Polysaccharide Storage Myopathy (PSSM 2)

Summary

There are cases of PSSM that are not associated with the GYS1-R309H variant. These cases are referred to as PSSM Type 2. The genetic basis of PSSM2 is under investigation. There appear to be multiple genetic causes of PSSM2 in different breeds.

In most cases, a definitive diagnosis of PSSM2 requires both a muscle biopsy and a negative DNA test for the GYS1-R309H variant (P1) that is associated with PSSM1. This will change as the genetic causes of PSSM2 are identified.

Muscle biopsy of horses with PSSM2 shows abnormal clumping of normally-sized glycogen granules in regions of focal myofibrillar disruption. The primary cause of the defect in PSSM2 therefore appears to be disorganization of myofibrils, rather than a disorder of glycogen metabolism as is the case in PSSM1.

In contrast to PSSM1 and RER, horses with PSSM2 may show levels of serum CK and AST that are at the high end of the normal range. This means that the measurement of serum CK and AST may not be useful as diagnostic criteria for PSSM2.

Researchers at EquiSeq have identified three semidominant genetic variants that cause PSSM2. The results are not yet published in a peer-reviewed academic journal. Prior to publication, the variants has been termed P2, P3, and P4. These are missense alleles of MYOT, FLNC, and MYOZ3, respectively.

PSSM2 is also associated with a recessive variant of an undisclosed gene designated P5.

The images above show Gal's Magnificent Blunder (Maggie), a Quarter Horse with PSSM2 born in 1999, in May 2015 (top) and May 2016 (bottom). Maggie is heterozygous for both the P2 (n/P2) and P3 (n/P3) variants and does not carry the P1 variant (n/n). The P3 variant is associated with Myofibrillar Myopathy (MFM). Maggie lost 200 pounds over a period of one year. The muscle wasting is most apparent in the hindquarters.

The video shows Supernatural, a Thoroughbred heterozygous for both P3 and P4 (n/P3 n/P4). Stiffness in the hindquarters is evident, as is "bunny hopping" in the canter.
Horses that carry two copies of the variants (P2/P2, P3/P3, or P4/P4) are more strongly affected, with an earlier age of onset and more severe symptoms. An early symptom in affected horses is a change in temperament likely related to pain. The horse may suddenly seem reluctant to be saddled or handled in other ways, and resist having a foot raised for the farrier. Another symptom is shifting lameness: the horse appears lame in one leg, which gets better on its own, then lameness appears in another leg. Muscle wasting, especially in the hindquarters (pelvic girdle and proximal limb) and topline (shoulder girdle), may be apparent. The horse may also show localized muscle wasting, divots that look like kick marks. Muscle wasting may produce a rippled or washboard appearance in some areas. Changes in gait are apparent. The most telling sign is at canter, where the horse may "bunny hop" by pulling both rear legs forward at once. In other gaits, the hind limbs may appear stiff with a short gait. Cross-firing (disunited canter) is also seen. "Rope walking," the placement of one foot directly in front of the other as if walking a tightrope, may appear in the rear legs or in all four.

Horses that carry one copy of a variant (n/P2, n/P3, or n/P4) have a predisposition to develop PSSM2. Not every n/P2, n/P3, or n/P4 horse develops symptoms. Those n/P2, n/P3, or n/P4 horses that develop symptoms have a later age of onset (7-10 years) and milder symptoms. The symptoms are the same as those seen in P2/P2, P3/P3, or P4/P4 horses. Development of symptoms appears to be related to whether more than one genetic variant is present in that horse. A horse that is n/P2 n/P3 or n/P2 n/P4 is more likely to develop symptoms than is a horse that is n/P2 but n/n for P3 and P4.

Dietary therapy (a diet supplemented with complete protein) and a specific exercise regimen may help to manage the symptoms. This is still an active area of investigation.

Date of Last Update: 01/31/2019

Results

Understanding the Results

Results of the genetic test for the P2 variant of MYOT are presented as shown below. Horses carrying the P2 variant develop symptoms of exercise intolerance as they age. The age of onset and the severity of symptoms is variable.

Polysaccharide Storage Myopathy Type 2 (PSSM2)
n/n	Clear	This horse tested negative for P2, a PSSM2-predisposing variant. The horse will not pass on the defect to its offspring.
n/P2	Affected	Both the normal and mutant alleles are present. This horse is positive for the P2 variant and may develop symptoms of exercise intolerance.
P2/P2	Affected	This horse carries two copies of the P2 variant. The horse is expected to develop symptoms of exercise intolerance.

