Myosin-heavy chain myopathy (MYHM) is a muscle disease that results in two distinct clinical disease presentations, immune-mediated myositis and non-exertional rhabdomyolysis. The specific genetic mutation associated with risk for MYHM is in the MYH1 gene and was first identified in horses with immune-mediated myositis or IMM and is why initially the DNA test was named IMM. However, upon determining that there are two distinct clinical forms associated with the same mutation, the name of the DNA test was changed to Myosin-heavy chain myopathy (MYHM) to better reflect the two clinical syndromes.
The genetic variant associated with myosin-heavy chain myopathy was identified by Drs. Finno (UC Davis) and Valberg (Michigan State University) in 2017. This missense mutation is in the Myosin Heavy Chain 1 (MYH1) gene (chr11:52,993,878T>C) and causes an amino acid change from a glutamic acid (E) to glycine (G) at position 321 of the protein, which affects protein function.
With the IMM form of myosin-heavy chain myopathy, horses initially experience stiffness, weakness, and a decreased appetite followed by the rapid loss of 40% of muscle mass within 72 hours. Inflammatory cells, particularly lymphocytes, are present in muscle fibers and surrounding blood vessels, with preferential targeting of the gluteal (hindquarter) and back muscles. With the non-exertional rhabdomyolysis form of myosin-heavy chain myopathy, horses initially show stiffness, a short stride, firm muscles and may quickly lie down and be unable to get back up. These horses can have dark coffee-colored urine and blood samples show very high levels of muscle enzymes. There is often no evidence of lymphocytes in the muscle of horses with non-exertional rhabdomyolysis.
The VGL tests for susceptibility to myosin-heavy chain myopathy and reports the variant as My. The mode of inheritance for this disorder is autosomal codominant with variable penetrance. This means that horses with one or two copies of My are susceptible to disease, but not all horses with My will develop signs of disease. My is considered an associated genetic risk factor and requires specific environmental “triggers” of the immune system (e.g. infection, vaccination) to manifest as clinical disease. It has also been noted that My/My (i.e. homozygous) horses that show clinical signs are more severely affected. Age has also been shown to contribute to disease risk, with younger and older horses more likely to develop disease due to environmental triggers. Affected horses are typically 8 years and younger or 17 years and older.
The frequency of the My variant in the general Quarter Horse population was initially estimated at about 4%, with approximately 7.5% of Quarter Horses having 1 copy of the My allele; the frequency being higher in the reining (13.5%), working cow (8.5%) and halter (8%) categories, and not observed in barrel and racing categories. In 2022, results from a retrospective study conducted with VGL clients revealed a higher prevalence of the MYH1 mutation in the study population. The study led by Dr. Stephanie Valberg, Mary Anne McPhail Dressage Chair in Equine Sports Medicine from Michigan State University, and Dr. Carrie Finno, Gregory L. Ferraro Endowed Director of the UC Davis Center for Equine Health (CEH), in collaboration with Dr. Rebecca Bellone and Shayne Hughes of the UC Davis Veterinary Genetics Laboratory (VGL), found the prevalence of the MYH1 mutation to be 29% in the study population, with homozygous horses being relatively rare in the population (~3% of the study population were My/My). Muscle atrophy that was less likely to resolve occurred in 80% of homozygous horses whereas only about 20% of the heterozygous horses experienced rapid muscle atrophy. Importantly, the study also showed that factors like vaccination or infectious diseases were not apparent in 75% of homozygous horses and 54% of heterozygous horses known to have developed atrophy or stiffness, indicating more work is needed to better understand additional environmental triggers.
Previous studies had indicated that about 40% of horses that develop signs of muscle atrophy with MYHM have a history of exposure to Streptococcus equi subsp. equi infection, respiratory virus, or vaccination with influenza, equine herpes virus 4, or Streptococcus equi subsp. equi. Males and females are equally affected.
All of the triggers for MYHM are not yet known but those that are known include;
Recommendations for horses who genotype N/My or My/My are:
Horse breeders can utilize the MYHM test to design appropriate breeding strategies that avoid producing at-risk horses. Testing for MYHM can also assist in clinical decisions about potential exposure to environmental triggers and help guide vaccination protocols for heterozygous (N/My) and homozygous horses (My/My), thereby lowering the chance of an autoimmune event. Testing results can also help clinicians confirm diagnosis of IMM or non-exertional rhabdomyolysis cases suspected to be caused by the My allele. Further, testing for MYHM has the potential to assist in additional research that should help to elucidate the other risk factors, allowing for the potential to develop more precise management strategies.
Testing is recommended for Quarter Horses, Quarter Horse crosses, and related breeds with Quarter Horse influence.
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