# Sticky  Information on Myopathies - PSSM1, PSSM2, MFM, and RER



## Espy

*PSSM1, PSSM2, MFM, and RER*


The symptoms of PSSM1, PSSM2, and MFM can be incredibly subtle and nonspecific. It makes these diseases very hard to diagnose. Every horse is different, but first I want to include a list of common symptoms. Horses can have all of them or just some of them. It’s very individualized.
The prevalence of all of these disorders is much higher than originally thought. There are no exact numbers yet, but they are found at surprisingly high frequencies in many different horse and pony breeds, especially quarter horses and thoroughbreds.

A university lab (which university must remain undisclosed due to unpublished research) recently examined the breed distributions of variants P2, P3, and P4 (these variants are explained below). Here are the results. Of course, this data is only from the tested samples which was relatively small. The number in parentheses is the number of horses tested from that breed. More variants could be found in the breeds, or more breeds added as variants are found. This is more to back up the idea that this is not “just a draft horse problem” or “just a quarter horse problem”.

Quarter Horses – P2, P3, and P4
Paints – P2, P3, and P4
Thoroughbreds – P2, P3, and P4
Fell Pony – P2, P3, no P4
Morgans – P2, P3, no P4
Cleveland Bay (23) - P2, P3, no P4
Arabian (20) - P2, no P3, P4
Nepal (20) - P2, P3, no P4
Fell Pony (20) - P2, P3, no P4
Mangalarga (25) - P2, P3, no P4
Campolina (24) - P2, no P3, P4
Mangalarga Marchadore (24) - P2, P3, no P4
Konik (19) - P2, no P3, no P4
Caspian Pony (19) - P2, no P3, P4
Turkoman (22) - P2, P3, P4
Kurd (22) - P2, P3, P4
Selle Francois (22) - P2, P3, no P4
Suffolk (29) - P2, P3, no P4
Haflinger (29) - P2, no P3, P4
Akhal Teke (28) - P2, P3, P4
Peruvian Paso (25) - P2, no P3, P4
Exmoor Pony (32) - P2, no P3, no P4
Tennessee Walker (28) - P2, no P3, no P4
Percheron (4) - no P2, P3, no P4 


Many people put these symptoms down the training issues, as I once did, but they are really signs of pain.

Symptoms list:

Difficulty standing for the farrier
“Girthiness” or biting/pinning ears when the girth is tightened
Frequently rubbing on posts/trees
Gait abnormalities including a hitch in the trot, “bunny hopping” (moving both hind legs at once during the canter instead of leading with a leg), rope walking (placing one leg in front of the other as if walking on a tightrope) in severe cases
General muscle stiffness
Lack of forward impulsion undersaddle
Intolerance to being groomed or touched
Holding tail to one side frequently
Being heavy on the forehand
Inability to engage the hind end
Difficulty or inability to make lead changes, especially in the hind
Explosive behavior undersaddle with no identifiable cause (bolting, bucking, rearing)
Lameness after being stalled
Reluctance to move
A sour attitude undersaddle or during other work
Respiratory distress (in severe cases)
Fear of being tied
Colic-like symptoms with no actual colic
Poor muscle development, especially in the topline and hindquarters
Shifting lameness (especially in stifles) with no identifiable cause
Muscle spasms
Muscle fasciculations

The symptoms for RER are different from the former three disorders, so I will detail them farther down.


*Polysaccharide storage myopathy type 1:*

This disorder is caused by a single base pair substitution in the GYS1 gene, which codes for glycogen synthase. Although PSSM1 is most common in quarter horses, it has been found in many other breeds. It is not safe to say that I have x or y breed, so he can’t have PSSM1.


Symptoms: See list at the top of the post. Serum AST and CK levels are usually not affected.

Testing: It can be diagnosed through muscle biopsy or through genetic testing.

Treatment: Special diet, supplementation, and exercise regime.
Helpful supplements include vitamin E, magnesium, and electrolytes.

Horses with PSSM1 should eat a low-sugar diet (10-12% or lower NSC) and have an increased fat intake (provided by oil or other fat supplements). These horses should get the majority of their energy from fat instead of carbohydrates.

Horses with PSSM1 tend not to do well in stalls and do best when given lots of turn out and regular exercise.
From the experience of owners of horses with PSSM1, it appears to be the most manageable myopathy with many horses continuing to compete once the disease is being properly managed.


