Impact of Paternal Inheritance of an Allele for Type I Polysaccharide Storage Myopathy on Exertional Rhabdomyolysis and Muscle Glycogen Concentration

Polysaccharide storage myopathy (PSSM1) is a form of exertional rhabdomyolysis caused by a dominant gain of function mutation in glycogen synthase 1. Penetrance is impacted by genotype, environment and, we hypothesized, genomic imprinting. The first objective was to retrospectively determine the frequency of paternal and maternal inheritance of the R309H mutation in symptomatic Quarter Horses (QH). Forty-eight registered PN QHs with exertional rhabdomyolysis were identified from our database and sire genotype was determined from AQHA records. The P allele was inherited significantly less often from the sire (12/48; 25%) than the dam (36/48; 75%) in symptomatic horses. The second objective was to prospectively determine if inheritance of a paternal P allele from an asymptomatic heterozygous (PN) stallion impacted signs of exertional rhabdomyolysis and glycogen storage in PN and normal (NN) offspring. While none of the stallion’s offspring exhibited rhabdomyolysis during a 15-minute exercise challenge, the PN offspring had higher indicators of subclinical muscle damage than NN offspring after exercise (plasma creatine kinase; PN 624.1 ± 78.9; NN 465.1 ± 86.8 u/l). In addition, muscle glycogen concentrations (PN 171.6 ± 37.8; NN 122.7 ± 22.6 mmol/kg) and muscle histopathology scores (two-fold) were significantly higher in PN than NN offspring. We concluded that signs of exertional rhabdomyolysis occur less frequently with paternal inheritance of the P allele, suggesting differential allelic expression due to genomic imprinting could affect PSSM1 penetrance. Clinically, inheritance of a P allele is not benign as it resulted in subclinical muscle damage and excessive muscle glycogen storage.