And...we have a positive PSSM type 2 test. We are n/px

[Michen]

I really don’t understand the aggression in your posts, particularly the one in the weekend thread. You posted with a problem, even if you didn’t have a problem what you are doing with this horse is still a lot for something her age and recent history. Maybe the wheels will truly fall off and you’ll listen to what people are trying to tell you or maybe they won’t and she will turn out great. No one is saying anything unkindly, most of us are speaking from experience of having made similar mistakes/imported young horses.

As for what your instructors are saying, I suspect they are more than happy to take your money for lessons etc as many are.

I really hope all goes well for you and her, I know you’ve had a ton of horse heartache and it’s just the worst thing.

 

[ycbm]

Just as a point of information esomeprazole is available in the UK via vets. It's a compounded preparation so although it is not licensed, it is formulated specifically for horses and available as coated granules or paste. It can be used legally via the prescribing cascade where appropriate.

Please pardon my ignorance Gamebird, I know you are a vet, but I thought the prescribing cascade only allowed you to prescribe a drug if a licenced one wasn't available. How do you get round the fact that omeprazole is available? Do you have to use omeprazole first and prove it didn't work?

 

[LadyGascoyne]

For treating active ulcers then esomeprazole 2mg/kg once daily, and for maintenance / prevention in racehorses then 0.5mg/kg. Both omeprazole and esomeprazole work best on empty stomachs / less forage, so there are studies showing decent ulcer healing with 0.5mg/kg for horses on high grain / low forage diets. It is also quite horse dependent - 4mg/kg is the standard dose for omeprazole, but there are studies showing that 2mg/kg or even lower might work for some horses. The trouble is you don't know if your horse will be that one so we standardly treat at 4mg/kg and then use 1mg/kg for prevention.

Thanks for sharing, both of your posts are so useful. Really valuable insights.

 

[Murphy88]

@Murphy88 what dose of aloe vera do you recommend please?
And is there any particular preparation or brand which seems more effective than others?
Thank you

Usually I just tell owners to find a reputable company selling one of the pure aloe vera products containing inner leaf gel, I don't have one that I necessarily prefer over others. And I tell people to just follow the instructions. In the one proper study, they used 18mg/kg so works out as approx 9g of aloe vera for your average horse.

 

[ycbm]

Usually I just tell owners to find a reputable company selling one of the pure aloe vera products containing inner leaf gel, I don't have one that I necessarily prefer over others. And I tell people to just follow the instructions. In the one proper study, they used 18mg/kg so works out as approx 9g of aloe vera for your average horse.

This is the one I recommend to people.

Pardon our interruption...

 

[SEL]

This is the one I recommend to people.

Pardon our interruption...

Thanks. Will try that

Microcob is tetchy around her gut. It's the grass and would be less of an issue if she'd stay the right side of the electric fence. But she's a native pony with a different opinion.

 

[BMA2]

Does it taste nice...if your horse is fussy?

I reason as I tried some once years ago myself and it was pretty yuk

 

[ycbm]

Does it taste nice...if your horse is fussy?

I reason as I tried some once years ago myself and it was pretty yuk

I've never tried it myself, but Holland and Barratt sell it for humans, so some do. I've never had a horse turn their nose up at it, tried it with 6, I think, and I've always introduced it full dose straight away. My last one was an extremely fussy horse, wouldn't even eat sugar beet, but he didn't seem to notice it.
.

 

[Peglo]

Does it taste nice...if your horse is fussy?

I reason as I tried some once years ago myself and it was pretty yuk

I doubt they’d be able to taste it over their feed. Especially since mine get oily herbs too

 

[BMA2]

I've never tried it myself, but Holland and Barratt sell it for humans, so some do. I've never had a horse turn their nose up at it, tried it with 6, I think, and I've always introduced it full dose straight away. My last one was an extremely fussy horse, wouldn't even eat sugar beet, but he didn't seem to notice it.
.

Oh...ive quite liked sugar beet when I've tried that

 

[DabDab]

Does it taste nice...if your horse is fussy?

I reason as I tried some once years ago myself and it was pretty yuk

It's bitter, but the horses seem to like it.

 

[Gamebird]

Please pardon my ignorance Gamebird, I know you are a vet, but I thought the prescribing cascade only allowed you to prescribe a drug if a licenced one wasn't available. How do you get round the fact that omeprazole is available? Do you have to use omeprazole first and prove it didn't work?

