Equine Hyperkalaemic Periodic Paralysis Biology Essay

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Introduction. Equine Hyperkalemic Periodic Paralysis (HYPP) is a hereditary, dominant, autosomal muscle disease caused by a missense point mutation in the α-subunit of the (SCN4A) gene of skeletal muscle voltage-gated sodium channel (VGSC)1-11. The disease principally affects Quarter Horses(but also American Paint Horses and Appaloosas) and is believed to be confined to descendants of a single quarter horse stallion - Impressive10-15. It was recently estimated that around 4% of the Quarter horse population could be affected1. HYPP is characterized by sporadic attacks of muscle tremors, weakness and/or collapse9. Plasma potassium concentrations are usually elevated during episodes2, 8. Affected horses appear clinically normal between episodes. HYPP in horses is homologous to the human genetic disorder also known as Adynamia Episodica Hereditaria that was first reported in the mid-1950s (4,5,16), however it does seem to be more serious in horses as a few have died during attacks.8; 10; 17. It was first reported in horses in the mid 1980s18,19.

Pathophysiology. Several studies in early 1990s linked this disease to a defect in the voltage gated sodium channel2, 20. Subsequent studies lead to the localization of the defect to a single point mutation (cytosine to guanine) in the cytoplasmic end of S3 in domain IV of the α-subunit of the SCN4A gene3, 21, 22. The SCN4A gene was mapped to chromosome 11 at 14247699-142752891. This change in a single base pair results in substitution of the amino acid phenylalanine for leucine at amino acid 1419 (F1419L)10, 21, 23, 24. VGSCs are protein complexes widely expressed in nerve and muscle tissue composed of a principal subunit which forms the ion pore through which ions can travel creating an electrical current that allow the propagation of muscle action potentials in excitable cells 22, 25-30. During the initial phase of the action potential, the typical resting VGSC activates (opens) in response to membrane depolarization resulting in a rapid increase in Na+ permeability due to favourable electrical and chemical gradients and inactivates within a few milliseconds following repolarization (6,22, 27,28, 31,32).. The α-subunit folds into four homologous domains (I- IV) each with six transmembrane α-helical segments (S1- S6)33-38. The voltage sensor is located in the S4 segment of each domain and contains positively charged amino-acid (originating from arginine or lysine) residues and plays an important role in channel activation35,37. The cytoplasmic linker that connects domains III and IV serves as an inactivation gate binding to the intracellular pore of the channel to inactivate it25,32. One study found that the deletion of or mutation of amino acids lead to the elimination of fast inactivation in the channel39. A hydrophobic triplet of amino acid residues (isoleucine-phenylalanine-methionine) form the inactivation gate receptor and is critical for fast inactivation25,32. In horses with HYPP, a permanent defect in ion transport across the skeletal muscle cell membrane because of the phenylalanine to leucine substitution results in a failure of sodium channels to inactivate when K+ concentrations are increased. This causes sodium to leak into muscle cells through the defective pores and a reduction of the electrical gradient across the membrane which in turn leads an increase in the concentration of extracellular K+ causing the increase of muscle cell excitability and persistent depolarization6,7,30-34. Potassium, too, plays a part in the defect because it is the main intracellular ion in the body and its levels are vital to normal homeostasis. Potassium concentrations are also very important for maintaining resting membrane potential and neuromuscular as well as having an important role in the synthesis of DNA and proteins40.

Symptoms. This disease exhibits incomplete penetrance, meaning horses with the disease show substantial clinical variability. Some horses will display no symptoms at all while others will display severe episodes of periodic paralysis and some horses have died usually from cardiac arrest and/or respiratory failure10,19,41,42. The is also a large variability in the duration of episodes that could last anywhere from 15-90 minutes18 and could last for much longer if not treated34. The onset of episodes is very unpredictable. Episodes may begin with a brief period of myotonia (muscle stiffness), with some horses showing prolapse of the third eyelid, hypotonia (twitching or delayed relaxation of muscles) and muscle fasciculations that are noticed initially in the flanks, neck and shoulders. Weakness that may manifest as swaying and staggering is also a common sign1,5,6,7,10,18,21,42-44. In more severe cases horses collapse into involuntary recumbency, Respiratory stridor due to paralysis of upper respiratory muscles, pharyngeal collapse, and laryngeal paralysis is mainly seen in foals that are homozygous (H/H) for HYPP. Although foals heterozygous (N/H) have been known to display similar signs they are usually less severely affected45,46. Factors implicated in the triggering of HYPP episodes include sudden dietry changes, diets that contain >1.1% of potassium in the total daily intake 1,5,42-44,47, local anesthetic47,48 which act by blocking Na flux through VGSCs49, fasting and physical stress during weaning or in transport. The factor(s) responsible for variability in symptoms between HYPP affected horses is not yet known. However some suggestions have included management factors. interesting study50 found that asymptomatic horses had more normal sodium channel mRNA, while symptomatic horses had more mutant mRNA suggesting a molecular mechanism behind clinical variability. However, a number of limitations in this study have cast doubt over the results. Firstly, the sample number was small (n=28), and there was also high experimental errors for at least two of the horses and there was a significant overlap of values between horses.

