CHAPTER 103 Heritable Muscle Diseases
HYPERKALEMIC PERIODIC PARALYSIS
Hyperkalemic periodic paralysis (HyPP) is an autosomal dominant trait affecting Quarter Horses, American Paint Horses, Appaloosas, and crossbred Quarter Horses. It was the first equine disease attributed to a specific genetic mutation. A single base-pair substitution in the SCN4A gene causes a phenylalanine/leucine substitution in a key part of the voltage-dependent skeletal muscle sodium-channel α-subunit. A prolific Quarter Horse sire born in 1969, named Impressive, appears to have been the origin of the HyPP mutation. Impressive and his 355,000 registered descendants are usually heavily muscled and have therefore dominated the halter horse industry. Approximately 4% of the Quarter Horse breed may carry the mutation, but most are heterozygous; however, some horses are homozygous for this dominant trait. It is highly advisable to perform genetic testing on horses related to Impressive during a prepurchase examination or before heavy sedation and anesthesia. Owners should be fully aware that breeding an affected horse to a normal horse results in a 50% chance of perpetuating the disorder in future generations.
Horses appear clinically normal between episodes. Intermittent clinical signs are usually evident by 3 years of age, but the severity of clinical signs is highly variable, ranging from no signs to infrequent muscle fasciculations to marked tremors that progress to weakness and paralysis. Expression of HyPP is influenced by dietary potassium concentrations, episodes of feed withdrawal or inappetence, heavy sedation, anesthesia, trailer rides, and stress. However, often there is no apparent inciting cause. Exercise per se does not appear to induce clinical signs, and usually serum creatine kinase (CK) is within normal limits or only slightly high during episodes.
Most clinical episodes are characterized by increased facial muscle tone; occasional prolapse of the third eyelid; sweating; and muscle fasciculations in the flanks, neck, and shoulders. Muscle fasciculations may spread to additional muscle groups and can be exacerbated by sensory stimulation. Some horses develop severe muscle cramping. Persistent depolarization of the muscle cells can progress to cause weakness characterized by staggering, dogsitting, and recumbency. Episodes often last 15 to 60 minutes, during which time horses remain anxious but alert. Respiratory stridor, distress, and dysphagia may occur, particularly in homozygous horses, as a result of pharyngeal collapse and edema, laryngopalatal dislocation, and laryngeal paralysis. Several horses have died during acute episodes.
Blood samples obtained during episodes show hyperkalemia (6 to 9 mEq/L), hemoconcentration, and mild hyponatremia. These changes occur because a subpopulation of skeletal muscle sodium channels fail to inactivate, resulting in an excessive inward flux of sodium and outward flux of potassium from muscle cells. Serum potassium concentration returns to normal soon after an episode.
One means of diagnosing HyPP when horses are not experiencing a clinical episode is by electromyography. Persistent abnormal findings include fibrillation potentials, complex repetitive discharges with occasional myotonic potentials, and trains of doublets. The definitive test for identifying HyPP is demonstration of the base-pair sequence substitution in the segment of the gene encoding for the α-subunit of the sodium channel. Submission of mane or tail hair should be made to a licensed laboratory such as the Veterinary Genetics Laboratory at the University of California, Davis (www.vgl.ucdavis.edu). Differential diagnoses for hyperkalemia include delay before sample centrifugation, hemolysis, acidosis, renal failure, severe rhabdomyolysis, and high-intensity exercise.
Many horses spontaneously recover from episodes of HyPP and appear normal by the time a veterinarian arrives. Some owners find that mild exercise or administration of corn syrup can abort a mild episode. In severe cases, intravenous (IV) administration of calcium gluconate (0.2 to 0.4 ml/kg of a 23% solution diluted in 1 L of 5% dextrose or saline) will often provide immediate improvement. Other treatment options include IV dextrose (6 mL/kg of a 5% solution) alone or combined with sodium bicarbonate (1 to 2 mEq/kg) or intramuscular (IM) administration of epinephrine (3 mL of 1:1000/500 kg). If signs of respiratory distress develop, a tracheostomy may be necessary.