If they were the same drug, then you wouldn't necessarily need to try the licensed one first, but you would need a strong clinical justification of why you were moving down the cascade to an unlicensed one. Cost is not usually a viable reason so for example we cannot prescribe ACP tablets instead of Sedalin on cost grounds.

However in this case esomeprazole is not the same drug as omeprazole (OK, it is an isomer of omeprazole, so very similar, but it is not technically the same drug, and it does have different pharmacological properties), and there are no licensed preparations of esomeprazole for animals. So if you think the horse requires esomeprazole then you can legally use it.

For those unfamiliar with the cascade it is essentially a risk based decision making tree. The steps for using a drug are:

1. Preparation licensed for use for that condition in that species in the UK
2. Preparation licensed for use for that condition in that species in NI (obtained via a special import certificate)
3. Preparation licensed for use for a different condition in that species, or for a different species in the UK or worldwide [eg. using dog eye drops in a horse, or using Equisolon (which is only licensed for respiratory conditions) for a skin condition in a horse]
4. Preparation licensed for use in humans in the UK or elsewhere, but obtained in the UK [eg. Invokana/canagliflozin for treating EMS]
5. 'Special' preparation, formulated in the UK [this covers things such as the BOVA omeprazole injection]
6. Human medicine obtained from abroad via a special import certificate

So for instance we often use Doxycyline (antibiotic) for horses. There isn't a licensed version so we skip step one. No license in NI, so we skip step 2. On to step 3 - there is a doxycycline licensed for use in chickens and poultry (Karidox) so that is the one we should go to. However if there are concerns about palatability or efficacy (it doesn't work if the horse doesn't actually ingest it!) then we can use a clinical justification to move past step 4 (no suitable licensed human preparation) to step 5 and use a 'Special' preparation eg. the BOVA paste, or the granules formulated by Coppax (both specially formulated for equine veterinary use).

Hope this helps! There a re a couple more nuances, but that is the gist of it. It is a bit of a ball and chain as vets in other countries are not generally similarly restricted, however it is law here, and that's that. We have to work with it, and the over-riding aim is animal safety and welfare.

 

[dorsetladette]

that's what I use!

me too.

 

[SEL]

If they were the same drug, then you wouldn't necessarily need to try the licensed one first, but you would need a strong clinical justification of why you were moving down the cascade to an unlicensed one. Cost is not usually a viable reason so for example we cannot prescribe ACP tablets instead of Sedalin on cost grounds.

However in this case esomeprazole is not the same drug as omeprazole (OK, it is an isomer of omeprazole, so very similar, but it is not technically the same drug, and it does have different pharmacological properties), and there are no licensed preparations of esomeprazole for animals. So if you think the horse requires esomeprazole then you can legally use it.

For those unfamiliar with the cascade it is essentially a risk based decision making tree. The steps for using a drug are:

1. Preparation licensed for use for that condition in that species in the UK
2. Preparation licensed for use for that condition in that species in NI (obtained via a special import certificate)
3. Preparation licensed for use for a different condition in that species, or for a different species in the UK or worldwide [eg. using dog eye drops in a horse, or using Equisolon (which is only licensed for respiratory conditions) for a skin condition in a horse]
4. Preparation licensed for use in humans in the UK or elsewhere, but obtained in the UK [eg. Invokana/canagliflozin for treating EMS]
5. 'Special' preparation, formulated in the UK [this covers things such as the BOVA omeprazole injection]
6. Human medicine obtained from abroad via a special import certificate

So for instance we often use Doxycyline (antibiotic) for horses. There isn't a licensed version so we skip step one. No license in NI, so we skip step 2. On to step 3 - there is a doxycycline licensed for use in chickens and poultry (Karidox) so that is the one we should go to. However if there are concerns about palatability or efficacy (it doesn't work if the horse doesn't actually ingest it!) then we can use a clinical justification to move past step 4 (no suitable licensed human preparation) to step 5 and use a 'Special' preparation eg. the BOVA paste, or the granules formulated by Coppax (both specially formulated for equine veterinary use).

Hope this helps! There a re a couple more nuances, but that is the gist of it. It is a bit of a ball and chain as vets in other countries are not generally similarly restricted, however it is law here, and that's that. We have to work with it, and the over-riding aim is animal safety and welfare.

That's really interesting - thank you

I've used a few human drugs and some have been easier for the vet to source than others. The thyroid drug was sorted pretty quickly because at the time it was also used for EMS horses, but robaxin was a lot less common and took a while to organise.

