Reading time 11 minutes  

Just like in humans, there are numerous muscle diseases in horses, the causes and variety of which are still partly unknown and not as well researched in our four-legged companions as in us. But what is the current state of scientific knowledge?

In general, there are inherited muscle diseases, where the mode of inheritance and the underlying mutation are known, as well as muscle diseases that can arise due to metabolic or hormonal disorders, become clinically noticeable as a result of incorrect feeding, or are caused by muscle trauma.

For humans, a wealth of data and studies is available on this topic, but unfortunately, we are still far from this level of knowledge when it comes to horses. However, there are new insights from current research in the field of myopathies – muscle diseases – for horses. This allows for a more nuanced differentiation between various conditions, and as a result, new causes are continually being discovered. We now know that, for example, PSSM2 is more of an umbrella term for several underlying, different muscle diseases. It is certain that the number of known myopathies – with their various causes and triggers – in horses will continue to increase in the coming years.

“Genetic mutations” do not necessarily lead to disease

Myopathies in horses with already established genetic causes include:

  • Polysaccharide storage myopathy 1 (PSSM1)
  • Hypercalaemic Periodic Paralysis (HYPP)
  • Glycogen Branching Enzyme Deficiency (GBED)
  • Malignant hyperthermia (MH)
  • Myosin Heavy Chain Myopathy (MYHM) or Immune-Mediated Myositis (IMM)

PSSM1 and HYPP each represent a genetic predisposition, the onset of which can be influenced by diet, leading to the clinically manifest disease. Horses affected by these conditions significantly benefit from an adapted diet. In contrast, with GBED (lethal in the first weeks or months), MH, and MYHM, diet has no impact.

The latter are genetic diseases, not predispositions. Both the genetic disease and the predisposition are inherited. The difference lies in the fact that with genetic diseases, the individual will inevitably develop the condition, regardless of diet, living conditions, etc., whereas with a genetic predisposition, the actual onset of the disease depends on environmental factors, such as diet.

Muscle diseases are not necessarily the result of a “gene mutation.”

In addition, there are myopathies with still unclear (genetic) causes:

  • Myofibrillar myopathy (MFM)
  • Polysaccharide storage myopathy 2 (PSSM2)
  • Recurrent exertional rhabdomyolysis (RER)
  • . Sporadic Exertional Rhabdomyolysis (SER)
  • Tying up

It is now well known that MFM, PSSM2, and RER can also be influenced by feeding. In the case of Tying up and SER, a variety of causes, ranging from diet to overexertion, may be involved. However, the diagnostics for these conditions are not quite as straightforward.

PSSM 2 – Genetically Detectable or Not?

For some time now, genetic tests for PSSM2 have been promoted as a reliable and, most importantly, simple diagnostic tool for struggling horse owners. Currently, however, the only reliable diagnostic method is the muscle biopsy – a tissue sample taken from the muscle, which is then stained and analysed under a microscope.

However, if we take a closer look at the scientific literature regarding these new genetic tests, it becomes clear that it’s not as simple as it might seem. Stephanie Valberg from Michigan State University, who has been researching this topic for over 20 years, has published several papers addressing this very issue. Two of these publications are worth highlighting here:

Valberg SJ, Finno CJ, Henry ML, Schott M, Velez-Irizarry D, Peng S, McKenzie EC, Petersen JL. Commercial genetic testing for type 2 polysaccharide storage myopathy and myofibrillar myopathy does not correspond to a histopathological diagnosis. Equine Vet J. 2021 Jul;53(4):690-700. doi: 10.1111/evj.13345. Epub 2020 Oct 29. PMID: 32896939; PMCID: PMC7937766.

Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL. Absence of myofibrillar myopathy in Quarter Horses with a histopathological diagnosis of type 2 polysaccharide storage myopathy and lack of association with commercial genetic tests. Equine Vet J. 2022 Mar 15. doi: 10.1111/evj.13574. Epub ahead of print. PMID: 35288976.

In these publications, warmbloods, Arabians, and Quarter Horses were studied. And just among these three breeds, the same diagnosis of “PSSM2” led to completely different symptoms, which suggests that we are likely dealing with entirely different conditions here.

PSSM2 in Warmbloods is different…

Surprisingly, more geldings than mares are affected by PSSM2 in Warmbloods. In more than two-thirds of Warmbloods, gait abnormalities are the first sign of PSSM2. Other signs include stiff gaits, shortened stride, lack of forward movement, and mild hindlimb lameness with no clear cause. The enzymes CK and AST also do not differ in the bloodwork from healthy horses.

In Warmbloods diagnosed with PSSM2, muscle tying up is very rarely observed compared to non-Warmbloods, which are more frequently affected. No increased glycogen concentration in the muscle is detectable in comparison to healthy horses; the glycogen in the muscles of affected horses simply has a different appearance. Another striking observation is that many PSSM2 Warmbloods have also been found to have gastric ulcers. Specific Warmblood lines in which PSSM2 occurs have not yet been identified, which is why a genetic component has so far been ruled out.

…Arabs and Quarter Horses too!

In contrast to Warmbloods, non-Warmbloods, where PSSM2 has been diagnosed through a muscle biopsy, are more frequently affected by muscle tying up with elevated CK and AST levels (especially Arabs and Quarter Horses). In Quarter Horses, PSSM2 is often associated with muscle atrophy and increased CK levels, and in very young Quarter Horses, it can also lead to an inability to get up or stiffness in the hindquarters.

