Current Facts About Hyperkalemic Periodic Paralysis (HYPP) Disease
Sharon J. Spier, D.V.M., Ph.D. University of California at Davis School of Veterinary Medicine, Department of Medicine

What is HYPP?
Hyperkalemic Periodic Paralysis Disease (HYPP) is a muscular disease that affects both horses and humans. It is caused by a hereditary genetic defect that disrupts a protein called a sodium ion channel, a tiny gateway in the membrane of muscle cells. The genetic defect disrupts the channel's normal opening and closing, such that uncontrolled sodium influxes occur. These influxes in turn change the voltage current of muscle cells, causing uncontrolled muscle twitching or profound muscle weakness. High levels of potassium in the blood usually are present when the disruptions in the ion channel occur.

What Are Effects of HYPP?
Horses with HYPP can experience unpredictable attacks of paralysis which, in severe cases, can lead to collapse and sudden death. The cause of death usually is cardiac arrest and /or respiratory failure. The disease is characterized by intermittent episodes of muscle tremors manifested by generalized or localized shaking, trembling and weakness. Occasionally, episodes are accompanied by respiratory noises resulting from paralysis of the muscles of the upper airway (larynx and pharynx). In cases of mild attacks, muscle tremors may be so subtle as to be detectable only by an experienced clinician performing EMG testing.

Can Symptoms of HYPP Vary in Severity?
Clinical signs of HYPP do vary widely among different horses. 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 but 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.

What is the Origin of the Genetic Defect Causing HYPP?
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.

Is HYPP Limited To A Particular Bloodline of Horses?
HYPP is associated with horses of heavy musculature, but this does not mean that all horses with well developed musculature are afflicted with the disease. The mutant gene causing HYPP presently has been identified in the descendents of the horse "Impressive." Research has not yet been performed on other bloodlines to ascertain whether the same or similar genetic mutation existing in other bloodlines also may cause HYPP. Since "Impressive" descendants are so numerous, the genetic mutation in the bloodline is widespread. Theoretically, it is possible that other mutations causing HYPP in different bloodlines may be more difficult to identify because they are not so widespread.

HYPP is unique in that it is the first equine disease in which breeding and molecular genetics have yielded a specific genetic mutation identifiable with a named bloodline. It only is a matter of time before other heritable conditions in various bloodlines likewise can be identified.

How is HYPP Inherited In Horses?
Based upon breeding trials conducted at the Equine Research Laboratory at the University of California at Davis, it was determined that HYPP is inherited as an autosomal dominant trait, which means it can occur in both males and females. The trait is inherited from generation to generation with equal frequency; it does not get "diluted" out. Breeding an affected heterozygous horse (N/H) to a normal horse (N/N) will result in approximately 50% normal offspring, while 50% will carry the defective gene (N/H). Breeding an affected homozygote (H/H) will result in all offspring carrying the gene mutation, regardless of the status of the other parent.

Normal (N/N) offspring safely can be bred, without fear of HYPP being inherited. Selective breeding to normal (N/N) horses could entirely eliminate HYPP disease. As HYPP is inherited as a dominant condition, it can and is being spread to other breeds. It is to everyone's benefit to take the necessary steps to selectively breed HYPP out of existence before it becomes so widespread that this is impossible.

Can Horses be Tested for HYPP?
A DNA test now has been developed and presently is available at UC Davis to identify horses carrying the defective gene causing HYPP. This blood test detects the presence or absence of the specific genetic mutation which has been found in the extended pedigree of "Impressive" descendants. From a whole blood sample a part of the gene coding for the horse muscle sodium channel is amplified, cut (using enzymes which cut specific DNA sequences), separated by electrophoresis, stained and read. Based on the number of DNA fragments observed, it can be determined whether the horse does not carry this specific mutation (a normal horse), or whether it carries one or two copies of this abnormal gene mutation (heterozygous or homozygous for HYPP, respectively).

How Accurate Is the DNA Blood Test for HYPP?
The test is accurate and reliable based upon research studies. The presence of the genetic mutation has been found to be associated with the disease. In a prior publication (Nature Genetics 1992, Volume 2, p.144-147), we reported upon our testing of 51 related horses which were diagnosed with HYPP based upon documented episodes of muscle fasciculations or paralysis not induced by exercise. All 51 horses were positive (for the sodium channel mutation) using this test. An equal number of related horses which were determined to be normal (based upon potassium challenge and /or free clinical signs of muscle disease) were negative for the gene mutation. We also tested 130 horses from 5 different breeds to determine if the mutation could be found with any frequency in the general horse population. The only horses to date which have shown the mutation have been descendants of "Impressive" but, theoretically, other mutations may exist for which we now have the tools to start looking. The test has proven to be reliably repeatable, as we routinely re-run samples and we have not encountered any discrepancies in results following retesting.

Are False Negative or False Positive HYPP Test Results Possible?
"False" Negatives: We have encountered a rare few horses which show various clinical signs of muscle disease but are negative for the specific gene mutation in the sodium channel. All are privately owned horses which we have been unable to study thoroughly. None of these horses has demonstrated increased blood potassium concentration in association with abnormal clinical signs. Two horses had markedly high muscle enzyme measurements, and one horse had marked muscle damage evident on muscle biopsy. We feel at this time that these horses probably have another muscle disease and not HYPP. We are sequencing the sodium channel for such horses to determine if a second mutation actually exists.

"False" Positives: We have not identified any horses which carry the gene mutation and do not have the disease. Of 142 samples we have received accompanied by clinical information, approximately 30% of the positive horses have not shown abnormal clinical signs (according to their owners). All have been young horses (aged 4 or less). None of these horses has tested negative by other means (such as response to potassium challenge or electromyography).

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