*Polysaccharide storage myopathy type 2 and myofibrillar myopathy:*

PSSM2 and MFM are currently being researched and candidate genes have been found. They are distinct from PSSM1 despite presenting with very similar symptoms. This information is not yet published, so the genes are being represented as P2 (PSSM2), P3 (MFM) and P4 (PSSM2). These genetic variants have also been found across a large range of horse and pony breeds. Many vets are insistent that PSSM2 is “just a draft horse thing”, but data has shown this to be false.

Symptoms: See list at the top of the post. Serum AST and CK levels are usually not affected.

Testing: It can be diagnosed through muscle biopsy or through genetic testing.

Treatment: Because PSSM2 is distinct from PSSM1, it requires different management.
Helpful supplements still include vitamin E, magnesium, and electrolytes, but the diet to manage these disorders is different from that of PSSM1. When horses with PSSM2/MFM go into negative nitrogen balance (usually due to infection or injury), they have trouble coming back out of it. This leads to muscle wasting and muscle dysfunction. These horses need a high protein diet to combat negative nitrogen balance and to be able to recover from sickness and injuries.

Methionine, threonine, and lysine are three amino acids that are generally found in low concentrations in plant matter. Horses with PSSM2/MFM should have them supplemented. This can be done through certain commercial supplements or by giving the amino acid powders directly.

They should also be fed a high protein ration balancer or be given whey protein isolate or soy protein isolate to increase their protein intake.

Just like horses with PSSM1, horses with PSSM2/MFM don’t do well stalled and need plenty of turn out. However, some affected horses can actually be made worse with structured exercise. This is very individual, as many horses improve while others deteriorate with exercise.

Horses with PSSM2/MFM are often not sugar sensitive like those with PSSM1, but it can depend on the individual.

For an acute episode (usually consisting of muscle spasms (but not always), extreme pain and stiffness, and sweating), there are several drugs that have proven beneficial. Methocarbamol (Robaxin) is a skeletal muscle relaxant that can reduce stiffness and muscle spasms. Acepromazine can be used to provide sedation and stress/anxiety relief which can certainly help with the severity of the symptoms. Banamine and phenylbutazone are effective in the short term for pain relief. Gastric ulcers often go hand-in-hand with acute muscle episodes due to the pain and stress of the situation, so treating for ulcers or taking preventative measures against them can be helpful. All medications should of course be given under the guidance of a veterinarian.

Preventing acute episodes is also helpful in managing PSSM2/MFM. Each horses’ triggers tend to be different but common triggers include stress (like in trailering or competing), injury, surgery, abrupt weather changes, over-exercising, and having to stand for a farrier. Some triggers are unavoidable, like weather changes and standing for the farrier, so drugs such as ace, robaxin, or banamine can be given prophylactically to prevent pain and stress during these events. 
How manageable PSSM2/MFM is depends on the individual horse. Horses with more than one variant tend to be worse off than those with only one. Homozygous horses also usually have worse symptoms than heterozygous horses. PSSM2/MFM can be manageable, but it is also a progressive disease. Many horses continue to deteriorate over time even with treatment. Many affected horses do not have the lifespan of a normal horse.


*Recurrent Exertional Rhabdomyolysis:*

RER has a different nature than PSSM1, PSSM2, and MFM. The three I have detailed so far are chronic diseases that generally cause damage over time. RER is more acutely dangerous and is the disease associated with what people refer to as “tying up”. During an episode of RER, a horse will present with muscle stiffness (often to the point of physically not being able to move, or lying on the ground unable to move), profuse sweating (often to the point of dripping), and coffee colored urine. This is an emergency and usually requires hospitalization with IV fluids to prevent kidney failure. It can be very expensive to treat an episode of RER.

Just as with PSSM2 and MFM, there are candidate genes being researched but nothing has been published. RER is very likely multigenic. Only one gene has been identified which is being represented as Px. There are other genes currently being investigated.

RER is found in highest frequency in thoroughbreds but also have been found in other breeds including quarter horses, Arabians, and others.

Symptoms: Stiff, rock-hard muscles, profuse sweating, coffee colored urine during an acute episode. Some horses with RER also present chronically with muscle pain, muscle wasting, and nervous/high-strung temperament.

Testing: RER isn’t easy to test for right now because it is multigenic and still being researched. There is a test available for the Px variant, but no other tests for other candidate genes have been made. A horse with the Px variant does not necessarily have RER because mutations in other genes are needed for the full-blown disease to be present. RER is mostly diagnosed symptomatically; horses that tie up after exercising with extremely elevated serum CK and AST levels generally have RER. Further genetic testing will likely become available with time.

