Equine polysaccharide storage myopathy

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Equine polysaccharide storage myopathy (EPSM, PSSM, EPSSM) is a hereditary glycogen storage disease of horses that causes exertional rhabdomyolysis. It is currently known to affect the following breeds American Quarter Horses, American Paint Horses, Warmbloods, Cobs, Dales Ponies, Thoroughbreds, Arabians, New Forest ponies, and a large number of Heavy horse breeds. While incurable, PSSM can be managed with appropriate diet and exercise. There are currently 2 subtypes, known as Type 1 PSSM and Type 2 PSSM.

Contents

Pathophysiology of glycogen storage disorders and sub-typing of PSSM

A representation of glucose molecules linked by a-1,4-glycosidic bonds, with a single a-1,6-glycosidic bond leading to a branch off of the chain. Glycogen spacefilling model.jpg
A representation of glucose molecules linked by α-1,4-glycosidic bonds, with a single α-1,6-glycosidic bond leading to a branch off of the chain.

Glycogen is a molecular polymer of glucose (a polysaccharide) used to store energy, and is important for maintaining glucose homeostasis in the blood, as well as for providing energy for skeletal muscle and cardiac muscle contraction. Molecules of glucose are linked into linear chains by α-1,4-glycosidic bonds. Additionally, branches of glucose are formed off of the chain by α-1,6-glycosidic bonds. 2 molecules of glucose are joined into an α-1,4-glycosidic bonds by an enzyme known as glycogen synthase. This bond may be broken by amylase when the body wishes to break down glycogen into glucose for energy. Glycogen branching enzyme is responsible for the required α-1,6-glycosidic bonds needed to start a branch off of these linear chains.

Any disruption to this system results in a glycogen storage disease. There are currently 2 subcategories of glycogen storage diseases in horses: Type 1 polysaccharide storage myopathy, glycogen branching enzyme deficiency, and Type 2 polysaccharide storage myopathy.

Type 1 PSSM

Type 1 PSSM is caused by an autosomal dominant genetic mutation known as GSY1. This mutation causes an up-regulation of glycogen synthase, and high levels of glycogen synthase relative to glycogen branching enzyme (GBE). This altered ratio of glycogen synthase to GBE results in glycogen molecules with long chains and few branches, making these molecules somewhat amylase resistant. [1] The GSY1 mutation is associated with altered glucose metabolism (but normal glycogen metabolism), as well as accumulation of high levels of glycogen and abnormal polysaccharide in the muscles of the horse. [2] Additionally, some horses have been shown to have insulin sensitivity, which improves glucose uptake by muscle cells and contributes to excessive glycogen storage that is already elevated secondary to the GSY1 mutation. [2]

Glycogen branching enzyme deficiency

Low levels of glycogen branching enzyme leads to a condition known as glycogen-branching enzyme deficiency. This condition is caused by a mutation of the GBE1 gene responsible for producing the glycogen branching enzyme. Subsequently, glycogen molecules are produced with few branches, which greatly decreasing the number of nonreducing ends, drastically slowing the rate as which the molecule can be synthesized or broken down. This causes low levels of muscle glycogen that is very resistant to amylase. [1] This disease is usually seen in Quarter Horse foals and is fatal.

Type 2 PSSM

Type 2 PSSM is a category for disorders that lead to abnormal deposition of glycogen in the skeletal muscles of the horse that is not due to mutations in GSY1 or GBE1. [1]

Presentation

The Belgian Draft is one breed with a very high prevalence of PSSM in their population. Trotting Belgian draft horse.jpg
The Belgian Draft is one breed with a very high prevalence of PSSM in their population.

PSSM is most prevalent in American Quarter Horses and their related breeds (Paint horse, Appaloosa, Appendix Quarter Horse), Draft horse breeds (especially Belgian Draft and Percherons), and Warmblood breeds. [3] The Belgian Draft been shown to have a 36% prevalence of PSSM. [4] Other breeds that have been diagnosed with PSSM include the Arabian, Lipizzaner, Morgan, Mustang, Peruvian Paso, Rocky Mountain Horse, Standardbred, Tennessee Walking Horse, Thoroughbred, and National Show Horse. [3] It has been suggested that the GSY1 mutation provided some benefit to hard working animals with poor-quality diets, and is now damaging members of those "thrifty" breeds that are managed with moderate to low levels of work and diets high in non-structural carbohydrates. [1]

