Polysaccharide Storage Myopathy (PSSM) is a form of equine exercise intolerance characterized by episodes of tying up. Horses with this condition have a particular set of clinical signs, including displays of pain, refusal to move forward, trouble standing for the farrier, and standing “parked out” as if to urinate. All of these are signs of a disease state affecting muscle.

Affected horses often show enlarged granules of glycogen in muscle tissue obtained by biopsy. These enlarged glycogen granules are relatively resistant to digestion by amylase, an enzyme that completely degrades normal glycogen granules under standard conditions.

Glycogen is a polysaccharide, a polymer of the simple sugar glucose, a monosaccharide. The synthesis of glycogen from glucose in muscle tissue provides a store of energy. When energy is needed, the glycogen is broken down into glucose, which can be metabolized for energy.

The image above shows a) the chemical structure of glucose, b) the general structure of glycogen in which glucose units are joined in a branching structure, and c) the chemical structure of the linear polymers of glucose and the branch points.

The synthesis of glycogen from glucose is highly regulated. In normal horses, glycogen is synthesized when energy needs are low compared to the amount of available glucose, and broken down back into glucose when energy is needed. Two enzymes are responsible for the synthesis of glycogen. One enzyme catalyzes the synthesis of the linear chains and the other catalyzes the synthesis of the branch points. Two different enzymes are responsible for the breakdown of glycogen. One cleaves the linkages in the linear parts of glycogen and the other catalyzes the cleavage of the branch points.

The finding of enlarged glycogen granules in muscle tissue of horses with PSSM suggested that the disease is a glycogen storage disease. This disease state has been described in human patients with defects in a number of different genes as shown in the table below.

Disease state	Affected gene	Reference
GSD1a	G6PC	1
GSD2	GAA	2
GSD3	AGL	3
GSD4	GBE1	4
GSD5	PYGM	5
GSD6	PYGL	6
GSD7	PFKM	7
GSD9	PHKA2	8
GSD10	PGAM2	9
GSD11	LDHA	10
GSD12	ALDOA	11
GSD13	ENO3	12
GSD14	PGM1	13
GSD15	GYG1	14

Quarter Horses have a relatively high incidence of PSSM, a condition that seemed to be hereditary, as are the human glycogen storage diseases. A genome-wide association study showed that the presence of enlarged glycogen granules in muscle tissue was associated with a particular genetic variant of the gene encoding glycogen synthase, GYS1-R309H (15). Glycogen synthase is the enzyme responsible for the synthesis of the linear portions of the glycogen molecule. The genetic variant of glycogen synthase associated with PSSM constitutively actives glycogen synthase (16). This means that glycogen metabolism is no longer subject to normal regulation. Glycogen is synthesized even under conditions of energy demand.

The presence of enlarged glycogen granules in muscle tissue of horses with exercise intolerance is not completely correlated with the presence of the genetic variant of glycogen synthase that constitutively activates glycogen synthase (17). In Quarter Horses showing enlarged glycogen granules, 95.6% have one or two copies of the GYS1-R309H variant, while 4.5% have two normal copies of the glycogen synthase gene. In Quarter Horses showing glycogen granules of normal size, 77.7% have two normal copies of the glycogen synthase gene, while 22.4% have one or two copies of the GYS1-R309H variant.

This suggests that genetic variants affecting other genes may cause glycogen storage disease in horses. On this basis, horses with the GYS1-R309H variant are said to have Polysaccharide Storage Myopathy type 1 (PSSM1), while horses showing enlarged glycogen granules but lacking the GYS1-R309H variant are unexplained. In the years since the discovery of the GYS1-R309H variant and its association with PSSM1, no variants of the genes shown in the table above associated with glycogen storage disease in human patients have been found.

One of the additional findings in horses with exercise intolerance is the occurrence of clusters of glycogen granules of normal size, suggesting a different disorder in which glycogen synthesis is constitutively activated. This condition was described as PSSM2 (18). Again, in the years since the discovery of the GYS1-R309H variant and its association with PSSM1, no variants of the equine orthologs of the genes shown in the table above, associated with glycogen storage disease in human patients, have been found.

Arabian horses initially diagnosed with PSSM2 were found to have defects in muscle similar to those found in human patients with a different disease state called Myofibrillar Myopathy. Human patients with Myofibrillar Myopathy have genetic variants of a growing group of genes that affect the structural integrity of muscle. Arabian horses initially diagnosed with PSSM2 do not synthesize abnormal quantities of glycogen; rather, the pooling of glycogen granules of normal size in structurally disorganized myofibrils presents the appearance of a glycogen storage disease (19).

It remains an open question whether there are any genetic variants associated with glycogen storage disease in horses besides GYS1-R309H, associated with PSSM1. For this reason, researchers have suggested an alternative nomenclature in which horses with observable structural defects in muscle and glycogen granules of normal size have Muscle Integrity Myopathy (MIM).

References

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