Myotonia congenita

Last updated
Myotonia congenita
Other namesCongenital myotonia, Thomsen syndrome, Becker syndrome
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Delayed relaxation of muscles, falls, difficulty swallowing
Usual onsetChildhood
TypesAutosomal dominant (Thomsen disease), autosomal recessive (Becker disease)
CausesGenetic, CLCN1 mutations
Diagnostic method Clinical, genetic testing
Differential diagnosis Myotonic dystrophy, Paramyotonia congenita
TreatmentPhysiotherapy, medication
Medication quinine, phenytoin, carbamazepine, mexiletine
Frequency1 in 10,000 (Finland) - 1 in 100,000 (worldwide)

Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles (muscles used for movement). 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. [1] 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 (from certain genetic mutations), 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).

Contents

Symptoms and signs

The prolonged muscle contractions, which occur most commonly in the leg muscles in recessive mutations, and more commonly in the hands, face, and eyelids in dominant mutations, [2] are often enhanced by inactivity, and in some forms are relieved by repetitive movement known as "the warm-up effect". This effect often diminishes quickly with rest. Some individuals with myotonia congenita are prone to falling as a result of hasty movements or an inability to stabilize themselves after a loss of balance. During a fall, a person with myotonia congenita may experience partial or complete rigid paralysis that will quickly resolve once the event is over. However, a fall into cold water may render the person unable to move for the duration of submergence. As with myotonic goats, children are more prone to falling than adults, due to their impulsivity.[ citation needed ]

The two major types of myotonia congenita are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease, and causes more severe myotonia, muscle stiffness and transient weakness. [3] Although myotonia in itself is not normally associated with pain, cramps or myalgia may develop. [3] People with Becker disease often experience temporary attacks of muscle weakness, particularly in the arms and hands, brought on by movement after periods of rest. They may also develop mild, permanent muscle weakness over time. [4] This muscle weakness is not observed in people with Thomsen disease. However, in recent times, as more of the individual mutations that cause myotonia congenita are identified, these limited disease classifications are becoming less widely used.[ citation needed ]

Early symptoms in a child may include:[ citation needed ]

Possible complications may include:[ citation needed ]

Phenotypic variability

Both Thomsen and Becker myotonia have high phenotype variability. Severity of symptoms can vary greatly between individuals and throughout the lives of the individuals themselves. This may be partly because there are over 130 currently known different mutations that can cause the disorder, each with their own specifics, and also because myotonia congenita is an ion channel disorder, and ion channels are sensitive to internal and external environmental factors. It has been shown that pregnancy [6] and the use of diuretics [7] aggravate myotonia, and both these conditions are linked to the loss of divalent cations such as magnesium and calcium. [8] It has further been shown that in chemically-induced myotonia in isolated rat muscle, myotonia could be dampened by increasing the magnesium and calcium content of the extracellular medium. [9] This has also been shown for isolated human muscle. [10]

Adrenaline/epinephrine is well known to make myotonia worse in most individuals with the disorder, and a person with myotonia congenita may experience a sudden increase in difficulty with mobility in a particularly stressful situation during which adrenaline is released.[ citation needed ]

Due to the invisible nature of the disorder, the fact that those with myotonia congenita often appear very fit and able bodied, the general lack of knowledge about the disorder by the general and medical community, and often by the individual themselves, and the potential for inconsistency with the symptoms, many people with myotonia congenita have experienced a degree of social persecution at one time or another because of the effects of their disorder.[ citation needed ]

The warm-up phenomenon

This phenomenon was described along with the disease by Thomsen in 1876 but its etiology remains unclear.[ citation needed ]

Patients report that myotonia congenita may present itself in the following ways (this is from first hand experience). If the person is sedentary and then decides to walk up a set of stairs, by the third or fourth step their leg muscles begin to stiffen significantly, requiring them to slow down almost to a complete stop. But as the muscles loosen up, a few steps later, they can once again begin to climb the steps at a normal pace. If this person plays any kind of a sport, a good warm-up is mandatory. Otherwise if they need to quickly and intensively use their muscles, such as in a sprint race or a basketball game, their muscles will freeze up, causing them to slow down or almost come to a complete stop. But once the muscles are warmed up, they can once again function normally. This can happen in various muscles, even in muscles such as the tongue. For example, if a person has not spoken for awhile and then wants to speak, their tongue may be stiff at first causing the words to come out a little garbled, but after a few seconds of trying to speak, the tongue muscle will loosen up and then they can speak normally for the remainder of the time that they are conversing.[ citation needed ]

