Polysaccharide Storage Myopathy (PSSM1)

Type 1 Polysaccharide Storage disease (PSSM1) is a potentially life-threatening glycogen storage disease (glycogenosis) that affects skeletal muscles. The disease results from the accumulation of abnormal glycogen (carbohydrate storage molecule) that can damage muscle cells. Abnormal accumulation of glycogen was historically diagnosed by taking a muscle biopsy and determining if glycogen in the muscle was resistant to digestion with an enzyme known as amylase. Horses with PSSM1 show clinical signs that range from muscle soreness and weakness to muscle atrophy and acute exertional rhabdomyolysis (breakdown of muscle fibers) which can result in the reluctance of a horse to move.

Research at the University of Minnesota by Drs. McCue, Valberg, Mickelson, and colleagues identified the causal mutation for PSSM1. A single base substitution in the glycogen synthase 1 gene (GYS1) results in a change in the protein that replaces the normal arginine with histidine at amino acid number 309 (denoted as p.309Arg>His or p.R309H). The normal protein functions in skeletal muscle cells to convert excess glucose to a normal glycogen. This glycogen is stored and later converted back to glucose when the muscle cell needs energy to function. When histidine is present instead of the normal arginine, the protein activity is higher and results in an excess of glycogen that is not properly made (less branched structure). Because this glycogen is not properly branched, the conversion of this storage molecule to an energy source muscle cells can readily use is hindered, thus causing damage to the muscle upon exercise.

PSSM1 is inherited as an autosomal dominant trait, which means a single copy of the PSSM1 variant can cause symptoms of disease. However, a study in 2012 by Naylor and colleagues, investigating genotype for PSSM1, histopathology, and enzyme function provided evidence that homozygotes may be more severely affected. Specifically, homozygotes tended to have more severe histopathological changes and more amylase-resistant polysaccharide inclusions (abnormal glycogen) particularly in type 2A fibers than heterozygotes. Another study published in 2009 by McCue and colleagues reported more severe clinical phenotypes of PSSM1 in horses with malignant hyperthermia (MH). MH is also inherited as an autosomal dominant trait and is caused by a mutation in another gene known as the ryanodine receptor 1 (RYR1). These findings illustrate the importance of utilizing results from both genetic tests in clinical diagnosis and management of disease. 

The PSSM1 variant has been documented in at least 30 horse breeds and has been observed to range in frequency among these breeds. The prevalence is reported to be highest in some draft horse breeds and lowest in warmblood breeds. The PSSM1 variant is believed to be an old mutation that may have been under positive selection in some draft breeds, particularly the Belgian horse. This mutation may have been advantageous to horses that had daily work schedules with limited sugar feed intake.

Testing for PSSM1 can help to inform clinical, management, and breeding decisions. If a horse tests positive for the PSSM1 variant, veterinarians should be consulted to develop a diet and exercise regime that best manages the disease.

It is important to note, however, that the PSSM1 variant does not explain all cases of excessive abnormal glycogen accumulation in the muscle. It is likely that other genetic factors contribute to this condition, but to date no genetic variants for other types of PSSM (for example, PSSM type 2) have been identified or scientifically validated.