Cleveland, Ohio (2) National Prion Disease Pathology Surveillance Center, Cleveland, Ohio..
IN THIS STUDY, THERE WERE autopsy-proven prion cases from the National Prion Disease Pathology Surveillance Center that were diagnosed between September 2016 to March 2017,
AND
included 104 patients. SEEMS THEY FOUND THAT The most common sCJD subtype was MV1-2 (30%), followed by MM1-2 (20%),
AND
THAT The Majority of cases were male (60%), AND half of them had exposure to wild game.
snip...see more on Prion 2017 Macaque study from Prion 2017 Conference and other updated science on cwd tse prion zoonosis below...terry
Sunday, December 9, 2018
***> Variable Protease-Sensitive Prionopathy Transmission to Bank Voles CDC December 14, 2018
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ??? Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.
by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).
http://www.ncbi.nlm.nih.gov/pubmed/?term=sporadic
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.
http://www.ncbi.nlm.nih.gov/pubmed/?term=familial
again, sporadic and familial is a red herring, in my opinion.
also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.
Alzheimer’s disease, iatrogenic, and Transmissible Spongiform Encephalopathy TSE Prion disease, that is the question ???
>>> The only tenable public line will be that "more research is required’’ <<<
>>> possibility on a transmissible prion remains open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer’s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
https://web.archive.org/web/2017012...einquiry.gov.uk/files/yb/1992/11/04001001.pdf
https://web.archive.org/web/2004031...einquiry.gov.uk/files/yb/1992/12/16005001.pdf
https://web.archive.org/web/20040315075058/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
snip...see full Singeltary Nature comment here;
http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments
see Singeltary comments to Plos ;
>>> The only tenable public line will be that "more research is required’’ <<<
>>> possibility on a transmissible prion remains open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer’s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
https://web.archive.org/web/2017012...einquiry.gov.uk/files/yb/1992/11/04001001.pdf
https://web.archive.org/web/2004031...einquiry.gov.uk/files/yb/1992/12/16005001.pdf
https://web.archive.org/web/20040315075058/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
snip...see full Singeltary Nature comment here;
http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments
see Singeltary comments to Plos ;
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
http://journals.plos.org/plosone/article/comment?id=info:do I/10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
https://www.frontiersin.org/articles/10.3389/fnagi.2016.00005/full
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
http://www.plosone.org/annotation/listThread.action?root=82860
Tuesday, December 12, 2017
Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology
http://tauopathies.blogspot.com/2017/12/neuropathology-of-iatrogenic.html
PRION Conference Roundtable 2018
http://prionconference.blogspot.com/
FRIDAY, DECEMBER 14, 2018
Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone December 14, 2018
TUESDAY, JANUARY 1, 2019
CHILDHOOD EXPOSURE TO CADAVERIC DURA
MONDAY, JANUARY 14, 2019
Evaluation of iatrogenic risk of CJD transmission associated with Chronic Wasting Disease TSE Prion in Texas TAHC TPWD Evaluation of iatrogenic risk of CJD transmission associated with Chronic Wasting Disease TSE Prion in Texas TAHC TPWD
It is a dimension as vast as space and as timeless as infinity. It is the middle ground between light and shadow, between science and superstition, and it lies between the pit of man's fears and the summit of his knowledge. This is the dimension of imagination. It is NOT, an area which we call the Twilight Zone, but an area that believes junk science, and the very industries and lobbyist some Texas Hunters, the cervid industry, that insist on shoving the fake news down their throats, we call this ted nugent junk science, and in TEXAS, sometimes you just can't fix stupid, this is where the rubber meets the road, here's your sign!
chronic wasting disease cwd tse prion aka mad deer elk disease, if you consume a cwd tse prion positive cervid, then months, years, decades later, go on to have surgery, dental, ophthalmology, endoscopy, donate tissue, blood, organs, you then expose those medical theaters and tissue, blood, organs, that are incubating the infectious cwd tse prion disease, to everyone that comes in contact.
these are not memes, these are actual statements from hunters/industry in Texas about CWD tse prion.
God help them, and us...terry
''Got a call today from TPWD, I’ve got a mule deer that tested early positive for CWD. I’m soon to turn into a zombie because I have already been eating it. They advised not to consume any of the meat...too late! They want to come confiscate what meat is left once they get more results back from another lab.''
snip...
Terry S. Singeltary Sr.
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