Hyperkalemic periodic paralysis - AbsoluteAstronomy.com

Hyperkalemic periodic paralysis (HYPP, HyperKPP) is a genetic disorder

Genetic disorder

A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant

Dominance relationship

Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...

disorder which affects sodium channels in muscle

Muscle

Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

cells and the ability to regulate potassium

Potassium

Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

levels in the blood

Blood

Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

. It is most commonly associated with horses, but also occurs in humans, where it may be called Gamstorp episodic adynamy. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium

Potassium

or cold, can lead to uncontrolled shaking followed by paralysis

Paralysis

Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...

. Onset in humans usually occurs in the twenties.

The mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

which causes this disorder is dominant on SCN4A with linkage to the sodium channel expressed in muscle

Muscle

. The mutation causes single amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

changes in parts of the channel which are important for inactivation. In the presence of high potassium levels, including those induced by diet, sodium channels fail to activate properly.

Equine hyperkalaemic periodic paralysis occurs in 1 in 50 quarter horses and can be traced to a single ancestor, a stallion

Stallion

A Stallion is a male horse.Stallion may also refer to:* Stallion , an American pop rock group* Stallion , a figure in the Gobot toyline* Stallion , a character in the console role-playing game series...

named Impressive

Impressive (horse)

Impressive was born an Appendix American Quarter Horse, however earned his full AQHA registration in 1971. He was the 1974 World Champion Open Aged halter stallion, the first such World Champion in his breed, despite carrying only 48 halter points in total. He is famous for his highly successful...

Symptoms and presentation

This inherited disease is characterized by violent muscle twitching and substantial muscle weakness

Muscle weakness

Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...

or paralysis

Paralysis

among affected horses. HYPP is a dominant genetic disorder

Genetic disorder

; therefore heterozygotes

Zygosity

Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...

bred to genotypically

Genotype

The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

normal horses have a statistic probability of producing clinically affected offspring 50% of the time.

Horses affected with HYPP can be treated with some possibility of reducing clinical signs, but the degree that medical treatment helps varies from horse to horse. There is no cure. Horses with HYPP often lose muscle control during an attack.

Some horses are more affected by the disease than others and some attacks will be more severe than others, even in the same horse. Symptoms of an HYPP attack may include:

Muscle trembling
Prolapse of the third eyelid - this means that you may note the third eyelid flickering across the eye, or covering more of the eye than normal
Generalized weakness
Weakness in the hind end - the horse may look as though it is 'dog-sitting'
Complete collapse
Abnormal whinny - this is because the muscles of the voicebox are affected as well as other muscles
Death - In a severe attack the diaphragm is also paralyzed and the horse can suffocate.

HYPP attacks occur randomly and can strike a horse standing calmly in a stable

Stable

A stable is a building in which livestock, especially horses, are kept. It most commonly means a building that is divided into separate stalls for individual animals...

just as easily as during exercise. Following an HYPP attack, the horse appears normal and is not in any pain which helps to distinguish it from Equine Exertional Rhabdomyolysis

Equine Exertional Rhabdomyolysis

Equine exertional rhabdomyolysis is a syndrome that damages the muscle tissue in horses...

(ER), commonly known as "Azoturia," "Monday Morning Sickness" or "tying up." Horses that are tying up usually suffer attacks in connection with exercise and may take anywhere from 12 hours to several days to recover. Muscle tissue is also damaged in an attack of ER, and the horse will be in pain during and following an attack. A blood test will reveal elevations in certain muscle enzymes after an episode of ER and so the two diseases, while superficially similar, are easily distinguished from one another in the laboratory.

Unlike with seizures, horses with HYPP are fully conscious and lucid during an attack. Horses may suffocate during an HYPP attack due to paralysis of the respiratory system. Horses which collapse during an episode are also clearly distressed as they repeatedly struggle to get to their feet again. If this occurs while the horse is being ridden or otherwise handled, the human handler or rider may be at risk of being injured by the movement of the horse.

