Facioscapulohumeral Dystrophy (FSHD)

Hutan said:
My son and I have sent samples off to the lab. The testing is free, and part of investigations into the genetics of neuromuscular disorders. I was interested to see that the scope of the investigations seems to be a bit wider than FSHD.

I can't really see a down-side to doing this, especially for people who can identify a family history of abnormal muscle fatiguability.
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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.
In addition, it should be noted that 10-30% of spontaneous FSHD1 patients (no family history) are mosaic (5) and mosaicism may not be detected by this epigenetic methylation analysis.
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It's terrific that the disease has a genetic researcher dedicated to it.
 
@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.
 
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!
 
Hutan said:
@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.
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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?
 
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.
 
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!
 
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
 
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 said:
I think the trial is happening here because there is a good neuromuscular disease registry which is run from Auckland.
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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.
 
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]
 
Hutan said:
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.
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The drug development companies certainly like an easy way to get hold of participants…
 
Hundreds of children born with a degenerative muscle-wasting disease are to be offered a new drug on the NHS that can slow the deadly condition’s progression.
The new treatment, vamorolone, has been seen in trials to buy time for DMD patients and allow them to stand and walk for longer.

Earlier this year the NHS spending watchdog, the National Institute for Health and Care Excellence (NICE), said it would not fund vamorolone, which costs about £4,500 for three months’ worth of treatment.

But it has now reversed its decision after a deal was struck with manufacturer Santhera Pharmaceuticals to provide the drug to the NHS at an undisclosed lower price.
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Those with DMD lack the dystrophin protein, which leads to muscle fibres slowly breaking down and being replaced by fatty tissue, gradually weakening muscles.

Steroids are used to treat DMD, but have limited success and unpleasant side effects, such as thinning bones, which raises the risk of life-threatening fractures.

Vamorolone comes as a liquid consumed once daily and works in a similar way to steroids by stopping the production of inflammatory cells that damage the muscle cells of patients. However, it also avoids triggering the side effects linked to long-term steroid use.
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Children with muscle-wasting disease to be offered new NHS drug
 
It does seem that drug trials are beginning for various forms of muscular dystrophy.

A ‘lack of progress’ update on my situation…
At this point, i have been told I am not being considered for the FSHD drug trial in this country. Apparently I am not sufficiently affected.
I haven’t actually seen the neurologist since my initial appointment where he confirmed that I do have FSHD and have some symptoms. That was over 2 years ago. I went to see my GP the other day and she has referred me back to Neurology. I am presuming that the one year follow up that was planned after my initial appointment has just been scrubbed. I don’t know whether the system just removes people from the waitlist if the appointments are so delayed… it certainly seems like things are not working well in the health system at the moment. But I am not prepared to just put up with being told that I am too mild for the trial if in fact the specialist has only seen me once 26 months ago.
 
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