Periodic paralysis is a group of rare
genetic disease
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s that lead to weakness or paralysis from common triggers such as cold, heat, high
carbohydrate
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...
meals, not eating, stress or excitement and physical activity of any kind. The underlying mechanism of these diseases are malfunctions in the
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
s that allow electrically charged ions to leak in or out of the muscle cell, causing the cell to depolarize and become unable to move.
The symptoms of periodic paralysis can also be caused by
hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...
, and are then labeled
thyrotoxic periodic paralysis; however, if this is the underlying condition there are likely to be other characteristic manifestations, enabling a correct diagnosis.
Types
Periodic paralysis is an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...
with considerable variation in
penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
, leading to a spectrum of familial
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
s (only one parent needs to carry the gene mutation to affect the children, but not all family members who share the gene are affected to the same degree). Specific diseases include:
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Hypokalemic periodic paralysis
Hypokalemic periodic paralysis (hypoKPP), also known as familial hypokalemic periodic paralysis (FHPP), is a rare, autosomal dominant channelopathy characterized by muscle weakness or paralysis when there is a fall in potassium levels in the blood ...
(), where potassium leaks into the muscle cells from the bloodstream.
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Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis (HYPP, HyperKPP) is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability ...
(), where potassium leaks out of the cells into the bloodstream.
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Paramyotonia congenita
Paramyotonia congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, ...
(), a form which often accompanies hyperkalemic periodic paralysis, but may present alone. The primary symptom of paramyotonia congenita is muscle contracture which develops during exercise or activity. Paramyotonia congenita attacks may also be triggered by a low level of potassium in the bloodstream. This means people with both hyperkalemic periodic paralysis and paramyotonia congenita can have attacks with fluctuations of potassium up or down.
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Andersen-Tawil syndrome (), a form of periodic paralysis that includes significant heart rhythm problems, fainting and risk of sudden death. Potassium levels may be low, high, or normal during attacks of ATS. Patients with ATS may also have skeletal abnormalities like
scoliosis
Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
(curvature of the spine), webbing between the second and third toes or fingers (
syndactyly
Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, ''syn'' 'together' and δάκ ...
), crooked fingers (clinodactyly), a small jaw (
micrognathia
Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorm ...
) and low-set ears. Patients need to have another form of periodic paralysis to have the Andersen-Tawil. If a patient has hypo or hyper periodic paralysis they have a 50% chance of getting Andersen-Tawil. They just have to have the gene that causes it. This is a rare occurrence of having this. Only around 100 people in the world are recorded to have it.
Cause
One of the most common descriptions of periodic paralysis are episodic attacks of muscle weakness, which are commonly associated with serum potassium levels. Physical activity and diet content (carbohydrates) have been identified as PP triggers. Unlike non-dystrophic myotonias, the periodic paralysis phenotype is triggered after resting following exercise. Voltage-gated sodium channel (Nav1.4) mutations are among the key causes behind periodic paralysis.
Hyper-kalemic PP (hyperPP) is identified with high extracellular potassium levels which are typically greater than 5 mM during attacks; however, HyperPP attacks can also take place without rise in potassium concentrations. HyperPP has a prevalence rate of 1/100,000. Patients become symptomatic around the age of 10. The weakness attacks in hyperPP are relatively short lasting, and range from minutes to hours. The attacks can happen upwards of ten times per month.
Hypo-kalemic PP (hypoPP) is associated with low potassium levels. The onset of hypoPP occurs between the ages of 15 and 35. The prevalence of hypoPP is estimated to 1/100,000. HypoPP can be triggered by many external factors such as stress, high-sugar diet, and rest after exercise. During hypoPP attacks, the serum potassium concentrations can drop to less than 3 mM. Furthermore, hypoPP attacks are considerably longer lasting than hyperPP. As exercise is a trigger for periodic paralysis attacks, recently there is more research going into the physiological changes that accompany exercise including changes in blood pH.
Diagnosis
This disease is unusually difficult to diagnose. Patients often report years of wrong diagnosis and treatments that made them worse instead of better. Part of this may be that
migraines are present in up to 50% of patients and can cause a confusing array of symptoms including headaches, speech difficulties and visual, auditory or sensory auras.
DNA testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
is available for only a half dozen common gene mutations, while dozens of known mutations are possible but are not routinely tested. Electromyography (EMG) findings are not specific but the McManis Protocol, also called the Compound Muscle Amplitude Potential test (CMAP) can be used by a skilled neurologist capable of utilizing the EMG, which can give assistance in diagnosing several of these PP disorders. The old glucose/insulin provocative testing can cause life-threatening symptoms and should not be used.
Also of note is that potassium levels do ''not'' have to range outside of normal limits to cause serious, even life-threatening paralysis. These diseases are ''not'' the same as having a very low level of potassium (
hypokalemia
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...
) or high potassium (
hyperkalemia
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...
) and must not be treated as such. The total body store of potassium is usually normal; it is just in the wrong place.
Treatment
Treatment of the periodic paralyses may include
carbonic anhydrase
The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). The active site ...
inhibitors (such as
acetazolamide
Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), urine alkalin ...
, methazolamide or
dichlorphenamide
Diclofenamide (or dichlorphenamide) is a sulfonamide and a carbonic anhydrase inhibitor of the ''meta''-disulfamoylbenzene class. Dichlorphenamide as a carbonic anhydrase inhibitor is used for the treatment of acute angle closure glaucoma. While ...
), taking supplemental oral
potassium chloride
Potassium chloride (KCl, or potassium salt) is a metal halide salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous crystal appearance. The solid dissolves readily in water, and its solutions have a salt ...
and a
potassium-sparing diuretic
Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone ...
(for hypos) or avoiding potassium (for hypers),
thiazide
Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first ...
diuretics
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
to increase the amount of potassium excreted by the kidneys (for hypers), and significant lifestyle changes including tightly controlled levels of exercise or activity. However, treatment should be tailored to the particular type of periodic paralysis.
Treatment of periodic paralysis in Andersen-Tawil syndrome is similar to that for other types. However,
pacemaker
An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eith ...
insertion or an
implantable cardioverter-defibrillator
An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion and pacing of the ...
may be required to control cardiac symptoms.
Prognosis
While the disability can range from minor, occasional weakness to permanent muscle damage, inability to hold a normal job and use of a powerchair, most people function fairly well with drugs and lifestyle changes.
References
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External links
NIH information page on periodic paralysis
{{Muscular Dystrophy
Myoneural junction and neuromuscular diseases
Periodic Paralysis
Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind. The underlying mechanis ...
Rare diseases