Inheritance and prevalence

The disease is linked to the bloodline of the famous American Quarter Horse

American Quarter Horse

The American Quarter Horse is an American breed of horse that excels at sprinting short distances. Its name came from its ability to outdistance other breeds of horses in races of a quarter mile or less; some individuals have been clocked at speeds up to 55 mph...

stallion Impressive

Impressive (horse)

, who has over 55,000 living descendants . Although the disease is primarily limited to the American Quarter Horse breed and closely related breeds such as American Paint Horse

American Paint Horse

The American Paint Horse is a breed of horse that combines both the conformational characteristics of a western stock horse with a pinto spotting pattern of white and dark coat colors. Developed from a base of spotted horses with Quarter Horse and Thoroughbred bloodlines, the American Paint Horse...

s and Appaloosa

Appaloosa

The Appaloosa is a horse breed best known for its colorful leopard-spotted coat pattern. There is a wide range of body types within the breed, stemming from the influence of multiple breeds of horses throughout its history. Each horse's color pattern is genetically the result of various spotting...

s at this time, cross-breeding has begun to extend it to crossbreds recognized by other breed registries

Breed registry

A breed registry, also known as a stud book or register, in animal husbandry and the hobby of animal fancy, is an official list of animals within a specific breed whose parents are known. Animals are usually registered by their breeders when they are still young...

as well as grade horse

Grade horse

A Grade horse is a horse whose parentage is unknown, unidentifiable, or of significantly mixed breeding. This differs from purebred animals of known bloodlines and also differs from deliberately crossbred animals that are produced with an intent of either creating a new breed of horse or an animal...

s. Until the AQHA restricted the registration of animals with the condition, the spread of the disease was perpetuated by the favorable placings given to affected horses in halter

Halter (horse show)

"Halter" is a term used to describe a type of horse show class where horses are shown "in hand," meaning that they are led, not ridden, and are judged on their conformation and suitability as breeding stock...

competition at horse show

Horse show

A Horse show is a judged exhibition of horses and ponies. Many different horse breeds and equestrian disciplines hold competitions worldwide, from local to the international levels. Most horse shows run from one to three days, sometimes longer for major, all-breed events or national and...

s, because a secondary characteristic associated with N/H and H/H horses is heavy, bulky muscling that is favored by stock horse

Stock horse

A Stock horse is a horse of a type that is well suited for working with livestock, particularly cattle. Such horses are riding horsescharacterized by agility, quickness, and powerful hindquarters...

judges, a trend that began with Impressive and predates the modern understanding of the disease. Some stock horse breeds with Quarter Horse bloodlines have yet to restrict registration in order to limit the perpetuation of HYPP.

Regulation

Recently, horse organizations have begun instituting rules to attempt to eliminate this widespread disease. The American Quarter Horse Association

American Quarter Horse Association

The American Quarter Horse Association , based in Amarillo, Texas, is an international organization dedicated to the preservation, improvement and record-keeping of the American Quarter Horse. The association sanctions many competitive events and maintains the official registry...

(AQHA) now mandates testing for the "Impressive" mutation and will no longer register homozygous

Zygosity

(H/H) foals as of 2007, with discussion of heterozygous

Zygosity

(N/H) foals pending. The Appaloosa Horse Club

Appaloosa Horse Club

The Appaloosa Horse Club, located in Moscow, Idaho is dedicated to preserving and promoting the Appaloosa breed. The state of Idaho adopted the Appaloosa as its state horse in 1975. More than 630,000 Appaloosas have been registered with the Appaloosa Horse Club since its founding in 1938...

(ApHC) will no longer accept homozygous foals as of 2008. It is believed that both primary palomino

Palomino

Palomino is a coat color in horses, consisting of a gold coat and white mane and tail. Genetically, the palomino color is created by a single allele of a dilution gene called the cream gene working on a "red" base coat...

registries will exclude any foal carrying the "Impressive" mutation as of 2007. The main organization affected by HYPP that has not yet taken action is the American Paint Horse Association

American Paint Horse Association

The American Paint Horse Association is a breed registry for the American Paint Horse. It is currently headquartered in Fort Worth, Texas. It was founded in 1965 with the merging of two different color breed registries that had been formed to register pinto-colored horses of Quarter Horse bloodlines...

(APHA), although many other smaller organizations are also affected.