Horses with HyPP should be fed a balanced diet containing between 0.6% and 1.1% total potassium concentration by weight. Each meal should contain less than 33 g of potassium. High-potassium feeds such as alfalfa hay, orchard grass hay, brome hay, soybean meal, sugar molasses, and beet molasses should be avoided. Optimally, later cuts of Timothy or Bermuda grass hay; grains such as oats, corn, wheat, and barley; and beet pulp should be fed in small meals several times a day. The potassium concentration of forages can vary widely, so it may be prudent to perform a forage analysis to determine potassium concentrations. Regular exercise or frequent access to a large paddock or yard is also beneficial. Although potassium concentrations may be high in grasses, the high water content in this forage appears to dilute the potassium load, making them safe for pastured horses. Commercially available complete feed with a guaranteed K+ content may be more convenient for some HyPP horses.
Acetazolamide (2 to 3 mg/kg orally [PO], every 8 to 12 hours) or hydrochlorothiazide (0.5 to 1 mg/kg PO, every 12 hours) may be indicated for horses in which episodes are not controlled by adjusting the diet. These diuretics increase renal potassium excretion, and acetazolamide also stimulates insulin secretion, which drives blood glucose and potassium into cells. Breed registries and other associations may have restrictions on the use of these drugs during competitions because diuretics may mask prohibited substances. In most cases HyPP is a manageable disorder.
GLYCOGEN BRANCHING ENZYME DEFICIENCY
Glycogen branching enzyme deficiency (GBED) is an autosomal recessive glycogen storage disorder that affects neonatal Quarter Horse or Paint Horse foals or aborted fetuses. The disease is due to a mutation in the GBE1 gene, which markedly reduces the function of the glycogen branching enzyme. As a result, tissues such as cardiac and skeletal muscle, the liver, and the brain cannot store and mobilize glycogen to maintain normal glucose homeostasis. Carriers of GBED trace back to the sire King P234 in most cases; however, King’s sire Zantanon may also have carried GBED. Most Quarter Horses, however, are descendants of these two stallions, so pedigree analysis is not very helpful. GBED has likely been carried in the Quarter Horse breed at least since its inception in 1940. Approximately 8% of both Quarter and Paint Horses are carriers of GBED. Homozygous GBED fetuses were detected in 2% to 4% of second- and third-trimester abortions submitted to two diagnostic laboratories. Many horses with GBED likely remain undiagnosed because of the similarity of clinical signs between GBED and many neonatal diseases and the current lack of genetic testing or because fetuses are stillborn or aborted.
The most common manifestation of GBED is likely stillbirth or second- or third-trimester abortion. Foals that survive to parturition are often hypothermic and weak but gain strength when given milk by bottlefeeding or when assisted to stand and nurse. Correctable flexural deformities of all four limbs are common in GBED foals. Progression of signs can be highly variable. Some foals have early onset ventilatory failure and die, even with mechanical ventilation. Other foals may collapse intermittently as a result of hypoglycemia, particularly if access to suckling is restricted. Sudden death is reported in some foals, whereas others are euthanized because of muscle weakness and inability to rise. Most affected foals die or are euthanized by 8 weeks of age; however, one foal survived with nursing care to 18 weeks of age. Common hematologic findings include a low white blood cell count (less than 4500 cells/μL) and mild to moderate elevations in serum CK, aspartate transaminase (AST) and γ-glutamyl transferase (GGT) activities.
Muscle biopsy specimens or samples of cardiac tissue obtained at necropsy from foals with GBED often, but not always, contain basophilic globules and eosinophilic crystalline material that is visible with routine hematoxylin and eosin stains. Aborted fetuses or foals of Quarter Horse–related breeds that die at less than 8 weeks of age should have cardiac and muscle sections obtained for periodic acid-Schiff (PAS) staining. Tissues of foals with GBED contain PAS-positive globular inclusions with, in some cases, smaller crystalline inclusions. Abnormal polysaccharide can be identified in neural tissue and is inconsistently found in the liver. The most accurate diagnosis of GBED can be obtained through genetic testing by licensed laboratories such as the University of California, Davis (www.vgl.ucdavis.edu) or Vet Gen (www.vetgen.com). Mane or tail hairs with roots intact should be submitted to identify foals homozygous for GBED.
Many stallion owners offer a free repeat breeding to mares that lose foals, and if a diagnosis is not established, there is a 25% chance of having another GBED affected offspring. Testing mane hairs for heterozygosity for GBED is strongly recommended for Quarter Horse–related mares that have abortion, stillbirth, or unexplained death of a neonate less than 8 weeks of age.
