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sCJD Woman Married Into a GSS Family Investigation Prions Transmission Microchimerism

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    sCJD Woman Married Into a GSS Family Investigation Prions Transmission Microchimerism

    MONDAY, NOVEMBER 26, 2018

    Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism

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    kind regards, terry

    this is too important not to post, here is deeper into this study...


    This is the first report of presumed sporadic CJD occurring in a person who married into a GSS family. The estimated prevalence of GSS is in the range of 2–5 per 100 million people worldwide, and the annual mortality rate for sCJD in Denmark is 1.46 per 1 million people (31). The population of Denmark consists of 5 740 185 individuals, and there are 2 registered GSS cases that belong to the same family. The Danish GSS family is only the thirty-fourth known GSS family in the world (32). One could assume that the risk for a Danish man with GSS to have a wife or a mother who would develop CJD in her seventies is as high as for any other man. On the basis of the mortality rate for sCJD, and assuming that the incidence of sCJD is the same among married and unmarried people, we could state that 1 man out of 684 932 men has a risk of marrying a woman who would develop CJD. However, in this case, the man a priori had GSS, which means that it would take 1 man out of 684 932 men with GSS for such a pairing to occur. Considering the worldwide rarity of GSS cases, the likelihood for co-occurrence of GSS and sCJD in one family is hence very low and warrants an investigation for the possible transmission of prions routes.

    Four cases of a random co-occurrence of prion diseases in the same family were reported before (12–15). In 3 of those reports, evaluation of the likelihood of prion diseases cooccurrence by chance implies a considerably low probability. For example, the occurrence of sCJD in a husband and wife has been reported in the United States in 1998. In the 15-year surveillance period, the evaluation of the statistical likelihood for a couple in the United States to develop sporadic CJD within 5 years from each other was presented as a 2.1% risk, given the size of the population and its assumed structure at the time (13). In a case study from Switzerland, the estimated probability for a sibling of an iCJD patient to develop any kind of CJD was 1.4  103 , and the probability that one patient with sporadic fatal insomnia occurs by chance in a fatal familial insomnia family in Italy ranged from 0.78–1.56  104 (14, 15).

    In the current study, a thorough neuropathological investigation of the CJD patient’s and GSS proband’s brain was performed and revealed a classic sCJD type V2 and GSS, respectively (33). In the CJD patient, the main histopathological findings were a characteristic diffuse synaptic and perineuronal PrPSc distribution throughout the brain, spongiosis, and neuronal loss, whereas in the GSS proband, the major finding was the presence of uni and multicentric PrPSc plaques, especially in the cerebellum.

    To ensure that the CJD patient was not exposed to known routes of PrPSc transmission and did not carry pathogenic mutations, her clinical history was studied, the PrPSc type was defined, and the coding region of her PRNP was sequenced. Neither the clinical history nor the biochemical findings of the CJD patient’s tissues provided evidence of iCJD or variant CJD.

    No established pathogenic mutations were found in the CJD patient’s PRNP coding region. However, she had a silent A117A mutation, which is present in only 5%–10% of the population in Western countries and is considered nonpathogenic because the evidence for its impact on prion diseases pathogenesis is lacking (34). Yet alanine-to-valine replacement at the same codon position (p.A117V) is known to cause GSS (35, 36). Whether or not the CJD patient’s possession of a silent A117A mutation in PRNP could have favored the CJD susceptibility in the given GSS family case remains to be elucidated, but if its presence was a cofactor, this could explain the rarity of CJD cases in GSS families.

    Given the unusual circumstances, we hypothesized that the cells of the fetus, which carried the P102L mutation in PRNP and PrPSc, might be transmitted to the mother’s brain via acquired microchimerism, thus triggering the conversion of maternal PrPC into PrPSc. The microchimerism would have marked the start of the CJD incubation period. Although more than a 50-year incubation period seems lengthy for sCJD, there were cases of iCJD and Kuru incubation lasting up to 40 and 56 years, respectively, underlining the possible variability of the incubation period of prion diseases (37, 38).

    During pregnancy, both the fetus’ and mother’s bloodbrain barriers exhibit increased permeability, allowing the exchange of DNA and cells (16). Microchimerism in female brains has been reported in 63% of all women who carried a male fetus, and it was detectable when measured 2 decades after the pregnancy (16).