 

[ycbm]

I've had a horse on human epilepsy drugs as part of the cascade, because nothing was available for horses at the time. But with omeprazole being so effective and so relatively free of side effects and contra indications, it sounds like it would be difficult to get a vet to prescribe you esomeprazole unless you could show that omeprazole had already failed?

It is readily available online, though in 20mg tablets coated for humans not horse digestive systems. It would be very interesting to know what a preventative dose might be. I think the gastrogard one is a quarter?
.

 

[Murphy88]

I've had a horse on human epilepsy drugs as part of the cascade, because nothing was available for horses at the time. But with omeprazole being so effective and so relatively free of side effects and contra indications, it sounds like it would be difficult to get a vet to prescribe you esomeprazole unless you could show that omeprazole had already failed?

It is readily available online, though in 20mg tablets coated for humans not horse digestive systems. It would be very interesting to know what a preventative dose might be. I think the gastrogard one is a quarter?
.

Gamebird has given a good explanation of cascade so I won't repeat, but to answer about prescribing esomeprazole. It is going to be vet dependent. In my practice, I standardly use gastrogard as a first line for "normal horses" where the owners are going to also make an effort to improve their management etc. However in racehorses who have very little in the way of management changes to help gastric ulceration and diets that are not conducive to ulcer healing, I think there is enough peer-reviewed research showing a more consistent acid-suppressing effect regardless of diet with esomeprazole than omeprazole to justify using eso in those cases under the cascade.

The human omeprazole and esomeprazole are not enteric coated so might as well give the horse water for all the effect it would have. Eso looks to be £4 for 7 tablets and omeprazole is £8 for 28 tablets - the preventative dose would be approx 13 tabs and 25 tabs respectively, so effectively you're spending £8 a day for preventative dose which is more expensive than the preventative dose of the equine formulations of both.

 

[daffy44]

Can I just thank the vets who come here and post such useful information, thankfully ulcer meds are not relevant to my horses at the moment, but I'm always eager to learn, so this has been very informative, thank you!

 

[Clodagh]

Can I just thank the vets who come here and post such useful information, thankfully ulcer meds are not relevant to my horses at the moment, but I'm always eager to learn, so this has been very informative, thank you!

I was thinking that, it’s very good of them and fascinating to learn.

 

[ycbm]

Gamebird has given a good explanation of cascade so I won't repeat, but to answer about prescribing esomeprazole. It is going to be vet dependent. In my practice, I standardly use gastrogard as a first line for "normal horses" where the owners are going to also make an effort to improve their management etc. However in racehorses who have very little in the way of management changes to help gastric ulceration and diets that are not conducive to ulcer healing, I think there is enough peer-reviewed research showing a more consistent acid-suppressing effect regardless of diet with esomeprazole than omeprazole to justify using eso in those cases under the cascade.

The human omeprazole and esomeprazole are not enteric coated so might as well give the horse water for all the effect it would have. Eso looks to be £4 for 7 tablets and omeprazole is £8 for 28 tablets - the preventative dose would be approx 13 tabs and 25 tabs respectively, so effectively you're spending £8 a day for preventative dose which is more expensive than the preventative dose of the equine formulations of both.

Great info, thanks!
.

 

[khalswitz]

I always hesitate to post on threads about RER/PSSM etc. But at the same time, my PhD was on the genetics of these syndromes (and I’m still involved in research in these areas) so I find it really hard to read and not post.

(This is a general thing not aimed at the OP, and is prefaced by saying I’m not a scientist, just an affected horse owner) I know I say this over and over but RER has absolutely nothing, diddly squat, zippo, zilcho to do with PSSM. It has zero to do with polysaccharide storage, zero to do with sugars in cells, etc etc etc.

From what I have read, horses that tested positive to the Equiseq RER test did not, on biopsy, show the more centrally located cell nucleus that is found in horses with RER, so I reserve judgement on the genetic test.

However, I will admit that managing a horse that has been diagnosed through biopsy as having RER is not straightforward. It cannot be controlled by diet in the way PSSM can. As said, the horse cannot regulate its calcium ion release properly. Excessive calcium ions floating about trigger excessive muscle contraction, and that tells the horses brain to get the heck out of dodge. Magnesium receptors are blocked so the horse doesn’t receive the signals it needs to allow its muscle sarcomeres to relax again. Stress triggers the process and it can be a self perpetuating cycle where the horse gets stressed, the muscles say run, the horse tries to run, the human says no, the horse gets stressed, the problem gets worse. There is a reason why racehorses are more prone to tie up from RER during fast canters when held back, than when allowed to shift the way they want to.

