Hypokalemic periodic paralysis
Encyclopedia
Hypokalemic periodic paralysis is a rare channelopathy
characterized by muscle weakness or paralysis with a matching fall in potassium
levels in the blood
. In individuals with this mutation, attacks often begin in adolescence
and are triggered by strenuous exercise followed by rest, high carbohydrate
meals, meals with high sodium
content, sudden changes in temperature, and even excitement, noise or flashing lights. Weakness may be mild and limited to certain muscle groups, or more severe full body paralysis. Attacks may last for a few hours or persist for several days. Recovery is usually sudden when it occurs, due to release of potassium from swollen muscles as they recover. Some patients may fall into an abortive attack or develop chronic muscle weakness later in life.
Some people only develop symptoms of periodic paralysis due to hyperthyroidism
(overactive thyroid
). This entity is distinguished with thyroid function tests, and the diagnosis is instead called thyrotoxic periodic paralysis
.
testing cannot diagnose a patient unless they are in a full blown attack at the time of testing. Provoking an attack with exercise and diet then trying oral potassium can be diagnostic, but also dangerous as this form of PP has an alternate form known as hyperkalemic periodic paralysis
. The symptoms are almost the same, but the treatment is different. The old glucose
insulin
challenge is dangerous and risky to the point of being life threatening and should never be done when other options are so readily available.
People with hypokalemic periodic paralysis are aften misdiagnosed as having a conversion disorder
or hysterical paralysis since the weakenss is muscle based and doesn't correspond to nerve or spinal root distributions. The tendency of people with hypokalemic periodic paralysis to get paralyzed when epinephrine is released in "fight or flight" situations further adds to the temptation to dismiss the disorder as psychiatric.
(Diamox) or another carbonic anhydrase inhibitor, may help prevent attacks of weakness. Paralysis attacks can be managed by drinking effervescent potassium bicarbonate dissolved in water, or potassium gluconate oral solution. Treatment with potassium chloride or use of intravenous steroids can cause intensification of symptoms. Some patients find positive results with time-released potassium tablets. IV potassium is seldom justified unless the patient is unable to swallow. Daily potassium dosage may need to be much higher than for potassium replacement from simple hypokalemia: 100-150 mEqs of potassium bicarbonate is often needed to manage daily fluctuations in muscle strength and function.
Life span is expected to be normal, but attacks can drop potassium to levels low enough to cause life threatening breathing problems or heart rhythm difficulties. Patients often report muscle pain and cognitive problems during attacks. Migraines occur in up to 50% of all hypokalemic periodic paralysis patients and may include less common symptoms like phantom smells, sensitivity to light and sound or loss of words. Medical literatures states that muscle strength is normal between attacks, but patients tell a different story. "Normal" for them is not exactly the same as "normal" for everyone else.
Because there are dozens of possible gene mutations, some drugs and treatments that work fine for one patient will not work for another. For example, most patients do well on acetazolamide, but some don't. Some patients will do well with extra magnesium
(the body's natural ion channel blocker
) or fish oil
, while these same nutrients will make other patients worse. Patients and care givers should take extreme caution with all new drugs and treatment plans.
An association with KCNE3
(voltage-gated potassium channel
) has also been described, but is currently disputed, and excluded from the disease definition in OMIM.
Action potential
s from the central nervous system cause end-plate potential
s at the NMJ which causes sodium ion
s to enter and depolarise the muscle cells. This depolarisation propagates to the T-tubules where it triggers the entry of calcium ions via Cav1.1 as well as from the sarcoplasmic reticulum through the associated ryanodine receptor
RyR1. This causes contraction (tensing) of the muscle. Depolarisation of the motor end plate causes potassium ions to leave the muscle cells, repolarising the muscle and closing the calcium channels. Calcium is pumped away from the contractile apparatus and the muscle relaxes.
Mutations altering the usual structure and function of these channels therefore disrupts regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in arginine
residues making up the voltage sensor of Nav1.4. This voltage sensor comprises the S4 alpha helix
of each of the four transmembrane domains (I-IV) of the protein, and contains basic
residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In Cav1.1, mutations have also been found in domains II and IV. These mutations are loss-of-function, such that the channels cannot open normally.
