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Myotonia | |
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Specialty | Neurology, neuromuscular medicine, medical genetics ![]() |
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation (prolonged contraction) of the skeletal muscles after voluntary contraction or electrical stimulation, and the muscle shows an abnormal EMG. [1] [2]
Myotonia is the defining symptom of many channelopathies (diseases of ion channel transport) such as myotonia congenita, paramyotonia congenita and myotonic dystrophy. [3] [4]
Brody disease (a disease of ion pump transport) has symptoms similar to myotonia congenita, however, the delayed muscle relaxation is pseudo-myotonia as the EMG is normal. [5] Other diseases that exhibit pseudo-myotonia are myositis, glycogen storage diseases, hyperkalemic periodic paralysis, root disease, anterior horn cell disorders, Isaacs syndrome, and Hoffmann syndrome. [2] [6] [7]
Generally, repeated contraction of the muscle can alleviate the myotonia and relax the muscles thus improving the condition, however, this is not the case in paramyotonia congenita. This phenomenon is known as the "warm-up" reflex [8] and is not to be confused with warming up before exercise, though they may appear similar. Individuals with the disorder may have trouble releasing their grip on objects or may have difficulty rising from a sitting position and a stiff, awkward gait.
Myotonia can affect all muscle groups; however, the pattern of affected muscles can vary depending on the specific disorder involved.
People with disorders involving myotonia can have life-threatening reactions to certain anaesthetics called anaesthesia-induced rhabdomyolysis.
Myotonia may present in the following diseases, with different causes related to the ion channels in the skeletal muscle fiber membrane (sarcolemma).[ citation needed ]
Two documented types, DM1 and DM2 exist. In myotonic dystrophy a nucleotide expansion of either of two genes, related to type of disease, results in failure of correct expression (splicing of the mRNA) of the ClC-1 ion channel, due to accumulation of RNA in the cytosol of the cell. [9] [10] The ClC-1 ion channel is responsible for the major part of chloride conductance in the skeletal muscle cell, [11] and lack of sufficient chloride conductance may result in myotonia, (see myotonia congenita). When the splicing of the mRNA was corrected in vitro, ClC-1 channel function was greatly improved and myotonia was abolished. [12]
(Congenital myotonia) of which two types called Becker's disease and Thomsen's disease exist. [13] Both diseases are caused by mutations in the gene CLCN1 encoding the ClC-1 ion channel. More than 130 different mutations exist in total, and a large phenotypic variation is therefore present in this disease. [14] The mutations are loss-of-function mutations that render the ClC-1 ion channel dysfunctional to varying degrees, with reduced chloride conductance as a result. Reduced chloride conductance may result in myotonia, due to accumulation of potassium in the transverse-tubules in skeletal muscle (see myotonia congenita). This is the same genetic disease that makes certain strains of North American goats faint when scared.[ citation needed ]
Symptoms of myotonia (documented in myotonia congenita) are more frequently experienced in women during pregnancy. [15]
Myotonia could be caused by genetic mutations in the SCN4A gene that encodes the skeletal muscle sodium channel subtype 4 (Nav1.4). Some studies have suggested that changes in physiological pH could have modulatory effects on Nav1.4 sodium channels, which could have manifestations in myotonic phenotypes. [16]
This disease results from mutation in the SCN4A gene encoding the voltage-gated sodium channel Nav1.4 in skeletal muscle fiber membrane. Mutations may alter the kinetics of the channel, such that the channel fails to inactivate properly, thus allowing spontaneous action potentials to occur after voluntary activity has terminated, prolonging relaxation of the muscle, or can result in paralysis if the relaxation is severely prolonged (see SCN4A). This inability of muscles to relax worsening with exercise is often termed "paradoxical myotonia." Paramyotonia also frequently triggered by exercise, cold, and potassium. [17]
Potassium-aggravated myotonia (PAM) results from in a mututation of the SCN4A gene that causes skeletal muscles to be unable to relax after contracting in bouts, typically following the consumption of potassium rich food. [18] It is debated if potassium-aggravated myotonia is a distinct disease from Paramyotonia Congenita, and recent academic papers have classified it both ways. [19] [20]
Also known as HyperKPP. Similar to Paramyotonia Congenita, where potassium exacerbates myotonia in many phenotypes, Hyperkalemic Periodic Paralysis is another disorder of the SCN4A gene where high blood potassium levels result in muscle weakness, muscle paralysis (through weakness or through over excitation preventing movement), and sometimes myotonia. Many phenotypes of HyperKPP result in issues regulating blood potassium levels, often cause it to be high or causing hyperkalemia, further exacerbating the condition.[ citation needed ]
Also known as HypoKPP. Similar to HyperKPP above, except that it's triggered by (and often causes) low potassium levels and hypokalemia. It too can result in myotonia, in addition to weakness and paralysis (from both lack of and excess signal to muscles). It also has been found to occur due to gene mutations other than SCN4A.[ citation needed ]
Neuromyotonia (also known as Isaac's Syndrome or NMT) causes peripheral nerve hyperexcitability that causes spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. 100-200 cases have been reported. [21]
Myotonia occurs also in certain types of limb-girdle muscular dystrophies, myofibrillary myopathies, distal myopathies, and inclusion body myopathies. [22] Other channelopathies may cause it as well. [3] It is also associated with Schwartz–Jampel syndrome. [23]
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 ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.
