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Facioscapulohumeral Dystrophy (FSHD)

Discussion in 'Neurological diseases' started by Daisybell, Jul 29, 2022.

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  1. voner

    voner Senior Member (Voting Rights)

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    @Hutan,

    Good to hear! Peter Jones is such a knowledgeable and enthusiastic communicator.

    I think I will take @Daisybell's recommendation about his podcast and give it a listen. it would be interesting to hear him talk about the genetic/inherited links he is seeing or not seeing.
     
    voner, Mar 22, 2023
    #41
    Ash, alktipping, Daisybell and 2 others like this.
  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SNT Gatchaman, Apr 21, 2023
    #42
    Ash, Amw66, alktipping and 2 others like this.
  3. Hutan

    Hutan Moderator Staff Member

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    We got our results back today (so two months including long distance postage) - both all clear of FSHD. It comes with a good detailed report.

    The report notes that if FSHD arises spontaneously (rather than inherited), then there may be a mosaic situation, when some cells have the genetic problem and some don't. In that case, the test might not identify the cells with the problem and therefore the clinical disease.
    It's terrific that the disease has a genetic researcher dedicated to it.
     
    Hutan, May 21, 2023
    #43
    ukxmrv, Ash, voner and 8 others like this.
  4. Kitty

    Kitty Senior Member (Voting Rights)

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    Yes, and offers free testing world-wide – that's such a great facility to include in their study.
     
    Kitty, May 21, 2023
    #44
    Ash, voner, Trish and 2 others like this.
  5. Hutan

    Hutan Moderator Staff Member

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    @Daisybell and @voner and others could talk about this in more detail, but it was really interesting to see how important the epigenetics is. From my quick skim of the report I received, there are gene alleles of at least two genes that are permissive of FSHD (and I have one of them, but so too do 75% of the population) and then it is a matter of how methylated the gene is. I'm not sure how the methylation is controlled in a way that is heritable.

    It really underlines how difficult it might be to find a genetic cause of an illness. I should watch the Peter Jones podcast that Daisybell mentioned some time to understand it better.
     
    Hutan, May 22, 2023
    #45
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  6. Daisybell

    Daisybell Senior Member (Voting Rights)

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    Ive been listening to the podcasts for some time now and I keep thinking i understand the genetics and epigenetics and then I realise I don’t really!
    My methylation levels for the implicated region are 8% which apparently is a clear indication that the gene is switched on rather than being off as it should be…
    It’s all a bit of a bummer really.
    And the complexity of the issue means that treatment is difficult.

    Hi everyone by the way!
     
    Daisybell, May 22, 2023
    #46
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  7. voner

    voner Senior Member (Voting Rights)

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    @Hutan, do you think it is possible that the UK DecodeME project might eventually lead to the pursuit of avenues like this? I am not suggesting we know anything yet, but is this a example of genetic hints leading to at least a diagnostic methodology?
     
    voner, May 22, 2023
    #47
    Ash, Hutan and Kitty like this.
  8. Hutan

    Hutan Moderator Staff Member

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    I'm not the person to ask. @Andy and @Simon M and especially @Chris Ponting may have some comments.

    I do think it's entirely possible that DecodeME might eventually point to mechanisms like this. It's just that it may well not be as simple as 'oh, the majority of people with a diagnosis of ME/CFS have a particular version of a gene while almost all healthy people do not. So, it's a problem with that particular gene.' The first pass to look for obvious things might come up with nothing.

    But, as we get more clues about where to look from things like proteomics, I'm sure that there will be genetic markers of at least predisposition to find. And I expect that clever people guiding relentlessly smart AI may be able to do complicated analyses of the genetic information to find distinguishing patterns. But, epigenetics... It seems bloody complicated.

    It would be really interesting to know how the genetic mechanism of FSHD was identified.
     
    Hutan, May 22, 2023
    #48
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  9. Daisybell

    Daisybell Senior Member (Voting Rights)

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    I had a holter monitor on for a couple of days last week. I’m trying to get to the bottom of whether my issues with my heart rate are linked to my FSHD. The health system is trying to find out whether I am making the issues up or not….!
    Anyway, I bent over to put on my socks and my heart rate (according to my iWatch) went up to 167, and stayed like that for a couple of minutes. Hopefully that will be enough evidence to a) convince them that I’m not imagining it and b) diagnose what is going on.

