PSSM (Polysaccharide Storage Myopathy)
Written by Daphney Boucher, Animal Health Technician
(Translation DR)
Polysaccharide storage myopathy (PSSM) is a genetic disease of muscle and metabolism in horses. It is characterized by acute muscle breakdown during physical exertion following a period of rest. PSSM is a member of the myopathy (muscle disease) family and is caused by an abnormal buildup of glycogen in the muscles. PSSM is also known as “Monday sickness” and “bloodstroke”, and is included in the general term “tying-up”. PSSM is observed more particularly in breeds of draft horses such as Belgians and Percherons, but also in horses associated with the Quarter Horse breed.
Clinical signs of PSSM
The clinical signs associated with PSSM, which are called “episodes”, appear in a healthy animal during exercise, especially after a period of rest or the intake of a high-grain diet. Clinical signs include muscle contractions, stiff muscles on palpation, sweating, pain, lameness and / or paralysis. Dark urine is another possible clinical sign of PSSM, which is caused by cell residues from damaged muscles that are carried by the blood to the kidneys to pass in the urine. In medical terms, the disease is referred to as “exertional rhabdomyolysis,” where rhabdo- means striated, myo- means muscle, and lysis- means damage. However, the clinical signs can be variable between animals and between episodes: they can be mild, moderate or severe up to and including the death of the animal. In combination with the particular genetics of the individual animal, these divergent variations in clinical signs are caused by environmental factors: periods of rest, degree of exercise and richness of nutrition.
The metabolism of glycogen in the muscles
PSSM is a glycogen storage disease. Glycogen is a long chain of polymers of glucose that is used by cells to maintain normal levels of glucose in the blood and also, in skeletal muscle cells, as a source of energy. Glycogen is synthesized in cells from glucose using the enzymes “Glycogen Synthase” (encoded by the GYS1 gene) and “Glycogen Branching Enzyme”. The release of glucose from glycogen for energy is accomplished with the help of the enzyme Amylase. A mutation in the GYS1 gene, identified in 2008, increases the activity of the enzyme “Glycogen Synthase” to overproduce glycogen in muscle cells. This overproduction of glycogen is the basis of the clinical signs seen with PSSM. Even though humans have a number of genetic diseases that involve a reduction in glycogen synthesis, PSSM in horses is unique for its overproduction of glycogen
The Genetics of PSSM
Simply put, PSSM is an inherited, autosomal dominant disorder with incomplete-penetration. The term autosomal means that the disease does not depend on the sex of the animal: females can have the disease as well as males and vice versa. As for the word dominant, this means that the animal must have only one copy of the mutated gene in question in order to develop the disease. The word incomplete-penetration states that symptoms present at varying intensities between animals and between episodes. The GYS1 gene (Glycogen Synthase 1) codes for the enzyme responsible for the synthesis of glycogen in skeletal muscles. In the case of PSSM, the gene is mutated and the enzyme is overactive, resulting in a build-up of glycogen in the muscles. However, this glycogen is difficult to access as an energy source in muscle cells during exercise, which can cause progressive muscle breakdown and clinical signs of a PSSM episode.
The identification of the mutation responsible for PSSM allowed the development of a DNA test to diagnose carrier animals M/N (at risk of PSSM) and also to determine the frequency of the mutation among different breeds of horses. These tests found that the mutation in question is not always present in animals with symptoms of PSSM. Thus, at least two types of PSSM exist: we speak of PSSM1 when the animal has the clinical signs of PSSM and the known mutation is present in the GYS1 gene, and we speak of PSSM2 when the animal bears the clinical signs in the absence of the known mutation. So, we must admit that our knowledge of the genetics of PSSM is incomplete. Another thing to mention, the mutation in the RYR1 gene which is responsible for malignant hyperthermia and also the mutation responsible for HYPP can increase the severity of PSSM.
Confirmation of the diagnosis for PSSM and for PSSM1
Normally, the diagnosis of PSSM is by clinical signs. To confirm the diagnosis of PSSM, the classic method is through a muscle tissue biopsy which is invasive. These days, diagnosis is through a DNA test. A DNA test to detect the known mutation in the GYS1 gene can determine if the animal is N/N (normal, not at risk for PSSM1), M/N (carrier, at risk for PSSM1) or M/M (double mutated, at high risk of PSSM1). Thus, animals at risk for PSSM1 can be detected early in an attempt to reduce disease episodes by modification of the environment (see the section on Prevention and Treatment of PSSM). Also, through selective breeding, we can reduce the prevalence of the disease in horse populations.