Results of the genetic test for the P3 variant of FLNC are presented as shown below. Horses carrying the P3 variant develop symptoms of exercise intolerance as they age. The age of onset and the severity of symptoms is variable.

Polysaccharide Storage Myopathy Type 2 (PSSM2)
n/n	Clear	This horse tested negative for P3, a PSSM2-predisposing variant. 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.

Results of the genetic test for the P4 variant of MYOZ3 are presented as shown below. Horses carrying the P4 variant develop symptoms of exercise intolerance as they age. The age of onset and the severity of symptoms is variable.

Polysaccharide Storage Myopathy Type 2 (PSSM2)
n/n	Clear	This horse tested negative for P4, a PSSM2-predisposing variant. 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.

Results of the genetic test for the P5 variant of an undisclosed gene are presented as shown below. Horses carrying the P5 variant develop symptoms of exercise intolerance as they age. The age of onset and the severity of symptoms is variable.

Polysaccharide Storage Myopathy Type 2 (PSSM2)
N/N	Clear	This horse tested negative for P5, a PSSM2-predisposing variant. The horse will not pass on the defect to its offspring.
N/P5	Carrier	Both the normal and mutant alleles are present. This horse is positive for the P5 variant and is not expected to develop symptoms of exercise intolerance but may pass the defect on to its offspring..
P5/P5	Affected	This horse carries two copies of the P5 variant. The horse is expected to develop symptoms of exercise intolerance.

What You Can Do

Horses that test positive for P2, P3, or P4 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. This management strategy may also be useful for P5/P5 horses.

Disease Name and Genes

PSSM2 is associated with semidominant variants (P2, P3, and P4) of MYOT, FLNC, and MYOZ3, respectively. PSSM2 is also associated with a recessive variant of an undisclosed gene designated P5.

Horse Genes Associated with PSSM2 and Human Diseases Associated with Variants of the Orthologous Genes
Variant	Inheritance	Gene Symbol	Gene Name	Associated Human Disease
P2	Semidominant	MYOT	Myotilin	Myofibrillar Myopathy 3
P2	Semidominant	MYOT	Myotilin	Limb-Girdle Muscular Dystrophy 1A
P3	Semidominant	FLNC	Filamin C	Myofibrillar Myopathy 5
P3	Semidominant	FLNC	Filamin C	Distal Myopathy 4
P4	Semidominant	MYOZ3	Myozenin 3	none
P5	Recessive	undisclosed	undisclosed	undisclosed

Inheritance

PSSM2 is associated with semidominant variants (P2, P3, and P4) of MYOT, FLNC, and MYOZ3, respectively. The semidominant alleles are abbreviated as P2, P3, and P4, with the recessive wild-type alleles abbreviated as n.

The illustrations below show the inheritance of P2 as an example. P3 and P4 are inherited in the same way. The three variants are inherited independently, and a horse may have more than one, as shown in the photographs above, of a horse that has the genotype n/P2 n/P3.

A horse with one copy of the semidominant allele (n/P2) will potentially have symptoms. If this horse is bred to a normal horse (n/n), each foal has a 50% chance of having one copy of the semidominant allele (n/P2) and a 50% chance of having two copies of the normal allele (n/n).

If two horses, each with one copy of the semidominant allele (n/P2), are bred, each foal has a 25% chance of having two copies of the normal allele (n/n), a 50% chance of having one copy of the semidominant allele (n/P2), and a 25% chance of having two copies of the semidominant allele (P2/P2). Because horses with one copy (n/P2) or two copies (P2/P2) of the semidominant allele are affected, each foal will have a 75% chance of potentially being affected.

Carriers of the recessive allele (N/P5) have no symptoms of the disease. If two such carriers are bred, each foal has a 25% chance of having two copies of the normal allele (N/N), a 50% chance of being a carrier (N/P5), and a 25% chance of being affected (P5/P5).

If a horse with two copies of the semidominant allele (P2/P2) is bred to a normal horse (n/n), all of the foals will have one copy of the semidominant allele (n/P2) and will potentially be affected.

PSSM2 is also caused by a recessive mutation in an undisclosed gene. The recessive allele is abbreviated as P5, with the dominant wild-type allele abbreviated as N.

If a carrier of the recessive allele (N/P5) is bred to a normal horse (N/N), each foal has a 50% chance of having two copies of the normal allele (N/N) and a 50% chance of being a carrier (N/P5).

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