PSSM Type 1 (homozygous or heterozygous for the GSY1 mutation) is more common in Quarter Horses and their related breeds, and draft breeds, while PSSM Type 2 (negative for the GSY1 mutation) is more commonly seen in other breeds, including warmbloods. There is no sex predilection to the disease. [1]

Clinical signs

Horses with Type 1 PSSM usually appear normal at rest, but show signs of exertional rhabdomyolysis ("tying up") such as shortened stride, stiffness, firm musculature, sweating, pain or reluctance to exercise, when asked to perform light work. [1] While episodes of exertional rhabdomyolysis is one of the most frequent signs associated with affected horses (reported in ~37% of affected animals), other common signs include gait abnormalities, shifting lameness, muscle weakness that may result in an inability to rise, colic-like pain, and muscle fasciculation, atrophy, and/or stiffness (most commonly seen in the semimembranosus, semitendinosus, and longissimus muscles). [3] [5]

These clinical signs usually first become apparent when the horse is placed into training as a young animal; however, affected horses will show histological changes consistent with muscle damage at one month of age, and may also show elevations in creatine kinase (CK), an enzyme that elevates with muscle damage. [6] Concurrent illness, such as respiratory or gastrointestinal infection, can lead to elevations in CK and potentially life-threatening rhabdomyolysis, even without exercise. [1] [6] Horses with PSSM often have a persistently elevated CK at rest, which differentiates the disease from recurrent exertional rhabdomyolysis, in which horses have normal CK concentrations between episodes. [7]

Variability in phenotype and modifying genes

Some affected animals may remain subclinical, others may have mild signs that do not impede athletic performance, while some horses will have clinical signs that prevent any forced exercise. Rarely, horses will die from acute episodes of rhabdomyolysis. The reason for such variability of phenotype is not fully understood. Temperament, gender, and body type have no effect on degree of clinical signs. [1] However, environmental factors such as diet and exercise, whether the horse is heterozygous or homozygous for the mutated GSY1 allele, and the presence of modifying genes all play a role. [8] Additionally, some affected horses may have PSSM Type 2, which will produce different cellular changes and subsequently different phenotypic effects. [1]

One such modifying genes is RYR1, which is responsible for calcium regulation in muscle cells. RYR1 mutation causes malignant hyperthermia, a rare but potentially fatal disorder usually associated with anesthesia. While RYR1 mutation is rare in horses, including the general Quarter Horse population, it is much more common in Quarter Horses with GSY1 mutation. Horses with both mutations are more likely to have a severe PSSM phenotype, including higher levels of blood creatine kinase (CK), more severe exercise intolerance, more severe episodes of rhabdomyolysis (more frequent muscle fasciculations, more frequent episodes that are not associated with exercise, acute death), and poor response to PSSM treatment. [8]

Additionally, defects in both GSY1 and the SCNA4 gene, responsible for hyperkalemic periodic paralysis (HYPP) in Quarter Horses and related breeds, has been found in 14% of Halter horses. [9] A combination of both of these genes can cause severe rhabdomyolysis should the horse become recumbent due to an HYPP attack. [1]

Diagnosis

A genetic test is available for Type 1 PSSM. This test requires a blood or hair sample, and is less-invasive than muscle biopsy. However, it may be less useful for breeds that are more commonly affected by Type 2 PSSM, such as light horse breeds. Often a muscle biopsy is recommended for horses displaying clinical signs of PSSM but who have negative results for GYS1 mutation.

A muscle biopsy may be taken from the semimembranosis or semitendinosis (hamstring) muscles. The biopsy is stained for glycogen, and the intensity of stain uptake in the muscle, as well as the presence of any inclusions, helps to determine the diagnosis of PSSM. This test is the only method for diagnosing Type 2 PSSM. Horses with Type 1 PSSM will usually have between 1.5-2 times the normal levels of glycogen in their skeletal muscle. [10] While abnormalities indicating muscle damage can be seen on histologic sections of muscle as young as 1 month of age, abnormal polysaccharide accumulation may take up to 3 years to develop. [6]

Management

Effect on metabolism

Horses with PSSM have elevated levels of muscle glycogen at rest. During exercise, glycogen levels are depleted faster than is seen in unaffected horses, and are reduced down to levels considered normal for a resting non-PSSM horse. This demonstrates that glycogen metabolism is actually normal in these animals. [11] However, PSSM horses synthesize muscle glycogen at double the rate of a normal horse once exercise has ceased, which leads to elevated muscle glycogen. [2] The exact mechanism of abnormal glucose metabolism has not yet been established, but it may have similarities to phosphofructokinase deficiency in humans. [2]

