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CAG GmbH – Center for Animal Genetics: Update on the Equine Myopathy PSSM2 Genetic Testing Panel

Muscle diseases in horses often have similar manifestations, a main one of which is the broad category of “exercise intolerance”.

In 2008, McCue and colleagues characterized one form of exercise intolerance at the molecular level. Biopsies of affected horses showed abnormal storage of glycogen (sugar) in muscle cells, and a mutation was identified in the GYS1 gene.  This disease was called PSSM, short for Polysaccharide Storage Myopathy.  Many other horses had similar symptoms, and some had similar biopsies, but did not have the mutation.  These horses were diagnosed with “PSSM2”.

Recently, further research has demonstrated that PSSM2 is actually an umbrella term for a variety of muscle diseases which are not related to defects in glycogen storage.  New methods of examining the biopsies of these horses showed that the abnormal appearance of sugar in the muscle cells was not the cause of the disease. The new biopsy examination method described by Valberg and colleagues (2016) allows scientists to see that a defect in muscle structure is the actual problem in these horses (myofibrillar myopathy, MFM).  However, the defect can only be seen in horses that are actively symptomatic.  Furthermore, it has been confirmed that glycogen concentration is not increased in these muscle cells (Williams et al., 2018).  This means that the “PSSM2” name is incorrect; however, it is still being used because people are familiar with it.

Research by the company EquiSeq has identified several mutations that cause defects in muscle structure and/or function. The genetic mutations affect proteins that work together in the muscle, which explains why they have similar symptoms.  Symptoms can include shifting lameness, muscle tension/stiffness/cramping, a lack of power or propulsion from the hind quarters, muscle wasting, behavioural changes, and pain.  The diseases are adult-onset, and symptoms are usually noted at 7-10 years of age; however, depending on the breed and environmental factors, symptoms may be seen much younger, or older.

Two of the mutations identified by EquiSeq cause what in humans is called Limb-girdle Muscular Dystrophy (LGMD). The P2 and P3 variants (mutations in the genes Myotilin and Filamin C) each cause forms of Myofibrillar Myopathy (MFM).  The P4 variant (Myozenin 3) does not yet have a human disease correlate but has been diagnosed as Myofibrillar Myopathy (MFM) by muscle biopsy.  The Px variant is associated with Recurrent Exercise Rhabdomyolysis (RER) in some families of horses.  All of these mutations are semi-dominant with incomplete penetrance.  This means that having one copy of a mutation gives a high risk of developing symptoms of PSSM2.  Having more copies (for example P2/P2, n/P2 and n/P3, etc.) results in a much higher risk of developing symptoms, and at an earlier age.

Genetic background (breed, strain, etc.) appears to have an influence on the development/severity of symptoms, as does the environment.  Many horses have minimal symptoms until they have a period of negative nitrogen balance (NNB) due to an injury, infection, operation, or other major stressor.  The diseases are not curable, but high protein diets with supplementation of the limiting amino acids (lysine, threonine, methionine) can help with symptoms.

The genetic variants identified by EquiSeq have not yet been published in a peer-reviewed journal.  There are many possible combinations of genotypes (n/P2, P2/P2, n/P2 n/P3, etc.), so the interactions of the mutations and the overlapping symptoms are compounded. In semi-dominant mutations with incomplete penetrance, under optimal conditions, not all horses with one copy of a mutation will necessarily show obvious symptoms.  Other horses with the same mutation(s) that have an episode of Negative Nitrogen Balance may show very severe symptoms.  Ongoing research is also showing that breed (and thus background genetic variation) also has an influence on the age of onset and severity of symptoms.  On average symptoms appear at 7-10 years of age, but horses in some breeds appear to often show symptoms as early as 5 years, while others have a later average age of onset, at 12 years or later.  The complicated nature of these differences has meant that it takes a longer time to fit together all of the smaller “puzzle pieces” required for publication.  At CAG GmbH we have independently evaluated all data from EquiSeq and its university collaborators.  We are convinced that these mutations are real and causative for a subset the diseases known as PSSM2.  We are looking forward to the research undergoing formal peer review.  Naturally, we respect the decision of any one who waits until the data is published before using the tests.

It is not unusual for universities to offer genetic tests commercially before the tests have gone through peer-reviewed publication.  The difference in this case is that the research has been done, and the tests offered, by companies – EquiSeq and its university collaborators, and CAG, which has licensed the patent rights in Europe.  The testing panel is comparatively expensive for several reasons.  First, universities get grants to do their research, and do not need to recoup all of their costs by selling their tests.  Secondly, the PSSM2 panel includes mutations in four genes, each of which must be analysed independently in the laboratory.  Selling them as lower-priced single tests would be inappropriate and misleading to the customer; because the variants interact, it is important to know which combination an animal may have.

Breeders and breeding associations are naturally concerned about what these tests mean for their horses and breeding programs.  It is extremely important that genetic diversity be preserved, especially in breeds with limited gene pools.  A horse that is symptomatic with any disease should not be used for breeding due to animal welfare concerns.  An asymptomatic horse with one “P_” allele may still be used for breeding, with the understanding that each of its foals has a 50% probability of inheriting the parents “P_” allele.  Taking a multigenerational approach makes sense – it is rarely a good idea with autosomal recessive or dominant diseases to eliminate all carriers or asymptomatic affected animals immediately.  It is also possible to continue to breed asymptomatic horses with two “P_” alleles, as long as they are bred only to horses tested to not have any “P_” alleles.  This will gradually eliminate the mutations from the population without artificially limiting the breeding population and losing all of the good traits a horse may possess.

Genetic testing is an important tool for breeders, owners, and veterinarians for safeguarding animal physical and genetic health. Used responsibly, the prevalence of desired traits in a breed can be maximized, and undesired traits, such as hereditary diseases, can be minimized.  The accurate diagnosis of such diseases helps owners optimize nutrition and environmental factors to support their animals’ health and quality of life.  CAG GmbH is committed to supporting our customers with reliable tests and top quality service.

Melissa L. Cox, Ph.D., Scientific Lead, CAG GmbH – Center for Animal Genetics,

Tuebingen, Germany, 8 Feb 2019


More information about the Equine Myopathy PSSM2 panel is available on the CAG and EquiSeq websites:


Publications mentioned in statement:

McCue ME et al. (2008). “Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis.” Genomics. 91(5):458-66.

Valberg SJ et al. (2016). “Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis.” Equine Vet J.. 48(5):548-556.

Williams ZJ et al. (2018) “Muscle glycogen concentrations and response to diet and exercise regimes in Warmblood horses with type 2 Polysaccharide Storage Myopathy”. PLoS One. 13(9):e0203467.

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