PSSM2 (Equine Myopathy Horse)
Equine myopathy (PSSM2) is a collective term for a number of related muscle disorders with similar clinical symptoms. Typical symptoms include reluctance to move, intermittent lameness, stiffness, and in daily practice it can manifest as exercise intolerance. Symptoms are generally adult-onset, usually after 7-10 years of age (depending on breed and environment); mild symptoms may be obvious at a younger age or after a stressful event (injury, operation, infection, move) leading to negative nitrogen balance.
DNA tests are now available for six variants associated with horses developing symptoms of PSSM2.
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- Pain-related changes in temperament/behavior
- Shifting lameness
- Atactic gait/coordination problems (cross firing or disunited canter/bunny hopping/rope walking)
- Frequent muscle tremors/tension
- Stiff hindquarters and topline
- Difficulties with collection
- Sudden, explosive behaviour
- High muscle tension, often worsened by cold
- Muscle wasting (most obvious in hindquarters and shoulder)
- Local muscle atrophy (small divots that could look like kick marks or "washboard" appearance)
- Most horses with PSSM2 do not have changes in muscle enzyme values
Two types of Polysaccharide Storage Myopathy (PSSM) are currently described in horses: Type 1 and Type 2.
- The disorders have similar symptoms; in the past horses with PSSM1 symptoms that were negative for the PSSM1 GYS1 gene mutation were classified as having "PSSM2" because it was assumed that similar symptoms must have a similar cause.
- Research has shown that PSSM2 is not a polysaccharide storage disease and there is no increased glycogen present in their muscle cells.
- The name “PSSM2” is still used because people are familiar with it.
Two subtypes of PSSM2 can be described:
- “Myofibrillar Myopathy (MFM)” is associated with variants P2, P3, P4, P8 and K1.
- “Recurrent Exertional Rhabdomyolysis (RER)” is associated with the variant Px.
Several variants (P2, P3, P4, Px, P8, K1) in the genes MYOT, FLNC, MYOZ3, CACNA2D3, PYROXD1 and COL6A3 have been shown to be associated with horses developing symptoms of PSSM2. The proteins coded by the genes are involved in the structure (myofibrils) and function of the muscles.
- A horse can have more than one P-variant, e.g. n/P3 + n/P4 or n/P2 + P8/P8, etc.
- The combination of several variants generally increases the risk of a severe course of the disease and an earlier onset of symptoms.
- Although there is no cure, it is possible to support symptomatic animals with an adapted diet and optimized husbandry, including regular exercise.
Research is on-going to identify more genetic variants that may be responsible for subtypes of PSSM2.
Genes involved/Test Information
Six semi-dominant gene variants (P2, P3, P4, P8, Px and K1) are currently being investigated as risk factors for the occurrence of PSSM2 symptoms.
This Panel test identifies the changes in the MYOT (P2), FLNC (P3), MYOZ3 (P4), PYROXD1 (P8), COL6A3 (K1) and CACNA2D3 (Px) genes.
The Equine Myopathy/PSSM2 panel is offered under license from EquiSeq Inc. and is based upon their research.
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Subtypes of PSSM2
Muscle disorders in humans and horses have an number of overlapping descriptions and names, depending upon the primary finding (for example, based on evaluation of clinical signs, biopsy findings). Some subtypes include:
Myofibrillar Myopathy (MFM)
MFM is a subtype of PSSM2. MFM can cause a specific type of damage in the muscles, however, this is not apparent in a normal muscle biopsies and was only revealed by a recently developed staining methods. However, many horses with physical symptoms similar to what we classify as MFM still do not show changes on biopsy outside of an acute episode.
Research by EquiSeq has identified semi-dominant alleles in five genes that are associated with MFM (P2, P3, P4, P8 and K1). Horses carrying one copy of one of the variants (n/P2, n/P3 or n/P4) have a predisposition to develop MFM (diagnosed as PSSM2).
Horses with two copies of the variant (P2/P2, P3/P3, P4/P4, P8/P8 or K1/K1) are often more severely affected, with more severe symptoms and an earlier age of onset.
In humans, mutations in:
- MYOT (the gene in which the P2 variant is found in horses) are associated with Limb-girdle muscular dystrophy 1A (LGMD1A) and MFM3.
- FLNC (the gene in which the P3 variant is found in horses) are associated with MFM5.
- MYOZ3 (the gene in which the P4 variant is found in horses) is a candidate for several "orphan" myopathies.
- PYROXD1 (the gene in which the P8 variant is found in horses) are associated with MFM8.