And it is hard because we put horses in stressful situations every day. We ride when they have a tweak, we accidentally pinch with the girth, we keep them stabled or in small paddocks, or with companions they don’t really like, or we separate them out, travel them, whatever. Horses constantly undergo stress. We should always be mindful to the stressors we put them through, but with an RER horse we should be even more so, as their body escalates the situation without their brains permission more than a ‘normal’ horse.

So their management and successful life depends upon how many sacrifices the owner is prepared to make. For BBP, competition was too much. Trec was his forte, the patterns of obstacles made sense to him, he had practiced them (a bit like the TRT method where the familiarity of the movement patterns help) but only when working in a pair. Being asked to move away from the other horses/his pair was a massive trigger and too much for him. He would melt down. And As much as it’s nice to be told how well you sat and how sympathetically you rode, my horse wasn’t having any fun. So I retired him from even the low level competing I did to just hacking and schooling. Hacking he was beautiful. Polite, forward, easy, light. Until he saw ‘something’. He had no middle ground. The something would trigger a full blown panic attack with whole body wobbling like a bowl full of jelly, everything in his body screaming at him to run. It was dangerous trying to get him away, and far more dangerous trying to keep going. So with that and his hypermobility injuries and anxiety I retired him completely. At home, in his safe place, with his friends, he was perfect. Never an issue.

So I do have sympathy if this mare does have RER.
BUT, I also think we have to take some responsibility ourselves for what we ask of them (and I’m not criticising OP as thousands of other riders may have done the same). You have a baby horse, a baby. Already been through what can be quite a stressful experience for a baby in being backed at 3 and ridden to the point where the new owner believes her to be ready to go to XC clinics etc. Then transported to a whole new place (was she from Ireland) and thrown straight in the deep end with ridden work. It may not have seemed like asking a lot, but she is a baby. Her growth plates aren’t fused, her teeth may not be through yet, her musculature won’t be fully developed got carrying a human, and yet we treat them like a grown up well established horse. They don’t owe us anything, no matter how much we spend on them, we throw them into our world, they didn’t ask for any of it.

I 100% know I’m in a tiny minority here, but i don’t intend to ride my pony til he is 5 or 6. His work right now as a 4yo is on being a nice guy to have around and developing the posture and skills to carry a rider once his body and his mind is ready. Now as I’m older I spend far more time thinking about how they feel about what I am asking, rather than just whether they have done as I asked. Even my older mare who I bought in March, I haven’t ridden her more than 5 times as she told me she just wasn’t comfortable yet. There is so much more joy in developing a relationship and learning how to have a happy horse than there is in riding a horse because I bought one to ride.

That was preachy. My apologies.

There’s actually not much convincing evidence that RER is caused by calcium dysregulation. Some studies have suggested it, others have found the opposite, and none of the many genetic studies in RER have had a hit on any calcium regulation genes. The fact dantrolene acts as a prophylactic is the best evidence we have, and that doesn’t indicate causality, only that the pathways are somehow impacted.

Calcium regulation also comes up in transcriptomic and proteomics studies because calcium regulation is a major and inherent part of how muscles function, and so when they are damaged, these genes and proteins are differentially regulated. But there’s no real evidence it’s causal rather than symptomatic.

Interestingly, because we don’t know what RER or PSSM2 are actually caused by, they could be more or less distinct than we think. For example, some evidence of polyglucosan on histology is evidenced in episodes of non-genetic muscle damage, or seen in well described other neuromuscular diseases with an unrelated cause, so histological evidence of polyglucosan is perhaps not as good as diagnostic tool as we thought - and in some cases of PSSM2 the only distinguishing factor from RER is that polyglucosan. So there’s not necessarily any clear evidence that PSSM2 is linked to polysaccharide storage either.

In humans, exertional rhabdomyolysis (tying up) can be caused by thousand of genetic variants in fifty plus genes in different muscle function and energy metabolism pathways. There is a train of thought that we should be treating RER/PSSM2 the way human medics treat ER, as a symptom rather an outright disease. But the real evidence for that is the lack of ability to find genetic causes for a significantly heritable disease, which we’d expect to be able to do unless the disease were polygenic or the phenotyping poor (ie symptom not disease).

