Discovered at UC Davis Hyperkalemic Periodic Paralysis (HYPP)

Quick Summary

Hyperkalemic periodic paralysis (HYPP) is an inherited disease of the muscles primarily found in Quarter Horses which is characterized by sporadic episodes of muscle tremors or paralysis.

Phenotype: Hyperkalemic periodic paralysis (HYPP) is characterized by sporadic attacks of muscle tremors (shaking or trembling), weakness, and/or collapse. Attacks can also be accompanied by loud breathing noises resulting from paralysis of the muscles of the upper airway. Occasionally, sudden death can occur following a severe paralytic attack, presumably from heart failure or respiratory muscle paralysis.

Manifestation of clinical signs of HYPP depends on many factors including stress, diet, and changes in exercise. Some horses may manifest severe signs of the disease while others exhibit little or no signs.

Mode of Inheritance: Autosomal dominant

Alleles: N = Normal/Unaffected, H = Hyperkalemic periodic paralysis

Breeds appropriate for testing: Quarter Horse and related breeds

Explanation of Results:

  • Horses with N/N genotype will not have hyperkalemic periodic paralysis and cannot transmit this hyperkalemic periodic paralysis variant to their offspring.
  • Horses with N/H genotype can display episodes of hyperkalemic periodic paralysis. Horses with this genotype are heterozygous for the variant that makes them susceptible to sporadic episodes of muscle tremors or paralysis; clinical symptoms and frequency of episodes depends on other factors such as diet and exercise. They may transmit this hyperkalemic periodic paralysis variant to 50% of their offspring. Matings with N/N genotype will result in a 50% chance of producing a foal with the affected allele.
  • Horses with H/H genotype can display episodes of hyperkalemic periodic paralysis and typically are more severely affected. They will transmit this hyperkalemic periodic paralysis variant to all of their offspring.
Price

$40 one test per animal

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Additional Details

Hyperkalemic periodic paralysis (HYPP) is an inherited disease of the muscle which is caused by a genetic mutation. In affected horses, a point mutation exists in the sodium channel gene (SCN4A) that can be passed on to offspring. 

HYPP was one of the first genetic disorders to be elucidated in the horse. A missense mutation in SCN4A (c.4248C>G) produces an altered alpha chain of the skeletal muscle sodium channel. Specifically the change in the DNA causes a substitution from phenylalanine to leucine (denoted as p.F1416L) at position 1416 of the protein product (sodium channel).

Sodium channels are "pores" in the muscle cell membrane which control contraction of the muscle fibers.  In horses with the defective sodium channel protein, the channels can become "leaky" and makes the muscle overly excitable and contract involuntarily. The channel becomes "leaky" when potassium levels fluctuate in the blood. This may occur with fasting followed by consumption of a high potassium feed such as alfalfa. Hyperkalemia, which is an excessive amount of potassium in the blood, causes the muscles in the horse to contract more readily than normal. This makes the horse susceptible to sporadic episodes of muscle tremors or paralysis.

This genetic defect has been identified in descendants of the American Quarter Horse sire Impressive. The original genetic defect causing HYPP was a natural mutation that occurred as part of the evolutionary process. The majority of such mutations, which are constantly occurring, are not compatible with survival. However, the genetic mutation causing HYPP produced a functional, yet altered, sodium ion channel. This gene mutation is not a product of inbreeding. The gene mutation causing HYPP inadvertently became widespread when breeders sought to produce horses with heavy musculature. To date, confirmed cases of HYPP have been restricted to descendants of this horse.

Symptoms and Signs of the Disease

Homozygous horses are affected more severely than heterozygous horses. Under ideal management practices, the defective gene does not appear to have adverse effects, but stress and/or increased potassium in the serum can trigger clinical signs of muscle dysfunction. Why some horses manifest severe signs of the disease and other exhibit little or no signs is unknown and currently under investigation. Unfortunately, a horse carrying the defective gene but showing minimal signs has the same chance of passing the gene to future generations as does the affected horse with severe signs.