Quarter Horse-related breeds with PSSM show insulin sensitivity, which improves glucose uptake by cells, and these horses clear the blood of glucose more quickly after eating than unaffected horses. [12] This provides easy access to glucose by the muscles, which can then use the substrate to produce glycogen. The GYS1 defect, which up-regulates the glycogen synthase enzyme, allows the muscles to use this glucose to rapidly produce glycogen for storage in the muscle. [13] Surprisingly, increased insulin sensitivity is not seen in draft horse breeds. [14]

Dietary and exercise manipulation may be used to counteract these metabolic changes. Approximately 50% of horses that adhere to the dietary recommendations, and 90% of horses that adhere to both dietary and exercise recommendations, have few to no episodes of exertional rhabdomyolysis. [13]

Diet

For most horses, diet has a significant impact on the degree of clinical signs. PSSM horses fed diets high in nonstructural carbohydrates (NSC), which stimulate insulin secretion, have been shown to have increased severity of rhabdomyolysis with exercise. [1] Current recommendations for horses with PSSM include a low-starch, high-fat diet. Low-starch diets produce low blood glucose and insulin levels after eating, which may reduce the amount of glucose taken up by the muscle cells. High fat diets increase free fatty acid concentrations in the blood, which may promote the use of fat for energy (via free fatty acid oxidation) over glucose metabolism. Horses with the most severe clinical signs often show the greatest improvement on the diet. [11]

Dietary recommendations usually include a combination of calorie restriction, reduction of daily NSC content, and an increase in dietary fat. Diet recommendations need to be balanced with the animal's body condition score and exercise level, as it may be beneficial to wait on increasing dietary fat after an obese animal has lost weight. [13] The diet should have <10% of digestible energy coming from NSC, and 15-20% of daily digestible energy coming from fat. [15]

Exercise

Horses with PSSM show fewer clinical signs if their exercise is slowly increased over time (i.e. they are slowly conditioned). Additionally, they are much more likely to develop muscle stiffness and rhabdomyolysis if they are exercised after prolonged stall rest. [6]

Horses generally have fewer clinical signs when asked to perform short bouts of work at maximal activity level (anaerobic exercise), although they have difficulty achieving maximal speed and tire faster than unaffected horses. They have more muscle damage when asked to perform lower intensity activity over a longer period of time (aerobic activity), [1] due to an energy deficit in the muscle. [16]

Related Research Articles

<span class="mw-page-title-main">American Quarter Horse</span> American horse breed

The American Quarter Horse, or Quarter Horse, is an American breed of horse that excels at sprinting short distances. Its name is derived from its ability to outrun other horse breeds in races of a quarter mile or less; some have been clocked at speeds up to 44 mph (70.8 km/h). The development of the Quarter Horse traces to the 1600s.

<span class="mw-page-title-main">Polysaccharide</span> Long carbohydrate polymers comprising starch, glycogen, cellulose, and chitin

Polysaccharides, or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with water (hydrolysis) using amylase enzymes as catalyst, which produces constituent sugars. They range in structure from linear to highly branched. Examples include storage polysaccharides such as starch, glycogen and galactogen and structural polysaccharides such as cellulose and chitin.

<span class="mw-page-title-main">Adenosine monophosphate deaminase deficiency type 1</span> Medical condition

Adenosine monophosphate deaminase deficiency type 1 or AMPD1, is a human metabolic disorder in which the body consistently lacks the enzyme AMP deaminase, in sufficient quantities. This may result in exercise intolerance, muscle pain and muscle cramping. The disease was formerly known as myoadenylate deaminase deficiency (MADD).

<span class="mw-page-title-main">Glycogen storage disease type V</span> Human disease caused by deficiency of a muscle enzyme

Glycogen storage disease type V, also known as McArdle's disease, is a metabolic disorder, one of the metabolic myopathies, more specifically a muscle glycogen storage disease, caused by a deficiency of myophosphorylase. Its incidence is reported as one in 100,000, roughly the same as glycogen storage disease type I.

<span class="mw-page-title-main">Glycogen storage disease</span> Medical condition

A glycogen storage disease is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.

<span class="mw-page-title-main">Glycogen</span> Glucose polymer used as energy store in animals

Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.

<span class="mw-page-title-main">Rhabdomyolysis</span> Human disease (condition) in which damaged skeletal muscle breaks down rapidly

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury.