In patients with mutations in SCN4A or CACNA1S, therefore, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise the muscle. As a result, the muscle cannot contract efficiently (paralysis). The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential
more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.
In contrast, hyperkalemic periodic paralysis
refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by high potassium ion concentrations.
This condition is inherited in an autosomal dominant pattern (but with a high proportion of sporadic cases), which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Channelopathy
Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired .There are a large number of distinct dysfunctions known to be caused by ion channel...
characterized by muscle weakness or paralysis with a matching fall in 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....
. In individuals with this mutation, attacks often begin in adolescence
Adolescence
Adolescence is a transitional stage of physical and mental human development generally occurring between puberty and legal adulthood , but largely characterized as beginning and ending with the teenage stage...
and are triggered by strenuous exercise followed by rest, high carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
meals, meals with high sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
content, sudden changes in temperature, and even excitement, noise or flashing lights. Weakness may be mild and limited to certain muscle groups, or more severe full body paralysis. Attacks may last for a few hours or persist for several days. Recovery is usually sudden when it occurs, due to release of potassium from swollen muscles as they recover. Some patients may fall into an abortive attack or develop chronic muscle weakness later in life.
Some people only develop symptoms of periodic paralysis due to hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(overactive thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
). This entity is distinguished with thyroid function tests, and the diagnosis is instead called thyrotoxic periodic paralysis
Thyrotoxic periodic paralysis
Thyrotoxic periodic paralysis is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism . Hypokalemia is usually present during attacks...
.
Diagnosis
Patients often report years wasted with wrong diagnosis, wrong treatments, deadends and multiple doctors, test and clinics. The CMAP (Compound Muscle Amplitude Potential) test, also called the exercise EMG or X-EMG, is diagnostic in 70-80% of cases when done correctly. Besides the patient history or a report of serum potassium low normal or low during an attack, the CMAP is the current standard for medical testing. Genetic diagnosis is often unreliable as only a few of the more common gene locations are tested, but even with more extensive testing 20-37% of people with a clinical diagnosis of hypokalemic periodic paralysis have no known mutation in the two known genes. Standard EMGElectromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
testing cannot diagnose a patient unless they are in a full blown attack at the time of testing. Provoking an attack with exercise and diet then trying oral potassium can be diagnostic, but also dangerous as this form of PP has an alternate form known as hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
. The symptoms are almost the same, but the treatment is different. The old 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...
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....
challenge is dangerous and risky to the point of being life threatening and should never be done when other options are so readily available.
People with hypokalemic periodic paralysis are aften misdiagnosed as having a conversion disorder
Conversion disorder
Conversion disorder is a condition in which patients present with neurological symptoms such as numbness, blindness, paralysis, or fits without a neurological cause. It is thought that these problems arise in response to difficulties in the patient's life, and conversion is considered a psychiatric...
or hysterical paralysis since the weakenss is muscle based and doesn't correspond to nerve or spinal root distributions. The tendency of people with hypokalemic periodic paralysis to get paralyzed when epinephrine is released in "fight or flight" situations further adds to the temptation to dismiss the disorder as psychiatric.
Treatment
Treatment of hypokalemic periodic paralysis focuses on preventing further attacks and relieving acute symptoms. Avoiding carbohydrate-rich meals and strenuous exercise, and taking acetazolamideAcetazolamide
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...
(Diamox) or another carbonic anhydrase inhibitor, may help prevent attacks of weakness. Paralysis attacks can be managed by drinking effervescent potassium bicarbonate dissolved in water, or potassium gluconate oral solution. Treatment with potassium chloride or use of intravenous steroids can cause intensification of symptoms. Some patients find positive results with time-released potassium tablets. IV potassium is seldom justified unless the patient is unable to swallow. Daily potassium dosage may need to be much higher than for potassium replacement from simple hypokalemia: 100-150 mEqs of potassium bicarbonate is often needed to manage daily fluctuations in muscle strength and function.