The stress aspect is also interesting. We’ve got unpublished work showing no increase in long term cortisol deposits in hair in horses with RER - I’m pretty interested in what that suggests.

On the note of the tests, I won’t belabour the point, but these unvalidated tests are causing real concern in the international equine genetics and veterinary neuromuscular disease communities as there is so little evidence they are in any way indicative of a disease instead of normal genetic variation. I find it personally quite upsetting.

To be clear, I have no competing interests or any stake in any currently available genetic tests, nor am I affiliated with a lab offering these tests. (All my genetic work is just published and not commercialised)

 

[Bernster]

Thankful to have such valuable inputs to help our understanding!

 

[Fieldlife]

The human omeprazole and esomeprazole are not enteric coated so might as well give the horse water for all the effect it would have.

Confused I thought human enteric coated versions of both are available?

• Prilosec (omeprazole)
• Nexium (esomeprazole)

Thanks

 

[SEL]

@khalswitz thank you for such a detailed post.

I think a lot of people echo your concerns but are shouted down on social media if they try to voice them.

I know quite a few people who have tested, have had a positive result(s) and later found their issues related to something else entirely. The lack of muscle biopsies for horses who are clearly struggling is also an issue (why biopsy when a hair test is less invasive is the argument). Some of those biopsies have turned up treatable conditions which the owners would never have known about otherwise. (Lyme, EPM type issues etc)

 

[paddy555]

I always hesitate to post on threads about RER/PSSM etc. But at the same time, my PhD was on the genetics of these syndromes (and I’m still involved in research in these areas) so I find it really hard to read and not post.


There’s actually not much convincing evidence that RER is caused by calcium dysregulation. Some studies have suggested it, others have found the opposite, and none of the many genetic studies in RER have had a hit on any calcium regulation genes. The fact dantrolene acts as a prophylactic is the best evidence we have, and that doesn’t indicate causality, only that the pathways are somehow impacted.

Calcium regulation also comes up in transcriptomic and proteomics studies because calcium regulation is a major and inherent part of how muscles function, and so when they are damaged, these genes and proteins are differentially regulated. But there’s no real evidence it’s causal rather than symptomatic.

Interestingly, because we don’t know what RER or PSSM2 are actually caused by, they could be more or less distinct than we think. For example, some evidence of polyglucosan on histology is evidenced in episodes of non-genetic muscle damage, or seen in well described other neuromuscular diseases with an unrelated cause, so histological evidence of polyglucosan is perhaps not as good as diagnostic tool as we thought - and in some cases of PSSM2 the only distinguishing factor from RER is that polyglucosan. So there’s not necessarily any clear evidence that PSSM2 is linked to polysaccharide storage either.

In humans, exertional rhabdomyolysis (tying up) can be caused by thousand of genetic variants in fifty plus genes in different muscle function and energy metabolism pathways. There is a train of thought that we should be treating RER/PSSM2 the way human medics treat ER, as a symptom rather an outright disease. But the real evidence for that is the lack of ability to find genetic causes for a significantly heritable disease, which we’d expect to be able to do unless the disease were polygenic or the phenotyping poor (ie symptom not disease).

The stress aspect is also interesting. We’ve got unpublished work showing no increase in long term cortisol deposits in hair in horses with RER - I’m pretty interested in what that suggests.

On the note of the tests, I won’t belabour the point, but these unvalidated tests are causing real concern in the international equine genetics and veterinary neuromuscular disease communities as there is so little evidence they are in any way indicative of a disease instead of normal genetic variation. I find it personally quite upsetting.

To be clear, I have no competing interests or any stake in any currently available genetic tests, nor am I affiliated with a lab offering these tests. (All my genetic work is just published and not commercialised)

very good post, thank you.

you say it is causing concern in genetics and vet communities and there is also the very serious effect this is having on both owners and horses. The owners start to fail to listen to reason. Is it feasible that someone has 7? very likely not until you get onto the FB PSSM forums and then it is quite normal and ordinary people just don't understand. Many (not all) of these horses have logical explanations. In this case simply a young horse needing an experienced rider and a fair bit of time.
The only thing linking these 7 horses is the owner. They are different breeds and a DNA test I don't expect would reflect management and this one hasn't lived there long enough anyway.


and then the rider writes
And someone contacted me from NX to say to be very careful as in her experience all px horses are explosive and dangerous.

bye bye any confidence the rider had in bringing on a purely young horse. It is now explosive and dangerous and it has spooked and she has fallen off anyway so it must be true most likely because people on FB say so. .

the last time I looked which was a long time ago this test was £250, probably more now. Who on earth would pay that sort of money for an unvalidated test and then worry themselves silly at the results.
The greatest worry in this particular instance is of course the young horse who has the potential to go wrong. I really hope he doesn't.