HYPP is characterized by sporadic attacks of muscle tremors (shaking or trembling), weakness and/or collapse. Attacks can also be accompanied by loud breathing noises resulting from paralysis of the muscles of the upper airway. Occasionally, sudden death can occur following a severe paralytic attack, presumably from heart failure or respiratory muscle paralysis.

Attacks of HYPP can take various forms and commonly have been confused with other conditions. Because of the muscle tremors and weakness, HYPP often resembles exertional rhabdomyolysis ("tying-up" syndrome). "Tying-up" syndrome can be caused by many different circumstances, including exercising a horse beyond the capacity to which it has been trained, as well as nutritional deficiencies and other metabolic diseases. A distinguishing feature of HYPP from "tying-up" syndrome is that horses usually appear normal following an attack of HYPP. Horses with "tying-up" syndrome, on the other hand, tend to have a stiff gait and painful, firm muscles of the hind limbs, rump and/or back. "Tying-up" syndrome is also generally associated with some type of exercise. HYPP, by contrast, is not usually associated with exercise, but occurs when horses are at rest, at feeding time, or following a stressful event such as transport, feed changes, or concurrent illness.

Because a horse may be down and reluctant or unable to stand during an HYPP attack, many owners have thought their horses were experiencing colic. HYPP has also been confused with seizures due to the pronounced muscle trembling and collapse. Unlike seizures and other conditions that cause fainting, horses with HYPP are conscious and aware of their surroundings during an attack and do not appear to be in pain. Respiratory conditions and choking have also been confused with HYPP because some horses make loud breathing noises during an attack.

Causes of an Attack

Environmental factors can actually cause an attack of muscle weakness. Owners of HYPP-positive horses should be aware that external stimulus and events could increase the chance of paralysis onset. These factors include dietary changes, fasting, general anesthesia, and concurrent illness and exercise restriction.

Prevention and Control of HYPP Attacks

Dietary management is extremely important in the management of affected horses. Dietary adjustments include (1) avoiding high potassium feeds such as alfalfa hay, brome hay, canola oil, soybean meal or oil, and sugar molasses and beet molasses, and replacing them with timothy or Bermuda grass hay, grains such as oats, corn, wheat and barley, and beet pulp; (2) feeding several times a day; and (3) exercising regularly and/or being allowed frequent access to a large paddock or yard. Due to the high water content of pasture grass, a horse is unlikely to consume large amounts of potassium in a short period of time if kept on pasture. If the horse is experiencing problems on its present diet, it is recommended to feed a diet containing between 0.6% and 1.5% total potassium concentrations.

Several drugs have been used for prevention of clinical episodes of paralysis. Horses have been treated with either acetazolamide (2-4 mg/kg orally, every 8 to 12 hours) or hydrochlorthiazide (0.5-1 mg/kg orally, every 12 hours) with apparent success. These agents exert their effects through different mechanisms; however, both cause increased renal potassium ATPase activity. Acetazolamide has been shown to stabilize blood glucose and potassium by stimulating insulin secretion. Breed registries have restrictions on the use of these drugs during competitions (some require a veterinary certificate).

Inform your veterinarian of the HYPP condition prior to any general anesthesia, as this may precipitate an episode of paralysis. If your horse is receiving medication, maintain him or her on therapy before and after surgery or anesthesia. Use common sense while hauling and be sure to stop and water horses frequently (every two hours).

During a severe attack of HYPP, emergency treatment from a veterinarian is necessary. For long term therapy, many horses can be managed by exercise and diet control alone. Regular exercise and access to a large paddock or pasture is preferred over stall confinement. Maintain a regular feeding schedule, preferably equally spaced, two to three times per day. Avoid rapid changes in feed, such as bringing a horse off pasture grass and immediately switching to alfalfa hay. Most horses improve when the potassium content in the diet is decreased.

Inheritance and Transmission of HYPP

HYPP is inherited as an autosomal dominant trait, which means it can occur in both males and females and only one copy of the mutated allele is required to produce the disease.