<span class="mw-page-title-main">Phosphoglucomutase</span>

Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.

<span class="mw-page-title-main">Malignant hyperthermia</span> Medical condition

Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, fever, and a fast heart rate. Complications can include muscle breakdown and high blood potassium. Most people who are susceptible to MH are generally unaffected when not exposed to triggering agents.

<span class="mw-page-title-main">Phosphofructokinase deficiency</span> Medical condition

Phosphofructokinase deficiency is a rare muscular metabolic disorder, with an autosomal recessive inheritance pattern.

<span class="mw-page-title-main">Glycogen phosphorylase</span> Class of enzymes

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

Glycogen-branching enzyme deficiency (GBED) is an inheritable glycogen storage disease affecting American Quarter Horses and American Paint Horses. It leads to abortion, stillbirths, or early death of affected animals. The human form of the disease is known as glycogen storage disease type IV.

<span class="mw-page-title-main">Equine exertional rhabdomyolysis</span>

Equine exertional rhabdomyolysis (ER) is a syndrome that affects the skeletal muscles within a horse. This syndrome causes the muscle to break down which is generally associated with exercise and diet regime. Depending on the severity, there are various types of ER, including sporadic and chronic.

<span class="mw-page-title-main">Glycogen synthase</span> Enzyme class, includes all types of glycogen/starch synthases

Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.

<span class="mw-page-title-main">Glycogen storage disease type IV</span> Human disease

Glycogen storage disease type IV (GSD IV), or Andersen's Disease, is a form of glycogen storage disease, which is caused by an inborn error of metabolism. It is the result of a mutation in the GBE1 gene, which causes a defect in the glycogen branching enzyme. Therefore, glycogen is not made properly and abnormal glycogen molecules accumulate in cells; most severely in cardiac and muscle cells. The severity of this disease varies on the amount of enzyme produced. GSD IV is autosomal recessive, which means each parent has a mutant copy of the gene, but show no symptoms of the disease. Having an autosomal recessive inheritance pattern, males and females are equally likely to be affected by Andersen's disease. Classic Andersen's disease typically becomes apparent during the first few months after the patient is born. Approximately 1 in 20,000 to 25,000 newborns have a glycogen storage disease. Andersen's disease affects 1 in 800,000 individuals worldwide, with 3% of all GSDs being type IV. The disease was described and studied first by Dorothy Hansine Andersen.

<span class="mw-page-title-main">Glycogen storage disease type III</span> Medical condition

Glycogen storage disease type III (GSD III) is an autosomal recessive metabolic disorder and inborn error of metabolism (specifically of carbohydrates) characterized by a deficiency in glycogen debranching enzymes. It is also known as Cori's disease in honor of the 1947 Nobel laureates Carl Cori and Gerty Cori. Other names include Forbes disease in honor of clinician Gilbert Burnett Forbes (1915–2003), an American physician who further described the features of the disorder, or limit dextrinosis, due to the limit dextrin-like structures in cytosol. Limit dextrin is the remaining polymer produced after hydrolysis of glycogen. Without glycogen debranching enzymes to further convert these branched glycogen polymers to glucose, limit dextrinosis abnormally accumulates in the cytoplasm.

<span class="mw-page-title-main">Myophosphorylase</span> Muscle enzyme involved in glycogen breakdown

Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen into glucose-1-phosphate, so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease, a glycogen storage disease of muscle.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Shivers, or equine shivering, is a rare, progressive neuromuscular disorder of horses. It is characterized by muscle tremors, difficulty holding up the hind limbs, and an unusual gait when the horse is asked to move backwards. Shivers is poorly understood and no effective treatment is available at this time.