 

[khalswitz]

very good post, thank you.

you say it is causing concern in genetics and vet communities and there is also the very serious effect this is having on both owners and horses. The owners start to fail to listen to reason. Is it feasible that someone has 7? very likely not until you get onto the FB PSSM forums and then it is quite normal and ordinary people just don't understand. Many (not all) of these horses have logical explanations. In this case simply a young horse needing an experienced rider and a fair bit of time.
The only thing linking these 7 horses is the owner. They are different breeds and a DNA test I don't expect would reflect management and this one hasn't lived there long enough anyway.


and then the rider writes
And someone contacted me from NX to say to be very careful as in her experience all px horses are explosive and dangerous.

bye bye any confidence the rider had in bringing on a purely young horse. It is now explosive and dangerous and it has spooked and she has fallen off anyway so it must be true most likely because people on FB say so. .

the last time I looked which was a long time ago this test was £250, probably more now. Who on earth would pay that sort of money for an unvalidated test and then worry themselves silly at the results.
The greatest worry in this particular instance is of course the young horse who has the potential to go wrong. I really hope he doesn't.

There were two studies by Valberg et al in 2021 and 2022 that genotyped horses they’d diagnosed by biopsy with PSSM2 or MFM (one study only the former is QH and the other both in Arabians and WBs). They found what we call a high allelic frequency - ie, these variants are really common (which isn’t normal for disease causing variants due to selection). So it’s absolutely possible that you could have 7 horses test positive for one of these variants in a row.

The problem isn’t that they’ve tested positive for the variants - it’s that there’s no evidence the variants are associated with disease.

Some variants won’t cause a change in amino acid sequence, others cause a change but to a similar size and charge amino acid that won’t affect the function of the protein. So not every variant has what we call a functional effect and therefore is highly unlikely to cause disease - they are just variation, often termed as benign. Equally, even if they have an effect, is it a disease effect? Variants can give advantages, or neutral changes.

A validated genetic test should present a well designed study with strong association with a well phenotyped disease versus controls, ideally also in an independent validation population, identify a likely pathogenic variant, and then demonstrate a functional effect of the variant in causing the disease. We can see this in the case of PSSM1, HYPP, malignant hyperthermia, GBED, HERDA, fragile foal syndrome and many more genetic diseases. At the moment, we don’t even have the basic level of suggestion that these tests are testing for a disease, and in fact the two Valberg studies suggest the opposite.

 

[khalswitz]

@khalswitz thank you for such a detailed post.

I think a lot of people echo your concerns but are shouted down on social media if they try to voice them.

I know quite a few people who have tested, have had a positive result(s) and later found their issues related to something else entirely. The lack of muscle biopsies for horses who are clearly struggling is also an issue (why biopsy when a hair test is less invasive is the argument). Some of those biopsies have turned up treatable conditions which the owners would never have known about otherwise. (Lyme, EPM type issues etc)

Yes - I don’t post on Facebook at all now on this because of that reaction.

Frustratingly, the reaction to geneticist and BEVA advising against these tests has been for these groups to double down - even changing the name of the diseases! ‘Muscle integrity myopathy’ has never had a single published paper on it, and the only references to it I’ve found online are on Facebook and the company websites. Vets are not diagnosing this disease because it doesn’t exist.

People have horses with undiagnosed issues, I think that’s easy to agree. It’s just that this isn’t the answer to what is wrong with them. Other findings wouldn’t surprise me.

 

[shortstuff99]

Yes - I don’t post on Facebook at all now on this because of that reaction.

Frustratingly, the reaction to geneticist and BEVA advising against these tests has been for these groups to double down - even changing the name of the diseases! ‘Muscle integrity myopathy’ has never had a single published paper on it, and the only references to it I’ve found online are on Facebook and the company websites. Vets are not diagnosing this disease because it doesn’t exist.

People have horses with undiagnosed issues, I think that’s easy to agree. It’s just that this isn’t the answer to what is wrong with them. Other findings wouldn’t surprise me.

You should see how they denigrate Valberg on these sites and yet she has published her studies?!