The trait is inherited from generation to generation with equal frequency; it does not get "diluted" out or skip generations. Breeding an affected heterozygous horse (N/H) to an affected heterozygous horse (N/H) will result in approximately 50% carrying the defective gene (N/H), approximately 25% will be normal (N/N) and approximately 25% will be homozygous (H/H). Breeding an affected heterozygous horse (N/H) to a normal horse (N/N) will result in approximately 50% normal offspring and approximately 50% with one copy of the defective gene (N/H).

Myths about HYPP

Some people have felt that the disease can be diluted out and not carried to distant generations. This is false because an affected horse has just as much chance to pass on the trait as the affected parent which passed the gene to him. Some people also believe the horse will "grow out of it." This is not true. For unknown reasons, attacks of HYPP tend to occur most often at the beginning of intense training and fitting for shows (age three to seven years old). It is important to realize that horses with HYPP are affected for life. It is possible that older horses do not experience the same conditioning stresses as young horses or owners have discovered the best management strategies for the older horses with HYPP.

Some people also think that if a horse does not show any signs up to a certain age, it does not carry the trait. Unfortunately, this is not the case. Once again, horses with HYPP are affected for life. There was a stallion and a broodmare with HYPP who did not show signs of the disease until age eight and 15, and both horses only experienced one isolated attack.

Testing for this HYPP variant can be useful for clinicians and owners in making an appropriate diagnosis and can help inform management and breeding decisions.

Turnaround Time
2-6 business days
Type of Sample

Species

Type of Test

Results Reported As
Test Result Hyperkalemic Periodic Paralysis (HYPP)
N/N Normal. Horse does not have the HYPP gene.
N/H Affected. Horse carries 1 copy of the HYPP gene.
H/H Affected. Horse has 2 copies of the HYPP gene.
References

Steiss, J. E., & Naylor, J. M. (1986). Episodic Muscle Tremors in a Quarter Horse: Resemblance to Hyperkalemic Periodic Paralysis. Canadian Veterinary Journal, 27(9), 332-335.

Spier, S. J., Carlson, G. P., Holliday, T. A., Cardinet III, G. H., & Pickar, J. G. (1990). Hyperkalemic periodic paralysis in horses. Journal of the American Veterinary Medical Association, 197(8), 1009-1017.

Cox, J. H., & DeBowes, R. M. (1990). Episodic weakness caused by hyperkalemic periodic paralysis in horses. The Compendium on Continuing Education for the Practicing Veterinarian, 12, 83-89.

Pickar, J. G., Spier, S. J., Snyder, J. R., & Carlsen, R. C. (1991). Altered ionic permeability in skeletal muscle from horses with hyperkalemic periodic paralysis. American Journal of Physiology-Cell Physiology, 260(5). doi: 10.1152/ajpcell.1991.260.5.c926

Naylo, J. M., Robinson, J. A., & Bertone, J. (1992). Familial incidence of hyperkalemic periodic paralysis in quarter horses. Journal of the American Veterinary Medical Association, 200(3), 340-343.

Rudolph, J. A., Spier, S. J., Byrns, G., & Hoffman, E. P. (1992). Linkage of hyperkalaemic periodic paralysis in Quarter horses to the horse adult skeletal muscle sodium channel gene. Animal Genetics, 23(3), 241-250. doi: 10.1111/j.1365-2052.1992.tb00136.x

Rudolph, J. A., Spier, S. J., Byrns, G., Rojas, C. V., Bernoco, D., & Hoffman, E. P. (1992). Periodic paralysis in Quarter Horses: A sodium channel mutation disseminated by selective breeding. Nature Genetics, 2(2), 144-147. doi: 10.1038/ng1092-144

Spier, S. J., Carlson, G. P. (1992). Hyperkalemic periodic paralysis in certain registered Quarter Horses. The Quarter Horse Journal, 120, 68-69.

Zhou, J., Spier, S. J., Beech, J., & Hoffman, E. P. (1994). Pathophysiology of sodium channelopathies: Correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis. Human Molecular Genetics, 3(9), 1599-1603. doi: 10.1093/hmg/3.9.1599

License Info

Sections reprinted with permission of: Sharon J. Spier, DVM, Ph.D., Associate Professor, Department of Medicine and Epidemiology, University of California, Davis.