In the aforementioned 2021 study, 55 out of 68 Warmbloods and 18 out of 30 Arabs had so-called PAS aggregates, meaning abnormal glycogen distribution was detected in the muscles. Among the Warmbloods, 37 out of 68 horses exhibited Desmin aggregates, while an astonishing 30 out of 30 Arabs had them! All horses (both Warmbloods and Arabs) with Desmin aggregates in the muscle cells were reclassified as myofibrillar myopathy (MFM), one of the myopathies that likely fall under the umbrella term PSSM2.

Interestingly, none of the Quarter Horses studied in the various PSSM2 investigations showed any staining for Desmin, meaning that myofibrillar myopathy (MFM) has not been detected in Quarter Horses so far.

All the horses studied in the studies mentioned here tested negative for GYS-1, meaning there was no PSSM1 present, and the horses in the control group showed neither abnormal glycogen aggregates nor Desmin aggregates in the muscle biopsy. This is summarised in the following table:

Comparison Warmblood and Arabian Control and PSSM2/MFM
Quelle: Valberg SJ, et al. Equine Vet J. 2021 Jul;53(4):690-700

In the next step, the genetic variants that are offered as commercial tests within the framework of PSSM2 investigations were examined. The results of these investigations present the following picture:

The number of horses homozygous for the reference allele, heterogyzous or homozygous for each P variant by phenotype and breed as well as the percentage of horses in each classification possessing each P variant and the variant allele frequencies
Quelle: Valberg SJ, et al. Equine Vet J. 2021 Jul;53(4):690-700

Horses from the control group (with neither abnormal glycogen nor desmin aggregates) were compared with Warmbloods (WB) and Arabs (AR) diagnosed with PSSM2 or MFM based on muscle biopsies.

In summary, this analysis shows that both in the control group and the PSSM2/MFM group, there were horses that exhibited one or more mutations in the P-Loci, meaning they would be considered “PSSM2-positive” according to genetic tests. One could argue here that the disease may not have fully manifested clinically in all the horses, which could explain the negative results in the biopsies from the control group. However, among the horses that were clearly clinically diagnosed with MFM or PSSM2 based on the muscle biopsies, there was a large number of individuals who did not show any of the mutations. This means that horses can develop PSSM2 without possessing any of the mutations.

Controls and MFM/PSSM2
Quelle: Valberg SJ, et al. Equine Vet J. 2021 Jul;53(4):690-700

The lack of correlation between genetic test results and clinical presentation is reproducible.

In the 2021 study, which examined 229 healthy Quarter Horses and 163 Quarter Horses with (muscle biopsy confirmed) PSSM2, no correlation between the P-variants and the presence of PSSM2 was found.

According to this, 57% of healthy Quarter Horses would be classified as sick or even removed from breeding based on this genetic test. (43.2% of the healthy Quarter Horses showed no P-variant, 56.8% displayed at least one variant, while 39.3% of the PSSM2 Quarter Horses showed no P-variant at all, and 60.7% of the PSSM2 Quarter Horses had at least one P-variant detectable).

Control-QH PSSM2-QH
Quelle: Valberg SJ, et al. Equine Vet J. 2022 Mar 15, 00:1-9

In Quarter Horses, the most common muscle disease is currently PSSM1, with a prevalence of under 10% in the entire Quarter Horse population. This makes it highly unlikely that almost 60% of all Quarter Horses would be affected by PSSM2 and ultimately have to be removed from breeding.

Another finding from these studies is the fact that even the presence of multiple variants did not lead to a stronger manifestation of symptoms, which further makes it less likely that the investigated genes are involved in the clinical picture of PSSM2.

What does it mean for my horse if it tests positive for PSSM2 based on a genetic test?

In consequence, this would mean that completely healthy horses, which show no signs of muscle disease in histology (based on which the genetic test was developed!!!), would be labelled as sick. The true cause of their inadequate performance – because genetic testing isn’t done just for fun – would never be sought or found. And breeding associations would be removing perfectly healthy horses from breeding due to a test that has not been sufficiently validated.

FFor the horses that truly suffer from a muscle disease in the sense of PSSM2, it means, conversely, that only about 40% would be “diagnosed” as sick by the test. And this is only by chance, as the presence of the variants – as definitively proven in the two studies – has nothing to do with the muscle disease itself. What happens to the other 60%? The suffering continues, both for the horse, which may be asked to perform tasks it is not capable of, and for the owner, who spends a fortune on further diagnostics, because the muscle disease “PSSM2” has already been ruled out by the negative genetic test.

A group of scientists involved in the Horse Genome Project is calling for commercially available genetic tests to be scientifically validated and verified through peer-reviewed literature, ensuring a clear correlation between the involved gene and the disease. This has not been the case with the commercially available PSSM2 genetic test to date. A test is being offered and aggressively marketed that not only lacks validation by a neutral authority or at least the scientifically recognized peer-review process, but as outlined above, even produces highly inaccurate results, meaning it is not suitable for diagnostic purposes in any way.

Overall, this creates an unsatisfactory situation for both the horse and the owner.

If you don’t want to immediately resort to a biopsy (with all the associated costs and risks), one of the simplest options is to feed the affected horses a low-sugar diet and avoid adding easily digestible carbohydrates. Over 80% of all Warmbloods suspected of having PSSM2 respond positively to these measures.

Horses with MFM (Myofibrillar Myopathy) are a bit more specific in their needs. While they do benefit somewhat from a low-sugar diet, they require additional dietary adjustments, as there is likely a disturbance in the cysteine metabolism in the muscle, especially in Arabs. Additionally, these horses cannot be trained every day. The amount of training each individual horse can handle must be determined on a case-by-case basis.

In the best interest of the horses, one can only hope that science will soon provide a better diagnostic tool for PSSM2 and the underlying myopathies, beyond the currently available, inconclusive genetic tests or costly and risky muscle biopsies.

Elke Malenke
Latest posts by Elke Malenke (see all)