If you ever try and discuss with the scientist man (can't remember his name) all he does is quote loads of scientific looking gumpf at you to try and blind you to the fact it is mostly useless. It's also not like he doesn't know how to publish he has plenty of fly genetics papers....

 

[BBP]

I always hesitate to post on threads about RER/PSSM etc. But at the same time, my PhD was on the genetics of these syndromes (and I’m still involved in research in these areas) so I find it really hard to read and not post.


There’s actually not much convincing evidence that RER is caused by calcium dysregulation. Some studies have suggested it, others have found the opposite, and none of the many genetic studies in RER have had a hit on any calcium regulation genes. The fact dantrolene acts as a prophylactic is the best evidence we have, and that doesn’t indicate causality, only that the pathways are somehow impacted.

Calcium regulation also comes up in transcriptomic and proteomics studies because calcium regulation is a major and inherent part of how muscles function, and so when they are damaged, these genes and proteins are differentially regulated. But there’s no real evidence it’s causal rather than symptomatic.

Interestingly, because we don’t know what RER or PSSM2 are actually caused by, they could be more or less distinct than we think. For example, some evidence of polyglucosan on histology is evidenced in episodes of non-genetic muscle damage, or seen in well described other neuromuscular diseases with an unrelated cause, so histological evidence of polyglucosan is perhaps not as good as diagnostic tool as we thought - and in some cases of PSSM2 the only distinguishing factor from RER is that polyglucosan. So there’s not necessarily any clear evidence that PSSM2 is linked to polysaccharide storage either.

In humans, exertional rhabdomyolysis (tying up) can be caused by thousand of genetic variants in fifty plus genes in different muscle function and energy metabolism pathways. There is a train of thought that we should be treating RER/PSSM2 the way human medics treat ER, as a symptom rather an outright disease. But the real evidence for that is the lack of ability to find genetic causes for a significantly heritable disease, which we’d expect to be able to do unless the disease were polygenic or the phenotyping poor (ie symptom not disease).

The stress aspect is also interesting. We’ve got unpublished work showing no increase in long term cortisol deposits in hair in horses with RER - I’m pretty interested in what that suggests.

On the note of the tests, I won’t belabour the point, but these unvalidated tests are causing real concern in the international equine genetics and veterinary neuromuscular disease communities as there is so little evidence they are in any way indicative of a disease instead of normal genetic variation. I find it personally quite upsetting.

To be clear, I have no competing interests or any stake in any currently available genetic tests, nor am I affiliated with a lab offering these tests. (All my genetic work is just published and not commercialised)

I’ll put my hands up and say that I only understood about 50%, but enough to remind me why I shouldn’t post on threads where I have such limited understanding and a case study of 1. I hate to spread misinformation so I apologise, I will stick to reading and learning instead of posting

 

[LadyGascoyne]

I always hesitate to post on threads about RER/PSSM etc. But at the same time, my PhD was on the genetics of these syndromes (and I’m still involved in research in these areas) so I find it really hard to read and not post.


There’s actually not much convincing evidence that RER is caused by calcium dysregulation. Some studies have suggested it, others have found the opposite, and none of the many genetic studies in RER have had a hit on any calcium regulation genes. The fact dantrolene acts as a prophylactic is the best evidence we have, and that doesn’t indicate causality, only that the pathways are somehow impacted.

Calcium regulation also comes up in transcriptomic and proteomics studies because calcium regulation is a major and inherent part of how muscles function, and so when they are damaged, these genes and proteins are differentially regulated. But there’s no real evidence it’s causal rather than symptomatic.

Interestingly, because we don’t know what RER or PSSM2 are actually caused by, they could be more or less distinct than we think. For example, some evidence of polyglucosan on histology is evidenced in episodes of non-genetic muscle damage, or seen in well described other neuromuscular diseases with an unrelated cause, so histological evidence of polyglucosan is perhaps not as good as diagnostic tool as we thought - and in some cases of PSSM2 the only distinguishing factor from RER is that polyglucosan. So there’s not necessarily any clear evidence that PSSM2 is linked to polysaccharide storage either.

In humans, exertional rhabdomyolysis (tying up) can be caused by thousand of genetic variants in fifty plus genes in different muscle function and energy metabolism pathways. There is a train of thought that we should be treating RER/PSSM2 the way human medics treat ER, as a symptom rather an outright disease. But the real evidence for that is the lack of ability to find genetic causes for a significantly heritable disease, which we’d expect to be able to do unless the disease were polygenic or the phenotyping poor (ie symptom not disease).