Treatment: Dantrolene is a useful skeletal muscle relaxant in treating RER. It works best as a preventative. Owners of horses with RER have found that keeping affected horses calm goes a long way in preventing episodes. Dantrolene can be used in situations where horses may become stressed or excited, such as trailering. Activities such as barrel racing where horses tend to get very excited have also been observed to contribute to episodes of tying up.
Vitamin E, magnesium, and electrolytes are still helpful because they promote proper muscle function.

RER is not really manageable through diet, but feeding a well-balanced diet is likely still important in keeping these horses healthy. Keeping these horses healthy and well-balanced can help prevent episodes.
Exercise is important for horses with RER but should be done carefully. RER is a form of exercise intolerance. Pushing a horse too much past its limit (which could be considerably lower than that of healthy horses) may cause an episode.

As an example, I will tell my mare Esperanza’s story who is n/P3 and n/Px. This means that she has myofibrillar myopathy. Despite having the Px variant, she does not have RER. Instead, the Px variant seems to act a sort of enhancer to make her MFM symptoms worse. She has been 5-panel tested and tested for the other variants and is clear.

She has been affected since I got her at 6 years old (she is now 14). She originally presented with shifting lameness after receiving a moderately severe puncture wound by a fence. The lameness didn’t appear to be due to the puncture wound and we were unable to find any other cause for it. I understand now that the fence injury was her original trigger for kicking off MFM symptoms. We thought she may have had stifle problems but were never able to find anything wrong with her stifles. She objected to the girth being applied and did not like her hindquarters touched. Undersaddle she was excessively heavy on her forehand no matter what I did, threw her body over jumps rather than jumping like a normal horse, lurched intensely into the canter, and was prone to having fits in the ring. Her fits never included bucking or rearing, but were more bulging, dancing around, stopping, swishing her tail, crow hopping, and pinning her ears. Many affected horses do buck, rear, and bolt. Her career as a competition hunter ended when she could no longer be stalled. At her very last show, she was stalled over night and when my trainer went into her stall to take her leg-wraps off, she attacked my trainer and caused injury due to the massive amount of muscle pain she was in. This was very significant because she is normally an extremely gentle and tolerant horse. After this point, she was not sound to ride. She would usually start the ride doing well but would progressively become more and more fussy (bulging, swishing her tail, pinning her ears, refusing to canter, and crow hopping) until she I was forced to end the session.


It wasn’t until November 2016 that she started to become more serious. She descended into episodes of muscle spasms, pain, and stiffness that seriously reduced her quality of life. She also has very severe muscle wasting. She had a pronounced line of musculature on her abdomen that looked identical to a heave line associated with COPD, which caused a lot of confusion for us. I’ve learned that this line has nothing to do with COPD in this case and just shows how much muscle tension and pain my mare was experiencing. The disorder affected her diaphragm as well so she started to get “hiccups” or rather spasms of the diaphragm. She was almost euthanized, but seemed to be improving. She recovered and did very well for about 2 months before having her second episode. Her second episode was worse than her first and she still has not fully recovered. Euthanasia is a very real possibility for this horse, and probably soon. It wasn’t until she started to present with more serious symptoms that we learned about PSSM/MFM and decided to do the genetic tests. She was finally diagnosed with MFM after many long years of failed medical tests and confusion. If I’d been able to diagnose her earlier, she may have had a longer life. It’s my hope that this thread can help others make a swifter diagnoses and begin managing their horses earlier, hopefully extending their life and improving their quality of life.

It's important to keep in mind that not all horses with muscle disease have visible muscle spasms. Some only present with the much more subtle symptoms.

She currently eats a diet of Bermuda grass hay, timothy grass hay, Triple Crown 30% ration balancer, and Purina Amplify (for maintaining her weight). This works for her because she is not sugar sensitive. She gets 10 g lysine, 5 g methionine, 2 g threonine, 7500 IU vitamin E in natural oil form, and full electrolytes every other day. The supplements and removal of alfalfa in her diet did seem to reduce her muscle symptoms, although her recovery wasn't great.

The drugs I found useful in managing her episodes were banamine, dantrolene, and xylozine (a sedative). Banamine reduced her pain significantly but gave us problems with ulcers. Dantrolene allowed her stiff muscles to relax enough for her to move around a bit. Standing still for long periods made her feel worse, so it was a vicious cycle. She didn't want to move because she was in pain but not moving made her worse. Xylozine was useful for when she fell into an acute episode just to sedate her long enough for an oral dose of banamine to kick in.