    Fun and games!
     
    Daisybell, Jun 10, 2023
    #49
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  10. Trish

    Trish Moderator Staff Member

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    Hi @Daisybell, it's good to hear from you. Thanks for keeping us updated.
    I'm sorry to hear you are still going through disbelief. I hope you they pay proper attention now.
     
    Trish, Jun 10, 2023
    #50
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  11. Daisybell

    Daisybell Senior Member (Voting Rights)

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    Hi everyone.
    There is a clinical trial for an anti-sense RNA treatment for FSHD which has been granted approval in NZ - I am very much hoping that I can be part of it…. Even if I get the placebo! At least that way, if the treatment does work, I will have perhaps a chance at getting the drug in the future. The drug being tested is called Aro-Dux 4. The link to the trial info is here
    https://clinicaltrials.gov/study/NCT06131983
     
    Daisybell, Jul 3, 2024
    #51
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  12. Hutan

    Hutan Moderator Staff Member

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    Wonderful news @Daisybell! That's fantastic that the trial is being done in New Zealand. Do you know why it is happening here?

    Good luck with getting into the trial. I'm very interested to hear how you go.
     
    Hutan, Jul 3, 2024
    #52
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  13. Daisybell

    Daisybell Senior Member (Voting Rights)

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    I think the trial is happening here because there is a good neuromuscular disease registry which is run from Auckland. And possibly because we can’t sue if anything goes wrong???!! They only need a small number of participants, and because of the nature of the treatment, no healthy volunteers.
    It’s been tested in mice, but there is no large animal model for testing FSHD interventions so the next step is straight to humans.
     
    Daisybell, Jul 3, 2024
    #53
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  14. Hutan

    Hutan Moderator Staff Member

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    That's interesting. @Snow Leopard recently commented about needing to build the dartboard before throwing the darts of possible treatments. I reckon good registries are part of the dartboard. We have a Long Covid one here in NZ now, but I think we need to extend it to cover ME/CFS generally, and better differentiate people with post-Covid-19 ME/CFS from other sorts of Long Covid.
     
    Hutan, Jul 3, 2024
    #54
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  15. Trish

    Trish Moderator Staff Member

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    Good to hear from you, @Daisybell. I hope you can participate in the trial.
     
    Trish, Jul 3, 2024
    #55
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  16. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Another preprint for you @Daisybell

    A novel family of lncRNAs relate facioscapulohumeral muscular dystrophy to nucleolar architecture and protein synthesis
    Valentina Salsi; Francesca Losi; Bruno Fosso; Marco Ferrarini; Sara Pini; Marcello Manfredi; Gaetano N. A. Vattemi; Tiziana E. Mongini; Lorenzo Maggi; Graziano D. Pesole; Anthony Henras; Paul D. Kaufman; Brian McStay; Rossella Ginevra Tupler

    Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite repeats at human chromosome 4q35. These deletions accompany local chromatin changes and the anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4.

    We discovered that FRG2A is one member of a family of long non-coding RNAs (lncRNA) expressed at elevated levels in skeletal muscle cells in an individual-specific manner. We found that FRG2A lncRNA preferentially associates with rDNA sequences and centromeres, and also promotes the three-dimensional association of centromeres with the nucleolar periphery in FSHD samples. Furthermore, we demonstrate that the elevated FRG2A expression in cells from FSHD patients reduces rDNA transcription and protein synthesis.

    Our results frame a new disease model in which elevated lncRNAs expression mediated by deletions of D4Z4 macrosatellite repeats leads to a diminished protein synthesis capacity, thereby contributing to muscle wasting.


    Link | PDF (Preprint: BioRxiv) [Open Access]
     
    SNT Gatchaman, Jul 3, 2024
    #56
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  17. Daisybell

    Daisybell Senior Member (Voting Rights)

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    Thanks @SNT Gatchaman - that makes my head hurt!!! I’ve sent it on to Prof Jones in Reno… If he thinks it is interesting, he might explain to us over Spotify!
     
    Daisybell, Jul 4, 2024
    #57
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  18. Daisybell

    Daisybell Senior Member (Voting Rights)

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    The drug development companies certainly like an easy way to get hold of participants…
     
    Daisybell, Jul 4, 2024
    #58
    Ash, AliceLily, forestglip and 3 others like this.
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