    We know that the CJD patient who married into the Danish GSS family was pregnant with the male fetus with GSS 52 years before her death. Therefore, her DNA samples from 15 different brain regions and blood plasma was extracted to search for the male sex-determining chr.Y. However, no male SRY was detected in the maternal brain. Besides, the number of high-quality chr.Y reads in the maternal plasma was too small to conclusively prove the presence of genuine male fetus’ cells (30, 39).

    Different factors may have influenced the negative results: 1) the fetus cells might have vanished from the mother’s body because of the 52-year period since the putative microchimerism; 2) the sensitivity of the chr.Y detection methods might not have been high enough for the presumed low level of the target Y-sequence; and 3) although the samples were taken from 15 brain regions, it could be possible that the fetal cells were missed (16, 20). Even though no fetal cells were detected, according to the hypothesis, it is likely that PrPSc from the fetal cells acted as seeds and started the process of maternal PrPC misfolding and, once triggered, this process could go on for many years, even after the microchimeric fetal cells were lost again.

    It is known that CJD susceptibility and phenotypes can differ greatly because of a person’s polymorphism at codon 129 in PRNP (40–42). In this case, the CJD patient was homozygous for V at codon 129 and had PrPSc type 2, which is the second most common sporadic CJD type, suggesting that V homozygosity may have favored PrPC misfolding and CJD pathogenesis (35, 43).

    The PrPSc biochemical and histological picture of the V homozygote CJD patient is very different from that of GSS although, hypothetically, the initial PrPSc seed was from the P102L-129M GSS fetus. This could be explained by the host PrPSc strain mutation and/or a strain selection phenomenon, which also might have contributed to the lengthy CJD incubation period.

    Strain mutation means that a distinct PrPSc strain can be propagated on the passage to a new host, even in the same species, if the PrPC primary sequence differs from that of the host. In humans, the propagation of certain PrPSc strains is thought to be influenced by variations in the host’s PRNP and likely in other genes that shape the microenvironment of the brain too (44, 45). For example, M at codon 129 is associated with the production of type 1 PrPSc and V with the production of type 2 PrPSc (46).

    Cases of PrPSc type 1 and type 2 co-occurring in the same patients prove that several PrPSc conformations defining the PrPSc types or strains can be found in a brain affected by prion disease (28, 35, 46). Moreover, it has been demonstrated that several rodents inoculated with the same human P102L GSS brain homogenate developed distinct pathologies and 2 different PrPSc strains corresponding to 8 and 21 kDa fragments (47, 48). Strain selection phenomenon refers to the propagation of one PrPSc strain over another that is selected by preferential “templating” against the host’s PrPC sequence and genetic background (44, 47). Studies on the transmissibility and conformation of synthetic PrPSc strains propose that when the host is introduced to a mixture of different PrPSc strains, those that are the most compatible with the host’s PrPC propagate the fastest and dominate the clinical symptoms (49).

    Detailed investigation of the CJD and GSS patients’ genomes and proteomes would perhaps reveal more possible explanations for CJD and GSS co-occurrence in one family. However, this would require fresh brain tissues from the GSS proband and the son. Studies of transgenic animal models with genotypes and PrPSc types corresponding to the Danish GSS and CJD family model could be the next step in resolving the possibility of PrPSc transmission via microchimerism. Moreover, knowing that the CJD patient’s husband was a PrPSc carrier too, the possibility of other new PrPSc transmission routes, such as body fluids exchange during sexual relations, should be considered.

    In conclusion, the current study is the first report of presumed sCJD and GSS presenting in the same family. We analyzed the clinical, neuropathological, and genetic findings of the affected family members; however, the co-occurrence of such rare diseases in the same family could not be explained by these findings. Thus, we have proposed and investigated a novel possible PrPSc transmission route in humans. We suggested that via acquired microchimerism, PrPSc could be freely transmitted from the fetus to the mother and possibly vice versa. Despite the data we have obtained, the time of sampling since the PrPSc seeding and the overall sensitivity of the genetic measurements necessarily limit the support for our novel transmission hypothesis in this extremely rare Danish case. However, the hypothesis should not be disregarded without further investigation. Exploring new possible prion infection routes and the biological mechanisms favoring them in animal models with controlled genetic and proteomic characteristics would help in elucidating the co-occurrence of CJD and GSS in one family.