The drugs I did not find useful were robaxin, phenylbutazone, and acepromazine. These drugs just plain did not work for her. It's very individual. I've talked to people with very different experiences with these drugs, so it is really trial-and-error based on the individual horse.

For the purpose of providing as much information as I can, I am including a few videos and pictures. showing her symptoms. Hopefully they will help someone better understand what is going on with their horse.

Picture of her muscle wasting. You can see how much is gone from the topline and hindquarters (click for larger image):










These videos show her gate abnormalities caused by the muscle pain. The heave line-like muscle ridge is also visible in both videos. See how she swishes her tail and is in obvious discomfort





 
In the end of this one, you can see the hitch in her trot as described in the symptoms list.





 
Here is a video showing muscle fasciculations:





 
These videos show the muscle spasms during an acute episode:





 




 
And this video shows the “hiccup” or diaphragm spasm.





 
Finally, this video is of her when she was in between two major episodes. Despite appearing pretty normal and healthy, you can see that she is still not comfortable by the tail swishing and slight objections to being asked to go forward.


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## Espy

There is new information available! I will post it here.

The horse in the above post succumbed to PSSM2/MFM in August of 2017.

The genes affected by P2, P3, P4, and Px have been disclosed.

P2 is a mutation in the gene that encodes myotilin (MYOT). Myotilin is a structural protein found in the z-disc of muscle. P2 is a non-conservative amino acid substitution in a highly conserved region of the protein. Mutations in MYOT are associated with limb-girdle muscular dystrophy 1A and myofibrillar myopathy in humans. It is semi-dominant.

P3 is a mutation in the gene that encodes filamin C (FLNC). Filamin C is a structural protein found in the z-disc of muscle. P3 is a non-conservative amino acid substitution in a highly conserved region of the protein. Mutations in FLNC are associated with myofibrillar myopathy in humans. It is semi-dominant.

P4 is a mutation in the gene that encodes myozenin 3 (MYOZ3). Myozenin 3 is a structural protein found in the z-disc of muscle. P4 is a non-conservative amino acid substitution in a highly conserved region of the protein. There is no human disease associated with this gene yet.

Px is a mutation in the gene that encodes the voltage-gated calcium channel on muscle (CACNA2D3). It is a synonymous mutation that may affect the density of voltage-gated calcium channels on muscle cells. It was found by GWAS to be associated with RER in some thoroughbred families. It almost certainly needs another genetic component to produce RER. The specific mutation is CACNA2D3-A525A.

P5 is the newest variant discovered. There is an ongoing study on it. It has a high incidence in draft breeds, particularly shires and clydesdales. It is expected to be recessive.

Finally, a peer-reviewed paper was recently published by Dr. Stephanie Valberg on immune mediated myositis (IMM). Here is that paper:

https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-018-0155-0

IMM is caused by the genetic variant MYH1-E321G. It is found in quarter horses and was not found outside of them (yet). It is prominent in reining lines. IMM is characterized by extreme muscle wasting on the topline and hindquarter following an infection (usually strangles). Muscle biopsies show infiltration of immune cells into muscle tissue. It can be treated successfully with steroid drugs. The paper has a lot more detail in it.

Here is some updated data on breed distribution:

Cleveland Bay (23) - P2, P3, no P4
Arabian (20) - P2, no P3, P4
Nepal (20) - P2, P3, no P4
Fell Pony (20) - P2, P3, no P4
Mangalarga (25) - P2, P3, no P4
Campolina (24) - P2, no P3, P4
Mangalarga Marchadore (24) - P2, P3, no P4
Konik (19) - P2, no P3, no P4
Caspian Pony (19) - P2, no P3, P4
Turkoman (22) - P2, P3, P4
Kurd (22) - P2, P3, P4
Selle Francois (22) - P2, P3, no P4
Suffolk (29) - P2, P3, no P4
Haflinger (29) - P2, no P3, P4
Akhal Teke (28) - P2, P3, P4
Peruvian Paso (25) - P2, no P3, P4
Exmoor Pony (32) - P2, no P3, no P4
Tennessee Walker (28) - P2, no P3, no P4
Percheron (4) - no P2, P3, no P4
Shetland Pony (24) - P2, P3, P4
Standardbred (24) - P2, no P3, no P4
Norwegian Fjord (12) - no P2, no P3, no P4
Shire (25) - P2, P3, no P4
Highland Pony (24) - P2, no P3, no P4
Icelandic (20) - no P2, no P3, no P4

New variants are being looked at always. Icelandics have been found by muscle biopsy to have MFM and there is ongoing research to find the variant affecting them.

