|Myofibrillar Myopathy (MFM)|
|Understanding the Results|
|What You Can Do|
|Disease Name and Genes|
Myofibrillar Myopathy (MFM) is a form of exercise intolerance. The clinical signs manifesting during or after exercise resemble other types of exertional rhabdomyolysis. During an episode, horses are reluctant to move, experience pain, stiffness, and tremors, and sweat profusely. Serum creatine kinase (CK) and aspartate aminotransferase (AST) may be elevated, indicating muscle damage. In severe episodes, pigmenturia (coffee-colored urine due to the presence of myoglobin), inability to stand, and death can occur. These symptoms resemble other forms of exercise intolerance such as Polysaccharide Storage Myopathy (PSSM), Recurrent Exertional Rhabdomyolysis (RER), and Vacuolar Myopathy (VM).
Myofibrillar Myopathy (MFM) is distinct from these other forms of exercise intolerance with respect to findings on muscle biopsy. Histopathology shows ectopic accumulation of cytoskeletal proteins (e.g. desmin) and Z-disc degeneration. Because this finding is only made when anti-desmin staining is used, muscle biopsies on the same horses performed without desmin staining would likely be scored as PSSM2. As in PSSM2, focal myofibrillar disruption with accumulation of glycogen particles is seen. The condition has been observed in a subset of Arabian horses with exercise intolerance. Initial descriptions of MFM classified it as a subtype of Recurrent Exertional Rhabdomyolysis (RER) because it was a form of exercise intolerance observed in Arabians and Thoroughbreds. Researchers at EquiSeq currently think that it more closely resembles Polysaccharide Storage Myopathy, type 2 (PSSM2).
Researchers at EquiSeq have identified semidominant alleles of three genes that cause MFM in Thoroughbred, Arabians, and related breeds. The results are not yet published in a peer-reviewed academic journal. Prior to publication, the variants have been termed P3, P4, and P8. These are missense alleles of FLNC, MYOZ3, and PYROXD1, respectively.
The P3, P4, and P8 variants are also found in horses diagnosed with PSSM2 by muscle biopsy when desmin staining is not used. The P2 variant of MYOT associated with PSSM2 has not yet been observed alone in horses diagnosed with MFM; n/P3, n/P4, and n/P8 horses that are free of other PSSM2 variants have been diagnosed with MFM.
Horses that carry one copy of a variant (n/P3, n/P4, or n/P8) have a predisposition to develop MFM (also diagnosed as PSSM2). Horses with two copies of the variant (P3/P3, P4/P4, or P8/P8) are more strongly affected, with more severe symptoms and an earlier age of onset. Dietary therapy (a high protein diet) and a specific exercise regimen may help to manage the symptoms. In addition, horses that are n/P8 or P8/P8 appear to require larger amounts of vitamin E supplementation to maintain normal serum vitamin E levels.
Date of Last Update: 10/28/2021
Results of the genetic test for MFM are presented as shown below.
|n/n||Clear||This horse tested negative for P3. The horse will not pass on the defect to its offspring.|
|n/P3||Affected||Both the normal and mutant alleles are present. This horse is positive for the P3 variant and may develop symptoms of exercise intolerance.|
|P3/P3||Affected||This horse carries two copies of the P3 variant. The horse is expected to develop symptoms of exercise intolerance.|
|n/n||Clear||This horse tested negative for P4. The horse will not pass on the defect to its offspring.|
|n/P4||Affected||Both the normal and mutant alleles are present. This horse is positive for the P4 variant and may develop symptoms of exercise intolerance.|
|P4/P4||Affected||This horse carries two copies of the P4 variant. The horse is expected to develop symptoms of exercise intolerance.|
|n/n||Clear||This horse tested negative for P8. The horse will not pass on the defect to its offspring.|
|n/P8||Affected||Both the normal and mutant alleles are present. This horse is positive for the P8 variant and may develop symptoms of exercise intolerance.|
|P8/P8||Affected||This horse carries two copies of the P8 variant. The horse is expected to develop symptoms of exercise intolerance.|
Horses that test positive for P3, P4, or P8 should receive dietary supplementation with complete protein (whey), complementary protein (soy) or with specific amino acids that are typically limiting in plant protein (lysine, methionine, and threonine). This is a management strategy and not a treatment or cure.
MFM is associated with semidominant genetic variants (P3, P4, and P8) of FLNC, MYOZ3, and PYROXD1 respectively.
|Horse Genes Associated with MFM and Human Diseases Associated with Variants of the Orthologous Genes||Variant||Inheritance||Gene Symbol||Gene Name||Variant||Associated Human Disease|
chr4:83,837,774 G/A in EquCab3.0
chr4:83,840,299 G/A in EquCab3.0
|Myofibrillar Myopathy 5|
Distal Myopathy 4
chr14:26,710,261 G/A in EquCab3.0
oxidoreductase domain 1
chr6:48,924,749 G/C in EquCab3.0
|Myofibrillar Myopathy 8|
MFM is associated with semidominant variants (P3, P4, and P8) of FLNC, MYOZ3, and PYROXD1, respectively. The semidominant alleles are abbreviated as P3, P4, and P8, with the recessive wild-type alleles abbreviated as n.
The illustrations below show the inheritance of P3 as an example. P3, P4, and P8 are inherited in the same way. The three variants are inherited independently, and a horse may have more than one, so a horse may have the genotype n/P3 n/P4 or n/P3 n/P8.