    The family case presented in the current study, and the 4 other previously reported family cases of rare prion diseases co-occurrence foster the necessity to explore the complexity of possible routes for prions transmission, as well as the biological and environmental factors contributing to the susceptibility of prion diseases. An in-depth comprehension of these aspects of prion diseases is essential for their prevention and for the proper genetic counseling of affected families.

    ACKNOWLEDGMENTS ...end...tss


      DEEP THROAT TO Singeltary 2000-2001

      (take these old snips of emails with how ever many grains of salt you wish. ...tss)

      The most frightening thing I have read all day is the report of Gambetti's finding of a new strain of sporadic cjd in young people...

      Dear God, what in the name of all that is holy is that!!!

      If the US has different strains of scrapie.....why????than the UK...then would the same mechanisms that make different strains of scrapie here make different strains of BSE...if the patterns are different in sheep and mice for scrapie.....could not the BSE be different in the cattle, in the mink, in the humans.......

      I really think the slides or tissues and everything from these young people with the new strain of sporadic cjd should be put up to be analyzed by many, many experts in cjd........bse.....scrapie

      Scrape the damn slide and put it into mice.....wait.....chop up the mouse brain and and spinal cord........put into some more mice.....dammit amplify the thing and start the damned research.....This is NOT rocket science...we need to use what we know and get off our butts and move....the whining about how long everything takes.....well it takes a whole lot longer if you whine for a year and then start the research!!!

      Not sure where I read this but it was a recent press release or something like that: I thought I would fall out of my chair when I read about how there was no worry about infectivity from a histopath slide or tissues because they are preserved in formic acid, or formalin or formaldehyde.....for God's sake........ Ask any pathologist in the UK what the brain tissues in the formalin looks like after a is a big fat sponge...the agent continues to eat the brain can't make slides anymore because the agent has never stopped........and the old slides that are stained with Hemolysin and Eosin......they get holier and holier and degenerate and continue...what you looked at 6 months ago is not there........Gambetti better be photographing every damned thing he is looking at.....

      Okay, you need to know. You don't need to pass it on as nothing will come of it and there is not a damned thing anyone can do about it. Don't even hint at it as it will be denied and laughed at..........

      USDA is gonna do as little as possible until there is actually a human case in the USA of the nvcjd........

      if you want to move this thing along and shake the earth....

      then we gotta get the victims families to make sure whoever is doing the autopsy is credible, trustworthy, and a saint with the courage of Joan of Arc........

      I am not kidding!!!!

      so, unless we get a human death from EXACTLY the same form with EXACTLY the same histopath lesions as seen in the UK nvcjd........forget any is ALL gonna be sporadic!!!

      And, if there is a case.......

      there is gonna be every effort to link it to international travel, international food, etc. etc. etc. etc. etc.

      They will go so far as to find out if a sex partner had ever traveled to the UK/europe, etc. etc. ....

      It is gonna be a long, lonely, dangerous twisted journey to the truth. They have all the cards, all the money, and are willing to threaten and carry out those threats....and this may be their biggest downfall...

      Thanks as always for your help.

      (Recently had a very startling revelation from a rather senior person in government here..........knocked me out of my must keep pushing. If I was a power person....I would be demanding that there be a least a million bovine tested as soon as possible and agressively seeking this disease. The big players are coming out of the woodwork as there is money to be made!!!

      In short: "FIRE AT WILL"!!! for the very dumb....who's "will"! "Will be the burden to bare if there is any coverup!"

      again it was said years ago and it should be taken seriously....BSE will NEVER be found in the US!

      As for the BSE conference call...I think you did a great service to freedom of information and making some people feign integrity...

      I find it scary to see that most of the "experts" are employed by the federal government or are supported on the "teat" of federal funds. A scary picture!

      I hope there is a confidential panel organized by the new government to really investigate this thing.

      You need to watch your back........but keep picking at a buzzard to the just may get to the truth!!! (You probably have more support than you know. Too many people are afraid to show you or let anyone else know. I have heard a few things myself... you ask the questions that everyone else is too afraid to ask.)

      ====END TSS====