Here is an image showing the pattern of muscle wasting in human limb-girdle muscular dystrophy. This is also the most common pattern in horses with PSSM2/MFM:


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## SilverMaple

Very interesting--


What have you found in your research with these variants among other draft breeds? I have heard many say PSSM is extremely common in Belgians and becoming more frequent in Percherons, yet studies seem not to include very many, if any, results in those breeds.


I'm glad to see that IMM has become more well-known and studied. It used to be something that many horsemen saw, but had no idea what the cause was--- the horses looked great one day, and a few days later looked horrible, had lost all definition and muscle along the topline, etc. The common treatment used to be steroids and pasture turnout for a few months-- looks like that's not all that wrong, after all.


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## Espy

PSSM1 is definitely common in Belgians and percherons, but some people will tell you that drafts aren't affected by it. Gypsy vanner people will especially say that. I can't say for sure whether or not it's true. PSSM1 isn't my area. I don't think it's true, personally.



PSSM2/MFM is also found in drafts, and it does affect them. The data up there has percherons, shires, fjords, haflingers, and suffolks. And of course, now there is P5. From what we've seen so far, P5 is pretty common in shires and clydesdales. The horse it was discovered in (homozygous) was a shire and was highly symptomatic with a muscle biopsy positive for MFM. We have a few drafts we've tested (friesian, Irish draught, clydesdales, gypsies) but over all they are super underrepresented in the samples we do have. There are definitely positive gypsies and clydes. There are a few Belgian crosses that are positive, but not purebreds.


As the P5 research takes off, we'll have a lot more data on PSSM2/MFM in draft breeds than we have now. Everyone who is selected for the P5 study will be tested for P2, P3, P4, and Px. It seems most people are testing quarter horses and thoroughbreds (but mostly quarter horses and related breeds).


What we've found over all is that almost no breed is safe from MFM, especially not the popular ones.


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## SilverMaple

The Belgian/Percheron guys around here (not really any other drafters represented, except for a few that have switched to Haflingers) treat and feed all of their horses like they are positive-- seems to work better for them, so one does wonder if it's more prevalent than originally thought, or if there is another variant at work that nobody has really looked into very much.


I'm seeing more Gypsy breeders testing for it, so that's good.


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## Espy

The latest paper published by Dr. Stephanie Valberg:



https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203467

Abstract:
"Type 1 polysaccharide storage myopathy (PSSM1) is a glycogen storage disorder of known cause whereas the basis for type 2 PSSM (PSSM2) is unknown. The same diet and exercise regime prescribed for PSSM1 is recommended for PSSM2; however, the benefit of these recommendations for PSSM2 is undocumented. The objectives of this study were to determine traits of PSSM2 Warmblood horses (WB), determine the changes in exercise responses that occur with a recommended low-starch/fat-supplemented diet and exercise regime, and determine if glycogen concentrations correspond to the severity of signs. Owners of PSSM2 WB (2008–2016), completed a retrospective questionnaire regarding their horse. Glycogen concentrations were analyzed in skeletal muscle of PSSM2 WB (n = 36) obtained prior to recommendations and in control WB with no evident myopathy (n = 23). Chi-square, Fisher’s exact, McNemar’s tests with Bonferroni correction and Mann Whitney testing were utilized. Abnormal exercise responses reported by owners, began at approximately 6 years of age and included a decline in performance, a reluctance to collect and reluctance to go forward in over 50% of horses. With the recommended diet and exercise regime, 80% of PSSM2 WB owners reported an overall improvement with significant decreases in the proportion of horses showing a decline in performance and rhabdomyolysis. However, 53% of PSSM2 WB were still not advancing as expected with reluctance to go forward and collect persisting in approximately one third of horses. Median muscle glycogen concentrations did not differ between PSSM2 WB and WB with no evident myopathy. PSSM2 WB with the highest glycogen concentrations were significantly more likely to show a decline in performance than those with lower glycogen concentrations. In conclusion, diet and exercise recommendations ideal for PSSM1 improve but do not eliminate the decline in performance and reluctance to go forward under saddle characteristic of PSSM2."


Too bad high protein diets weren't studied instead. I've seen a lot of horse owners succeed with a high protein diet.


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