Mutation Frequencies
In the original scientific article describing the mutation in the GYS1 gene identified as responsible for PSSM1, frequencies of 36% were described for the Belgian Horse breed and 3.4% for the Quarter Horse breed. So far, at the Laboratory of Veterinary Genetics (Labgenvet), we have performed more than a hundred DNA tests for PSSM1, with 13 breeds of horses represented. Overall, 67% of the horses tested N/N clear, 30% tested M/N carrier and 3% tested M/M double mutated. A majority of the tests requested were for the Quarter Horse breed while 5% for the Belgian breed. Of the Quarter Horses tested, 67% were N/N clear, 29% were M/N carrier (at risk) and 4% were M/M double mutated. Among the Belgian horses tested, 50% were N/N clear, 30% were M/N carrier (at risk) and 17% were M/M double mutated. The mutation for PSSM1 was seen in other breeds including the Percheron, Paint, Palomino, Canadian and Gypsy. At Labgenvet, 91% of samples were submitted by veterinarians and 9% of samples were submitted by horse owners; therefore, the frequencies of mutations observed by us are not representative of the races in question.
PSSM is an old Mutation
The fact that the mutation responsible for PSSM1 is found in several breeds of horses is an indication that this is an old mutation. The mutation probably arose naturally in the draft horse breeds. These workhorses did their daily physical activity, but they were always kept on a lower quality diet free of grain. Under these conditions, the overproduction of glycogen in the muscles brought about by the mutation was an advantage. Over several centuries and with the development of modern horse breeds, the GYS1 mutation has been transfered into different breeds including the Quarter Horse and related breeds. Also, the environment has changed for our modern horses, with less exercise in daily life and more grain in the diet. The mutation in the formerly beneficial GYS1 gene is now disadvantageous and responsible for the PSSM1 disease.
Prevention and treatment and prevention of PSSM
Unfortunately, there is no treatment available to cure PSSM. However, there are things you can do to prevent episodes. As far as exercise, it is suggested to avoid strenuous exercise after a period of rest. As for diet, it is preferable to increase the intake of fat and decrease the intake of carbohydrates (cereals). For a more detailed consultation you should consult your veterinarian.
Breeding strategies to avoid PSSM1 in offspring
The DNA test that is available for PSSM1 is very useful for mating decisions. Knowing that the mutation causing PSSM1 is dominant, the ideal strategy would be to mate horses that are N/N tested (clear) to produce offspring that are not at risk of developing PSSM1. If an N/N (clear) animal is mated with an M/N animal (carrier, at risk), there will be a 50% chance (1 in 2) of having M/N offspring, at risk of developing PSSM1. Mating two M/N animals or using one M/M animal for breeding is not recommended.
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Références:
- OMIA link: [1158-9796]
- Aldrich K, Belez-Irizarry D, Fenger C et al. (2021) Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyosysis in Thoroughbred racehorses. PLoS One 16: e0244556 [pubmed/33566847]
- Tosi I, Art T, Cassart D et al. (2018) Altered mitochondrial oxidative phosphorylation capacity in horses suffering from polysaccharide storage myopathy. J Bioenerg Biomembr 50(5):379-390. [pubmed/30143916]
- Lewis SS, Nicholson AM, Williams ZJ, Valbert SJ (2017) Clinical characteristics and muscle glycogen concentrations in warmblood horses with polysaccharide storage myopathy. Am J Vet Res 78:1305-1312. [pubmed/29076373]
- Maile CA, Hingst JR, Mahalingan KK et al. (2016) A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase. Biochim Biophys Acta 1861(1PtA):3388-3398. [pubmed/27592162]
- McCoy AM, Schaefer R, Petersen JL et al. (2014) Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations. J Hered. 105(2):163-72. [pubmed/24215078]
- McCue ME, Anderson SM, Valberg SJ et al. (2010) Estimated prevalence of the Type 1 Polysaccharide Storage Myopathy mutation in selected North American and European breeds. Anim Genet. 41 Suppl 2:145-149. [pubmed/21070288]