Diagnosis. Initially, diagnosis can be based on descendants of Impressive on the sire's or dam's side together with clinical signs such as sporadic attacks of muscle tremors, weakness, or recumbency are strongly suggestive of HYPP. Plasma potassium concentrations are usually elevated during and for around one to two hours after the

episodes in affected horses10 but that is not always the case as some studies have found horses to have normal plasma potassium concentrations even in severe cases47,51. Although these are strong indications of HYPP, they are not definitive. Prior to the development of the DNA test, provocative tests were conducted for diagnostic reasons. One such test was the potassium chloride challenge test which involved fasting of horses for 12 hours followed by oral administration of (88 to 160 mg/kg) potassium chloride (KCl) mixed in water. This induces symptoms in most HYPP affected horses usually within two to three hours due to the increase in extracellular K+ concentration52-54. Because of the small dose that is administered, normal horses are unaffected by the test. This test, however, is very time consuming as it involves the close monitoring of horses for several hours. Another problem with this test is that the dose of KCL needs to be increased until symptoms appear which increases the risk of inducing a severe attack and has in some cases proved to be fatal53. Electromyography (EMG) has also been used as a diagnostic aid for equine HYPP47,53 by detecting abnormal EMG signals due to increased muscular contraction. High-frequency myotonic discharges and doublets are the most sensitive and specific for HYPP47. One study found that EMG in combination with potassium challenge testing gave the most accurate diagnosis53. Although EMG is a useful, fast and safe diagnostic tool it has been far superseded in accuracy by gene probe for the DNA that codes for the defective sodium channel which has proved to be the most sensitive and specific test for HYPP to date54.

Treatment. For emergency treatment during a mild attack, light exercise either by walking or lunging is usually recommended in order to stimulate the secretion of adrenaline which causes an increase in the Na+/K+ pump activity that helps replace potassium inside cells. Oral administration of acetazolamide (2.2- 4.4 mg/kg) two to three times a day. Acetazolamide is a mild K+ wasting diuretic that increases K+ excretion from the kidney, stabilises blood glucose and K+ and works by decreasing the reabsorption of sodium, chloride and bicarbonate in the proximal tubules. It is mainly used in treating humans with HYPP but has been found to be effective for treating horses as well but pharmacokinetics of acetazolamide has not been studied in horses. The most commonly used method for treating severe episodes of HYPP is the intravenous administration of 100 ml 23% calcium gluconate diluted in 1 L of 5% dextrose or saline alone or combined with sodium bicarbonate. Phenytoin, an anticonvulsant, has been used effectively in treating a wide range of skeletal muscle disorders It decreases or eliminates the signs of HYPP by reducing sodium and calcium currents in cells55,56.

Management. The most important aspect of long term management of horses with HYPP is dietary management. A study by Reynolds II + III found that clinical signs were induced when HYPP affected horses were fed higher potassium diets. Horses did not show any symptoms when diet A (containing 1.1% potassium in total rations) was fed. However, when dietary potassium was increased to 1.9% (diet B) and 2.9% (diet C) horses showed frequent clinical signs along with an increase in plasma K+ concentrations which resulted from potassium absorption from the rations. HYPP affected horses should therefore be fed diets containing 1.1% K+ or less. Horses should also be allowed free pasture or paddock exercise41.

Selection. Before HYPP was discovered in horses a Quarter Horse stallion named Impressive has had a tremendous amount of success winning all the competitions he was entered into. Because of his success and expression of a super-muscular phenotype, Impressive was very sought after by Quarter Horse, Appaloosas and Paints breeders. By the time HYPP was linked to Impressive 20 years ago he had already had a profound impact on the genetics of Quarter Horse breed and has shown no sign of slowing down. It was initially hoped that with the increasing awareness of the disease and the development of genetic testing for HYPP breeders would be reluctant to breed their horse with one which they knew was positive for HYPP. However, that has not been the case and it seems clear that HYPP is being actively selected for due to high success of these horses. It was recently estimated that around 4% of the Quarter horse population could be affected with around 366,000 of Impressives' offspring registered with the American Quarter Horse Association (AQHA) and five million around the world21. The AQHA has played a major role in terms of funding scientific studies into equine HYPP. However their role in trying to limit or eliminate this disease is rather questionable. It almost seems as if the AQHA is embracing the disease and is trying to work with it rather than against it. Their decision to deny registration to homozygous affected foals born in 2007 or later only means that these horses would not be able to compete. Breeding two heterozygous horses would still mean a 25% chance of a homozygous foal being produced. An estimated 10% of most severly affected horses have died59.

Conclusion. Although there is no scientific evidence to suggest that HYPP horses' muscles are different than normal horses, the huge success of Impressive and his descendants is undeniable. As human beings, breeders are driven by success and that can sometimes lead to them turning a blind eye to whatever side effects that success might bring with it. The breeders main argument is that HYPP is a perfectly manageable disease and most horses lead a very successful life healthy lives proper management and medication. Although this is somewhat true, the other side of the coin still exists where some horses suffer a great deal and end up dying as a direct result of this disease. This raises serious ethical concerns If HYPP is to be eliminated, firm action by the AQHA is necessary as breeders will not stop breeding HYPP affected horses if there is nothing to prevent them. A great deal of information is now known

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