Hyperkalemic periodic paralysis 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 or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.
Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.
The myotonic goat or Tennessee fainting goat is an American breed of goat. It is characterised by myotonia congenita, a hereditary condition that may cause it to stiffen or fall over when excited or startled. It may also be known as the fainting goat, falling goat, stiff-legged goat or nervous goat, or as the Tennessee wooden-leg goat. Four goats of this type were brought to Tennessee in the 1880s.
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.
Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes. Each type of channel is a multimeric complex of subunits encoded by a number of genes. Depending where the mutation occurs it may affect the gating, conductance, ion selectivity, or signal transduction of the channel.
Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.
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 mechanism of these diseases are malfunctions in the ion channels in skeletal muscle cell membranes that allow electrically charged ions to leak in or out of the muscle cell, causing the cell to depolarize and become unable to move.
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. In individuals with this mutation, attacks sometimes begin in adolescence and most commonly occur with individual triggers such as rest after strenuous exercise, high carbohydrate meals, meals with high sodium content, sudden changes in temperature, and even excitement, noise, flashing lights, cold temperatures and stress. Weakness may be mild and limited to certain muscle groups, or more severe full-body paralysis. During an attack, reflexes may be decreased or absent. 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.
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, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.
Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intellectual disability and heart conduction problems. In men, there may be early balding and infertility. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.
Potassium-aggravated myotonia is a rare genetic disorder that affects skeletal muscle. Beginning in childhood or adolescence, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness, often painful, that worsens after exercise and may be aggravated by eating potassium-rich foods such as bananas and potatoes. Stiffness occurs in skeletal muscles throughout the body. Potassium-aggravated myotonia ranges in severity from mild episodes of muscle stiffness to severe, disabling disease with frequent attacks. Potassium-aggravated myotonia may, in some cases, also cause paradoxical myotonia, in which myotonia becomes more severe at the time of movement instead of after movement has ceased. Unlike some other forms of myotonia, potassium-aggravated myotonia is not associated with episodes of muscle weakness.
The CLCN family of voltage-dependent chloride channel genes comprises nine members which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).
Thyrotoxic periodic paralysis (TPP) is a rare condition featuring attacks of muscle weakness in the presence of hyperthyroidism. Hypokalemia is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to abnormal heart rhythms. If untreated, it is typically recurrent in nature.
Chloride channel openers refer to a specific category of drugs designed to modulate chloride channels in the human body. Chloride channels are anion-selective channels which are involved in a wide variety of physiological functions and processes such as the regulation of neuroexcitation, transepithelial salt transport, and smooth muscle contraction. Due to their distribution throughout the body, diversity, functionality, and associated pathology, chloride channels represent an ideal target for the development of channel modulating drugs such as chloride channel openers.
Louis Ptáček is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. He was also an HHMI investigator from 1997 to 2018. His chief areas of research include the understanding of inherited Mendelian disorders and circadian rhythm genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders, which include identifying and characterizing the genes responsible for neurological variations.
Hyperkalemic periodic paralysis is a genetic disorder that occurs in horses. It is also known as Impressive syndrome, after an index case in a horse named Impressive. It 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 or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis.
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