Hyperkalemic periodic paralysis is a genetic disorder that occurs in horses. It is also known as Impressive syndrome, after an index case in a horse named Impressive. It is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Mickelson JR, Valberg SJ (2015). "The Genetics of Skeletal Muscle Disorders in Horses". Annu. Rev. Anim. Biosci. 3: 197–217. doi: 10.1146/annurev-animal-022114-110653 . PMID   25387114.
  2. 1 2 3 4 Annandale, E. J.; Valberg, S. J.; Mickelson, J. R.; Seaquist, E. R. (October 2004). "Insulin sensitivity and skeletal muscle glucose transport in horses with equine polysaccharide storage myopathy". Neuromuscular Disorders. 14 (10): 666–674. doi:10.1016/j.nmd.2004.05.007. PMID   15351424. S2CID   121731.
  3. 1 2 3 McCue ME, Ribeiro WP, Valberg SJ (August 2006). "Prevalence of polysaccharide storage myopathy in horses with neuromuscular disorders". Equine Veterinary Journal. 38 (S36): 340–344. doi:10.1111/j.2042-3306.2006.tb05565.x. PMID   17402444. S2CID   1861689.
  4. ↑ Firshman AM, Baird JD, Valberg JS (December 15, 2005). "Prevalences and clinical signs of polysaccharide storage myopathy and shivers in Belgian Draft Horses". JAVMA. 227 (12): 1958–1964. doi: 10.2460/javma.2005.227.1958 . PMID   16379634.
  5. ↑ Valentine BA (2003). "Equine polysaccharide storage myopathy". Equine Veterinary Education. 15 (5): 254–262. doi:10.1111/j.2042-3292.2003.tb00537.x.
  6. 1 2 3 4 De La Corte FD, Valberg SJ, MacLeay JM, Mickelson JR (2002). "Developmental Onset of Polysaccharide Storage Myopathy in 4 Quarter Horse Foals". Journal of Veterinary Internal Medicine. 16 (5): 581–587. doi: 10.1111/j.1939-1676.2002.tb02391.x . PMID   12322710.
  7. ↑ Finno CJ, SPier SJ, Valberg SJ (2009). "Equine diseases caused by known genetic mutations". The Veterinary Journal. 179 (3): 336–347. doi:10.1016/j.tvjl.2008.03.016. PMID   18472287.
  8. 1 2 McCue ME, Valberg SJ, Jackson M, Borgia L, Lucio M, Mickelson JR (January 2009). "Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation". Neuromuscular Disorders. 19 (1): 37–43. doi:10.1016/j.nmd.2008.10.001. PMID   19056269. S2CID   28059829.
  9. ↑ Tryon RC, Penedo CT, McCue ME, et al. (January 2009). "Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses". JAVMA. 234 (1): 120–125. doi: 10.2460/javma.234.1.120 . PMID   19119976.
  10. ↑ Valberg SJ, Cardinet III GH, Carlson GP, DiMauro S (1992). "Polysaccharide storage myopathy associated with recurrent exertional rhabdomyolysis in horses". Neuromuscular Disorders. 2 (5–6): 351–359. doi:10.1016/S0960-8966(06)80006-4. PMID   1284408. S2CID   38373381.
  11. 1 2 Ribeiro WP, Valberg SJ, Pagan JD, Gustavsson BE (2004). "The Effect of Varying Dietary Starch and Fat Content on Serum Creatine Kinase Activity and Substrate Availability in Equine Polysaccharide Storage Myopathy". J Vet Intern Med. 18 (6): 887–894. doi:10.1111/j.1939-1676.2004.tb02637.x. PMID   15638274. S2CID   7326589.
  12. ↑ Corte FD, Valberg SJ, Mickelson JR, Hower-Moritz M (July 1999). "Blood glucose clearance after feeding and exercise in polysaccharide storage myopathy". Equine Veterinary Journal. 31 (S30): 324–328. doi: 10.1111/j.2042-3306.1999.tb05242.x . PMID   10659276.
  13. 1 2 3 Valberg, Stephanie; James Mickelson. "Polysaccharide Storage Myopathy (PSSM) in horses". University of Minnesota Equine Center. University of Minnesota. Retrieved 15 June 2015.
  14. ↑ Firshman AM, Valberg SJ, et al. (June 2008). "Insulin sensitivity in Belgian horses with polysaccharide storage myopathy". American Journal of Veterinary Research. 69 (6): 816–823. doi: 10.2460/ajvr.69.6.818 . PMID   18518664.
  15. ↑ Firshman AM, Valberg SJ, Bender JB, Finno CJ (October 2003). "Epidemiologic characteristics and management of polysaccharide storage myopathy in Quarter Horses". American Journal of Veterinary Research. 64 (10): 1319–1327. doi: 10.2460/ajvr.2003.64.1319 . PMID   14596472. S2CID   13060528.
  16. ↑ Annandale EJ, Valberg SJ, Essen-Gustavsson B (May 2005). "Effects of submaximal exercise on adenine nucleotide concentrations in skeletal muscle fibers of horses with polysaccharide storage myopathy". Am. J. Vet. Res. 66 (5): 839–845. doi: 10.2460/ajvr.2005.66.839 . PMID   15934611.
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