equiseq's Muscle Integrity Myopathy (pssm2)

EquiSeq, a company based in the USA, has concluded that PSSM type 2 is not a glycogen storage issue, but rather a chronic muscle atrophy or muscle breakdown issue. They have identified genes that cause symptoms of PSSM2, that have been dubbed  P2,P3, P4, Px, P8 and K1 for now. They are considered to be semi-dominant genes, meaning that having one copy of a gene (for example, n/P3) means a horse is affected by the disease associated with that gene, but having two copies (for example P3/P3) will make the symptoms more severe. The presence of any other gene on the MIM panel (for example n/P3 n/Px n/P4), or the presence of PSSM type 1 or IMM or MH (in Quarter Horses and related breeds) will also aggravate the horse’s symptoms, making the horse harder to manage.

Every variant on the MIM panel is associated with a different underlying mechanism, but their symptoms are similar (see “symptoms” for more information). MIM is an adult-onset disease with horses generally starting to show obvious symptoms between age 7 and 10. Symptoms are often triggered by an event causing a negative nitrogen balance in the body, such as medical procedure, an injury or a vaccination. Px is not considered to cause MIM, but rather a gene that causes Recurrent Exertional Rhabdomyolysis (RER), probably in combination with other genes, that still need to be discovered.

P2 is a mutation of the MYOT gene, a gene that encodes myotilin. This mutation affects the integrity of the Z-disc, weakening and atrophying the affected muscle. In humans, this mutation is associated with Myofibrillar Myopathy 3 (MFM3). This muscle abnormality is adult-onset and presents as symptoms of Limb Girdle Muscular Dystrophy 1A; a muscle disease with muscle weakness and muscle atrophy of the (control of the) limbs as its main symptoms.

P3 is a mutation in the FLNC gene, a gene that encodes filamin C. This mutation affects the integrity of the Z-disc, weakening and atrophying the affected muscle. In humans, this gene is associated with Myofibrillar Myopathy 5 (MFM5). It is a muscle abnormality that is adult-onset and expresses itself as symptoms of Limb Girdle Muscular Dystrophy, a muscle weakness and muscle atrophy in the muscle groups of the (control of the) limbs as its main symptoms.

P4 is a mutation of the MYOZ3 gene, a gene that encodes myozenin3. Myozenin is a component of the Z-disc that binds other Z-disc proteins and as such this mutation affects the integrity of the Z-disc. This mechanism has already been demonstrated in mice; in humans this could potentially be of interest in the diagnosis of previously undiagnosed muscle problems.

P8 is a mutation in the PYROXD1 gene, a gene necessary for the antioxidative defenses of the body. This mutation causes, among other things, degradation of the integrity of the Z-disc sarcomeres and the myofibrils or contractile elements, causing muscle weakness and atrophy. In humans, this mutation is associated with Myofibrillar Myopathy 8 (MFM8).

Px is a mutation in the CACNA2D3 gene, which encodes a regulatory subunit of the voltage-gated calcium channels. It affects the process by which motor neurons transmit signals to initiate muscle contraction. This gene is associated with Recurrent Exertional Rhabdomyolysis (RER); the classic tying-up or Monday morning sickness, in which the horse can hardly or no longer move, sweats profusely and (in severe cases) has coffee-coloured urine (myoglobinuria). In a less severe form, this can manifest itself in muscle stiffness and/or abnormal gait. Elevated muscle values (CK and AST) are common here. A special characteristic of horses with Px is their sensitivity to stress and (sometimes extreme) explosive behaviour as a result. The presence of Px can amplify the symptoms of a horse with P2, P3 or P4. It is known that several genes are involved in the expression of RER. Further research is being done on this.

K1 is a mutated version of COL6A3 and has been linked to a disruption in the collagen production of the endomysium, a layer of connective tissue that covers individual muscle fibres. In humans, this condition is known as Bethlem's disease, which is usually included in the group of congenital muscular dystrophies. In horses, it can manifest itself in symptoms that are considered typical for PSSM type 2, such as muscle stiffness, muscle tremors, abnormal gait such as rope walking and reluctance to move forward.

In 2023, the variants on the EquiSeq panel have been renamed to Muscle Integrity Myopathy (MIM) to better reflect the nature of the underlying causes of the disease.

In Europe (EU and UK), Generatio/CAG is the only lab that is licensed to test for these variants. Outside of the EU and the UK, testing is done by EquiSeq in the United States.

EquiSeq holds patents in multiple regions worldwide, including Australia, New Zealand, South Africa, the EU, UK and Canada. In Europe and the UK, testing can be done via Generatio/CAG in Germany. Outside of those countries, testing is done via EquiSeq in the USA.

The publication and peer review process of EquiSeq’s findings is currently ongoing.
In parallel, Dr. Molly McCue and her team of the University of Minnesota is doing research into the variants and its effect on affected horses. As these processes have not been finalised, vets may or may not currently want to use or recommend these tests.