The stress aspect is also interesting. We’ve got unpublished work showing no increase in long term cortisol deposits in hair in horses with RER - I’m pretty interested in what that suggests.

On the note of the tests, I won’t belabour the point, but these unvalidated tests are causing real concern in the international equine genetics and veterinary neuromuscular disease communities as there is so little evidence they are in any way indicative of a disease instead of normal genetic variation. I find it personally quite upsetting.

To be clear, I have no competing interests or any stake in any currently available genetic tests, nor am I affiliated with a lab offering these tests. (All my genetic work is just published and not commercialised)

Really interesting! Thank you for sharing, and I hope you continue to contribute to discussions on the topic because it’s wonderful to read responses from someone who is actually involved in the research.

I had wondered about the gold standard biopsy approach to muscle myopathy, and how replicable results would be on a different day, in a different environment, pre and post exercise or even with samples taken from different muscles in the same horse. Is that something you’ve looked into?

I can imagine that where you have uncertainty in genetic causality, and may also have variation in biopsy, and then potentially also slightly vague symptoms unless a horse is actively tying up, it might be difficult to establish which of these factors is actually confirmatory for a disease. It almost feels like diagnosis is in a constant state of ‘on the balance’ - but that’s purely an impression, looking in from the outside.

 

[khalswitz]

I’ll put my hands up and say that I only understood about 50%, but enough to remind me why I shouldn’t post on threads where I have such limited understanding and a case study of 1. I hate to spread misinformation so I apologise, I will stick to reading and learning instead of posting

Please don’t stop posting - like I said when it comes to these diseases, there are theories (and the one you mentioned is one), we just don’t actually know for sure the cause, that’s the main thing. And direct experience of trying to manage a horse with this condition is really important - like you said it can be near impossible and the effect it will have on their working life is variable but potentially massive. So please don’t stop posting because I jumped in on the ‘causal’ bit.

Sorry if it was a bit of a dense post - like I said elsewhere I usually avoid posting on eg social media so I’m not very practiced at explaining a lot of these concepts in a non-scientific context, but if it’s something people are interested in I’m certainly happy to try.

Really interesting! Thank you for sharing, and I hope you continue to contribute to discussions on the topic because it’s wonderful to read responses from someone who is actually involved in the research.

I had wondered about the gold standard biopsy approach to muscle myopathy, and how replicable results would be on a different day, in a different environment, pre and post exercise or even with samples taken from different muscles in the same horse. Is that something you’ve looked into?

I can imagine that where you have uncertainty in genetic causality, and may also have variation in biopsy, and then potentially also slightly vague symptoms unless a horse is actively tying up, it might be difficult to establish which of these factors is actually confirmatory for a disease. It almost feels like diagnosis is in a constant state of ‘on the balance’ - but that’s purely an impression, looking in from the outside.

Good question. I’m not a histopathologist myself, to note, but I have worked closely with people who are.

You see a different picture immediately after an episode than you do a longer time from it - the former is full of inflammatory signs and recent muscle damage, the latter will show signs of longer term damage-repair cycles. But both are indicative of myopathy and not confused for healthy tissue.

Different muscles absolutely make a difference - PSSM and RER affect Type 2X and to a lesser extent 2A muscle fibres preferentially, so large propulsive muscles with high content of these fibre types will show more disease signs than ones without. Sample a wrong muscle and the horse could appear normal. For these diseases, semimembranosus and gluteal muscles are recommended, but for other diseases the referral service might recommend a different muscle (eg atypical myopathy or EMND might use tail head muscle).

Pre and post exercise depends more on whether exercise induces muscle damage - there is less eg glycogen visible post exercise in healthy horses but it won’t make a healthy horse look like a myopathy under the microscope, the histological signs are specific to myopathy although perhaps not to specific myopathies (PSSM and polyglusocan being the real exception).

There does need to be care taken in taking, handling and prepping the sample though, and vets are given good instructions on that. The methods used for staining etc are of long standing and very standard practice so not something I’d be concerned about.

The biggest issue with the muscle biopsy for owners is that it might give a good diagnostic indication of whether the horse has a myopathy or not, but it often doesn't tell you what to do about it, because we simply don’t know beyond standard established management practices.

And yes - thankfully diagnostics isn’t my job as I’m not a vet, but working out exactly what’s causing the horse’s issue definitely isn’t straightforward.