Disease in humans

Although much less publicized, Hyperkalemic Periodic Paralysis has also been observed in humans. In humans the disorder causes episodes of extreme muscle weakness, with attacks often beginning in infanthood. Depending on the type and severity of the HyperKPP, it can increase or stabilize until the fourth or fifth decade where attacks may cease, decline, or, depending on the type, continue on into old age. Factors that can trigger attacks include rest after exercise, potassium-rich foods, stress, fatigue, weather changes, certain pollutants (e.g.: Cigarette smoke) and periods of fasting. Muscle strength often improves between attacks, although many affected people may have increasing bouts of muscle weakness as the disorder progresses (abortive attacks). Sometimes with HyperKPP those affected may experience degrees of muscle stiffness and spasms (myotonia) in the affected muscles. This can be caused by the same things that trigger the paralysis, dependent on the type of myotonia. (See also paramyotonia).

Some people with Hyperkalemic Periodic Paralysis have increased levels of potassium in their blood (hyperkalemia

Hyperkalemia

Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

) during attacks. In other cases, attacks are associated with normal blood potassium levels (normakalemia). Ingesting potassium can trigger attacks in affected individuals, even if blood potassium levels do not rise in response.

Genetics

In 1994, researchers at the University of Pittsburgh

University of Pittsburgh

The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...

, with a grant from various horse organizations, isolated the genetic mutation responsible for the problem and developed a blood test

Blood test

A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....

for it. Using this test, horses may be identified as:

H/H, meaning they have the mutation and it is homozygous. These horses always pass on the disease.
N/H, meaning they have the mutation and it is heterozygous. These horses are affected to a lesser degree, and pass on the disease 50% of the time.
N/N, meaning they do not have the mutation and cannot pass it on, even if they are descendants of Impressive.

In humans, the most common underlying genetic cause is one of several possible point mutation

Point mutation

A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

s in the gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

SCN4A
SCN4A
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.The Nav1.4 voltage-gated sodium channel is encoded by the gene...

. This gene codes for a voltage-gated sodium channel Na_v1.4 found at the neuromuscular junction

Neuromuscular junction

A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...

. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Action potential

Action potential

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s from the central nervous system cause end-plate potential

End-plate potential

End plate potentials are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance...

s at the NMJ which causes sodium ion

Ion

An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...

s to enter via Na_v1.4 and depolarise the muscle cells. This depolarisation triggers the entry of calcium from the sarcoplasmic reticulum to cause contraction (tensing) of the muscle. To prevent the muscle from being perpetually contracted, the channel contains a fast inactivation gate which plugs the sodium pore very quickly after it opens. This prevents further entry of sodium. In time, potassium ions will leave the muscle cells, repolarising the cells and causing the pumping of calcium away from the contractile apparatus to relax the muscle.

Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Na_v1.4. Mutations have also been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.

In patients with mutations in SCN4A, therefore, the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarised, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell in order to repolarise it to the resting potential

Resting potential

The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential....

, and this further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.

In the case of the horse Impressive

Impressive (horse)

, the muscles were always contracting which was equivalent to a constant work-out. Thus the development of an impressive musculature.

In contrast to HyperKPP, Hypokalemic Periodic Paralysis

Hypokalemic periodic paralysis

Hypokalemic periodic paralysis is a rare channelopathy characterized by muscle weakness or paralysis with a matching fall in potassium levels in the blood...

(noted in humans) refers to loss-of-function mutations in channels that prevent muscle depolarisation and therefore are aggravated by low potassium ion concentrations.

Treatment

Glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

or other carbohydrates can be given during an attack and may reduce the severity.
Intravenous calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

decreases activity of sodium channels. It may stop sudden attacks.
Diuretics such as furosemide
Furosemide
Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...

may be needed to stop sudden attacks. acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...

and thiazide diuretics such as chlorothiazide
Chlorothiazide
Chlorothiazide sodium is a diuretic used within the hospital setting or for personal use to manage excess fluid associated with congestive heart failure. It is also used as an antihypertensive....

are also effective.
Intravenous glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

stimulates potassium uptake into the cell by the Na-K ATPase and may reduce weakness without a loss of total body potassium.
A high-carbohydrate diet may be recommended.
Avoidance of other known attack triggers.

External links

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