- COL6A3 (the gene in which the K1 variant is found in horses) are associated with Bethlem myopathy and Ullrich congenital muscular dystrophy
Recurrent Exertional Rhabdomyolysis (RER)
RER is also considered a subtype of PSSM2, with some of the above symptoms. In addition, in symptomatic horses blood levels of creatine kinase (CK) and aspartate aminotransferase (AST) are elevated, and in severe cases, myoglobinuria (dark colored urine) may occur.
The Px variant is associated with RER in Arabian horses and Thoroughbreds and related breeds. With the identification of the genetic variant associated with this form of equine myopathy by EquiSeq, a genetic test on the horse's mane or tail hairs is now sufficient to determine if a horse has the Px variant which can add to the risk of a horse developing symptoms of RER.
Genotype and Lab Report
Inheritance: incomplete autosomal dominant / semidominant with incomplete penetrance
This type of inheritance is typical in complex hereditary diseases and applies to all known variants of hereditary myopathy/training intolerance.
It means that even a single altered gene copy (heterozygosity) can be sufficient to lead to a horse developing symptoms.
If both copies of the single gene are altered (homozygosity), the risk increases. This affects both the likelihood of the symptoms developing and their intensity.
The "amplification effect" also occurs when different variants come together in any combination.
Incomplete penetrance ('penetration') means that the symptoms do not necessarily occur. Diet, training condition and other (as yet unknown) genetic mutations can moderate the effect of the variants.
The following genotypes and effects apply for the variants P2, P3, P4, Px, P8, K1.
n/n = normal
→ The horse has no increased risk of developing symptoms of PSSM2. The risk of the offspring developing symptoms is not increased through this parent.
n/P = Heterozygous for the variant - high risk of developing symptoms
→ For each variant there is a 50% chance that it will be passed on to the offspring. The risk of the offspring developing symptoms depends on which and how many variant(s) the other parent also contributes.
P/P = Homozygous for the variant - higher risk of developing symptoms
→ The variant in question (P2, P3, P4, P8, Px, K1) is passed on 100% to the offspring. The risk of the offspring developing symptoms depends on which and how many variant(s) the other parent also contributes.
Recommendations for breeding
Having one or more P variants does not automatically exclude an animal from breeding. The goal is to step-wise reduce the frequency of P-variants in a breed population without affecting genetic diversity or eliminating desired traits.
Animals with clinical symptoms of PSSM2 should not be used for breeding for animal welfare reasons.
Animals with one or more P* variants which have no clinical symptoms can be considered for breeding if the breeding partner is tested normal for all variants.
If it is planned to breed horses which both have P-variants, it is recommended to pair animals which have different variants to limit the production of possible homozygotes.
EquiSeq does not recommend considering the Px variant in breeding decisions; alone, the variant may have little/no impact on the health of the horse. It appears that the Px variant is a greater problem when it is found in combination with other variants. For example, a horse with the profile n/P2 will usually have less severe symptoms than a horse that is n/P2 n/Px.
It is recommended to limit the breeding of homozygous animals (P/P) because all offspring will inherit at least one P variant from that parent.
Caring for a horse with PSSM2
Hereditary muscle diseases are not curable.
Most PSSM2 affected horses benefit from diets with high protein, and/or supplementation of the amino acids Lysine, Threonine, and Methionine, along with regular exercise.
Movement is important, so an active or open stall is helpful. Due to cold-sensitivity, many horses benefit from blanketing in cool weather.
McCue ME et al. (2008). „Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis.“ Genomics. 91(5):458-66. PMID: 18358695.
McCue ME et al. (2008). „Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy.“ Journal of Veterinary Internal Medicine. 22(0):1228–1233. PMID: 18691366.
McCue ME et al. (2009). „Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.“ Neuromuscular Disorders. 19(0):37–43. PMID: 19056269.
McCue ME et al. (2009). „Comparative skeletal muscle histopathologic and ultrastructural features in two forms of polysaccharide storage myopathy in horses.“ Vet Pathol. 46(6):1281-1291. PMID: 19605906.
Maile CA et al. (2017). „A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.“ Biochim Biophys Acta.. 1861(1):3388-3398. PMID: 27592162.
Valberg SJ et al. (2016). „Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis.“ Equine Vet J.. 48(5):548-556. PMID: 26234161.
Lewis SS et al. (2017). „Clinical characteristics and muscle glycogen concentrations in warmblood horses with polysaccharide storage myopathy“ Am J Vet Res. 78(11):1305-1312. PMID: 29076373.
Weitere Informationen sind auf der Webseite EquiSeq verfügbar.