POLYSACCHARIDE STORAGE MYOPATHY
Polysaccharide storage myopathy (PSSM) was first identified in Quarter Horse–related breeds in 1992 and is characterized by twofold higher glycogen concentrations and abnormal granular amylase-resistant inclusions in skeletal muscle. Several different acronyms have been used to describe PSSM, including EPSM and EPSSM. The variety of acronyms used are in part related to preferences of different laboratories as well as to differences in the criteria used to diagnose PSSM. The prevalence of PSSM in Quarter Horses is approximately 12% and in Belgians and Percherons is approximately 35%. recently, an autosomal dominant point mutation in the glycogen synthase 1 gene (GYS1) has been identified that appears to cause unregulated synthesis of glycogen. This GYS1 mutation, present in horses for over a 1000 years, is the same disorder described as “Monday morning disease” or “azoturia” in draft horses in the early twentieth century.
The GYS1 mutation is found in Quarter Horses and five draft horse breeds, Paint horses, Appaloosa horses, three Warmblood breeds, Haflinger, Morgan, Mustang, Rocky Mountain Horse, and Tennessee Walking Horse breeds, as well as mixed breed horses. When all horses diagnosed with PSSM at the University of Minnesota Neuromuscular Diagnostic Laboratory by muscle biopsy were screened for the genetic mutation, it was clear that there was a subset of horses with PSSM that did not have the GYS1 mutation. Nomenclature for PSSM therefore has changed; type 1 PSSM refers to horses with the GYS1 mutation, and type 2 PSSM refers to horses diagnosed with abnormal glycogen storage in muscle biopsy that lack the GYS1 mutation. Type 2 PSSM occurs in about 28% of Quarter Horses and in a wide variety of Warmblood breeds, such as Dutch Warmbloods, Hannoverian, Westfalian, Canadian Warmblood, Irish Sport Horse, Gerdlander, Hussien, and Rheinlander. The true prevalence in Warmbloods is unknown. A small percentage of light-breed horses may also be afflicted with type 2 PSSM.
The most common signs of both forms of PSSM in Quarter Horses are firm painful muscles, stiffness, fasciculations, sweating, weakness, and reluctance to move. The hindquarters are frequently most affected, but back muscles, abdomen, and forelimb muscles may also be involved. During exercise horses may stop and posture as if to urinate, perhaps as a means to alleviate muscle cramping. Signs of pain can be particularly severe, with 30% of horses having muscle pain for more than 2 hours and about 10% of horses becoming recumbent. Less common signs of PSSM in Quarter Horses include gait abnormalities, mild colic, and muscle wasting. There are no significant temperament, body type, or gender predilections for PSSM. Muscle pain often occurs with less than 20 minutes of exercise at a walk and trot, particularly if the horse has been rested for several days before exercise and on a high-grain diet. The mean age at onset of clinical signs is 5 years and ranges from 1 to 14 years of age. Serum CK and possibly AST activity are often persistently high in Quarter Horses with PSSM. The median CK and AST activities for all PSSM Quarter Horses with muscle biopsies submitted to the University of Minnesota were 2809 and 1792 U/L, respectively.
Belgian and Percheron horses appear to have a high prevalence of type 1 PSSM, but other draft breeds are also affected. Many draft horses with PSSM do not have clinical signs. Severe rhabdomyolysis and myoglobinuria may be seen in horses that are fed high-grain diets, exercised irregularly with little turnout, or undergoing general anesthesia. Other signs include progressive weakness and muscle loss resulting in difficulty rising in horses with normal serum CK activity. Gait abnormalities, such as excessive limb flexion, fasciculations, and trembling, have also been reported in draft horses. Although the condition “shivers” was previously attributed to PSSM, a recent study found no causal association between these two conditions. The very high prevalence of PSSM in draft horses indicates that there is a 36% chance that any clinical sign could be falsely associated with PSSM. The mean age of draft horses diagnosed with PSSM is about 8 years. No particular sex predilection has been identified. The median serum CK and AST activities in draft horses from which biopsies were sent to the University of Minnesota were 459 and 537 U/L, respectively.
The most common clinical signs reported in Warmbloods with PSSM are painful, firm back and hindquarter muscles; reluctance to collect and engage the hindquarters; poor rounding over fences; gait abnormalities; and muscle atrophy. Overt signs of exertional rhabdomyolysis are reported in fewer than 15% of Warmbloods with PSSM. Warmbloods derived from crosses with draft horses often have type 1 PSSM, whereas other specific Warmblood breeds may have a higher prevalence of type 2 PSSM. The mean age of onset of clinical signs in Warmbloods is 8 to 11 years of age, with median CK and AST activities being 323 and 331U/L, respectively.