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HYPP is a muscular disease that affects both horses and humans.
It is caused by a mutation that disrupts sodium ion channels, the gateway in the membrane of muscle cells. The channel's normal opening and closing is disrupted so that uncontrolled sodium influxes occur. These influxes alter the voltage current of muscle cells, causing uncontrollable muscle contractions. This causes potassium to leak from the inside of muscle cells into the bloodstream, thus, raising the blood potassium concentration. Uncontrolled muscle twitching, stiffness and profound muscle weakness results: affected horses can experience unpredictable attacks of paralysis which, in severe cases, can lead to collapse and sudden death.
HYPP attacks are often confused with other conditions, especially rhabdomyolysis ("tying-up" syndrome) and colic. "Tying-up" syndrome can be caused by various circumstances, including over-exertion, nutritional deficiencies and metabolic diseases. However HYPP horses usually appear normal following an attack, unlike with "tying-up" syndrome horses which tend to be stiff and painful. Also, whereas "tying-up" syndrome is usually associated with exercise, HYPP usually occurs when horses are at rest, sometimes following a stressful event such as transport, feed changes, or illness. Some owners of HYPP horses have thought their horses were experiencing colic or having a seizure, because they were down, trembling and unable to stand. HYPP has also been confused with respiratory conditions and choke because some horses breath loudly during an attack.
HYPP is most common in quarter horses and related breeds. It is thought to be derived from a single stallion, Impressive, whose presence is seen in the pedigrees of over 100,000 quarter horses. It seems to be associated with heavy muscles, a trait valued by quarter horse breeders. The disorder is inherited as a dominant condition. As such it requires only ONE PARENT to have and pass on the gene AND the disease. Breeding of an affected mare or stallion to a normal horse will result in a 50% chance of an affected foal. If two affected horses are bred together then there’s a 75% chance of the foal being affected.
Sometimes heterozygous animals (with one copy of the mutant HYPP gene) appear to be asymptomatic, the disorder perhaps showing itself later in life, for example, I read a report of one stallion and broodmare who did not show signs of the disorder until the ages of 8 and 15 years old. This can make it difficult to know whether a horse has, and will therefore pass on the mutant gene. This is expected for a widespread dominant mutation since if the health of every carrier was severely affected then few would be used for breeding and the mutation would be expected to become very rare.
The effects of HYPP aren’t usually apparent in foals unless they are homozygous for the mutant gene, when they have respiratory problems and may not survive. In horses where HYPP has been diagnosed a combination of regular exercise and a diet low in potassium can help to keep the disease under control. Potassium is an important electrolyte and is vital for the normal function of muscles, nerves and cells in general. However high concentrations of potassium are present in the normal diet of horses, with large amounts occurring in grass, hay and other forages. Normal horses usually consume an excess of potassium, which is excreted in the urine. Since potassium leaks into the blood stream of affected horses care must be taken to keep the potassium in their diet to low levels. Owners who suspect their horse of having HYPP should seek the advice of a vet, and may find it helpful to have their horses food analysed too.
It would be of benefit to try to selectively breed HYPP out of existence, before it becomes so widespread that this is impossible. To this end a DNA test was developed to identify horses carrying the defective gene. Horses that carry the mutant HYPP gene are candidates for bouts of muscle paralysis, and should therefore be put on suitable diets and exercise programmes. They would transmit the mutation to half of their foals on average and should not be used as brood mares or sires. Horses homozygous for the mutation are likely to be severely affected by HYPP and certainly should not be used for breeding purposes. Horses homozygous for the wild type non disease allele are normal and will not produce affected foals unless bred with to affected horse. If you look at adverts for quarter horses descended from Impressive (for sale or at stud) you will see that many state that the horse has been genetically tested and is HYPP negative (sometimes referred to as a “blood test” rather than a “genetic test”)!
The mutant HYPP gene occurs due to a single nucleotide change in the wild type non disease gene. This in turn leads to the replacement of the amino acid phenylalanine with leucine in the sodium channels of muscle proteins. The DNA test for HYPP detects the presence or absence of this specific mutation in the gene.
The part of the gene coding for the horse muscle sodium channel is amplified from whole blood samples using the polymerase chain reaction. The PCR fragments are then cut using host restriction enzymes, which recognise specific base sequences in DNA and cut the DNA at those sites (and those sites only). Since the mutation affects a host restriction enzyme cutting site the mutant and normal wild-type alleles yield a different number of restriction fragments.
Each of the three possible genotypes can therefore be distinguished from one another according to the number of restriction fragments observed. This is determined by subjecting the enzyme treated (“restricted”) DNA samples to electrophoresis, which separates DNA fragments according to their size.
The DNA may be visualised directly by exposing the electrophoresis gel to a DNA stain, or to a labelled probe (with homology to the restriction fragments of interest). A more permanent record may be made by transferring the DNA from the gel to a nylon or nitro-cellulose membrane – a process known as Southern blotting (named after its inventor, Edward Southern). This process basically involves placing a filter over the gel, using weights to keep the two in close contact and a glass plate to prevent desiccation. A solution is drawn up through the gel and onto a filter, bringing the DNA with it. The DNA is denatured (i.e. made single stranded) during this process and is left stuck to filter, to which it is fixed by baking.
The genotype of the horse is determined according to the number of DNA fragments observed, either directly on the electrophoresis gel, or on the filter.
It is theoretically possible that there may be other mutations causing HYPP, occurring in different bloodlines. In this case the genetic test developed may not correctly determine the chance of HYPP being transmitted by horses in those bloodlines. However the mutation present in descendants of Impressive seems to be the only cause of HYPP occurring at present. As with any genetic disorder there is also the possibility of mutations occurring “de novo” in the gametes. In this case an affected foal is possible even though neither parent is affected. However the chance of this occurring is extremely unlikely.
Rudolph, J.A., Spier, S.J., Byrns, G., Rojas, C.V., Bernoco, D. and Hoffman, E.P. 1992. Periodic paralysis in Quarter Horses: a sodium channel mutation disseminated by selective breeding. Nature Genetics 2, 144-147.