Prognosis
The prognosis for periodic paralysis varies. Over activity, bad diet or simply an unfortunate gene mutation can lead to a type of chronic, low level weakness called an "abortive attack," or to permanent muscle damage. Abortive attacks often respond to extra potassium, cutting carbohydrates, getting plenty of rest, increasing doses of medication and gentle daily exercise such as short walks. Permanent muscle weakness is just what it sounds like, permanent, irreparable damage to the muscles. Vacuoles and tubular aggregates form and destroy healthy muscle tissue. This type of damage should show on a muscle biopsy. Not even anabolic steroids can bring these damaged muscles back.Life span is expected to be normal, but attacks can drop potassium to levels low enough to cause life threatening breathing problems or heart rhythm difficulties. Patients often report muscle pain and cognitive problems during attacks. Migraines occur in up to 50% of all hypokalemic periodic paralysis patients and may include less common symptoms like phantom smells, sensitivity to light and sound or loss of words. Medical literatures states that muscle strength is normal between attacks, but patients tell a different story. "Normal" for them is not exactly the same as "normal" for everyone else.
Because there are dozens of possible gene mutations, some drugs and treatments that work fine for one patient will not work for another. For example, most patients do well on acetazolamide, but some don't. Some patients will do well with extra magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
(the body's natural ion channel blocker
Channel blocker
A channel blocker or ion channel blocker is a type of drug which binds inside the pore of a specific type of ion channel and blocks the flow of ions through it, resulting in an alteration of the electrochemical gradient of the cell membrane of neurons and therefore a change in...
) or fish oil
Fish oil
Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid , and docosahexaenoic acid , precursors of certain eicosanoids that are known to reduce inflammation throughout the body, and are thought to have many health benefits.Fish do not...
, while these same nutrients will make other patients worse. Patients and care givers should take extreme caution with all new drugs and treatment plans.
Genetics
Mutations in the following genes can cause hypokalemic periodic paralysis:| Type | OMIM | Gene | Locus |
|---|---|---|---|
| HOKPP1 | CACNA1S (a voltage-gated calcium channel Cav1.1 found in the transverse tubules of skeletal muscle Skeletal muscle Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle... cells) |
1q32 | |
| HOKPP2 | 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... (a voltage-gated sodium channel Nav1.4 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... ) |
17q23.1-q25.3 |
An association with KCNE3
KCNE3
Potassium voltage-gated channel, Isk-related family, member 3, also known as KCNE3, is a protein that in humans is encoded by the KCNE3 gene.- Function :...
(voltage-gated potassium channel
Voltage-gated potassium channel
Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state....
) has also been described, but is currently disputed, and excluded from the disease definition in OMIM.
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 and depolarise the muscle cells. This depolarisation propagates to the T-tubules where it triggers the entry of calcium ions via Cav1.1 as well as from the sarcoplasmic reticulum through the associated ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
RyR1. This causes contraction (tensing) of the muscle. Depolarisation of the motor end plate causes potassium ions to leave the muscle cells, repolarising the muscle and closing the calcium channels. Calcium is pumped away from the contractile apparatus and the muscle relaxes.
Mutations altering the usual structure and function of these channels therefore disrupts regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
residues making up the voltage sensor of Nav1.4. This voltage sensor comprises the S4 alpha helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
of each of the four transmembrane domains (I-IV) of the protein, and contains basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In Cav1.1, mutations have also been found in domains II and IV. These mutations are loss-of-function, such that the channels cannot open normally.
In patients with mutations in SCN4A or CACNA1S, therefore, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise the muscle. As a result, the muscle cannot contract efficiently (paralysis). The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise 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....
more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.
In contrast, hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by high potassium ion concentrations.
This condition is inherited in an autosomal dominant pattern (but with a high proportion of sporadic cases), which means one copy of the altered gene in each cell is sufficient to cause the disorder.
See also
- Hypokalemic sensory overstimulationHypokalemic sensory overstimulationHypokalemic sensory overstimulation is a form of attention deficit hyperactivity disorder that has several similarities to disorders of ion channels, in particular to the muscle disorder hypokalemic periodic paralysis.-Characterization of the disorder:...
External links
- http://www.hkpp.org/ The Periodic Paralysis Newsdesk
- http://www.periodicparalysis.org/ The Periodic Paralysis Assoc.
- http://www.mdausa.org/disease/pp.html Muscular Dystrophy Assoc. page on Periodic Paralysis
- GeneReview/NIH/UW entry on Hypokalemic Periodic Paralysis