Patients report that repeated contraction of muscle alleviates present myotonia with each contraction, such that myotonia is almost absent after a few contractions of the same muscle. The effect lasts about five minutes. [11] There have been several proposed mechanisms for this phenomenon, but none have been demonstrated conclusively; one hypothesis is that the Na+/K+-ATPase is stimulated during the myotonic activity by increased intracellular Na+ in the cytosol of the muscle cell, increasing the activity of the Na+/K+-ATPase. However, in experiments with patients where the Na+/K+-ATPase had been blocked in the underarm by infusion of the Na+/K+-ATPase-blocker Ouabain, no effect on warm-up was observed. [12] Another hypothesis states that the few remaining functional chloride channels in muscle may become more active with increased muscle activity. [13]

It has been proposed that inactivation of sodium channel protein type 4 subunit alpha, residing in skeletal muscle, could play an important role in the warm-up phenomenon. In particular, slow inactivation of the channel is believed to have a spatial and temporal extent that is correlated to warm-up and therefore may provide a plausible cause. [14]

Causes

The disorder is caused by mutations in part of a gene (CLCN1) encoding the ClC-1 chloride channel, resulting in muscle fiber membranes having an unusually exaggerated response to stimulation (hyperexcitability).[ citation needed ]

Three cases have been reported who were diagnosed with Thomsen's myotonia and proved on genetic testing not to have mutations in the chloride gene but rather in the alpha-subunit of the voltage gated sodium channel (SCN4A). [15] Like chloride channel mutations, patients with sodium channel mutations may have a very varied phenotype, making a diagnosis more difficult.[ citation needed ]

Mechanisms

Myotonia congenita is caused in humans by loss-of-function mutations in the gene CLCN1 . This is the gene encoding the protein CLCN1, that forms the ClC-1 chloride channel, critical for the normal function of skeletal muscle cells. This gene is also associated with the condition in horses, goats, and dogs. In short, in lack of sufficient functional chloride channels, the muscle fiber membrane becomes hyper-excitable and continues to be electrically active (firing action potentials) when stimulated, for longer periods of time, than a normal muscle fiber. This results in prolonged contraction/delayed relaxation of the muscle.[ citation needed ]

The dysfunctional Cl channels are located in the muscle fiber membrane and do not affect the motor nerve innervating the muscle. However, many studies have shown that denervation of muscle fibers alter the resting membrane conductance, but whether this affects myotonia in the muscle has been subject to heavy debate, and results from experiments are inconclusive. [16]

In skeletal muscle fibers, a large transverse tubule system with a high surface-area to volume ratio exists. The onset of skeletal muscle activity is associated with the initiation and propagation of action potentials again associated with an efflux of K+ to the extracellular fluid and transverse tubule system. When many action potentials are elicited subsequently more K+ is expelled from the cell into the transverse tubular system. As K+ accumulates in the transverse tubular system the equilibrium potential for K+ (EK+) normally around -80 mV, becomes more depolarized (depolarization), according to the Nernst equation. In skeletal muscle fibers the equilibrium potential for Cl is around -80 mV, equal to that of K+ at rest. Cl moves towards its equilibrium potential around -80 mV, while potassium moves towards its equilibrium potential more depolarized than -80 mV during activity. This results in a slightly more depolarized membrane potential of the fiber during repeated action potentials, see Goldman equation. The Na+ conductance is only elevated shortly compared to the K+ conductance during each action potential, which is why K+ largely determines the membrane potential (Cl is passively distributed during rest). In the case of myotonia congenita, the chloride channels that allow Cl to move across the membrane towards its equilibrium potential are defective, thus K+ is the only ion determining the membrane potential, and as more and more K+ accumulates in the transverse tubular system with each subsequent action potential the fiber depolarizes until the membrane potential comes close enough to the action potential threshold for spontaneous activity to ensue [17] Spontaneous action potentials can arise for several seconds, leading to the delayed relaxation that is the hallmark of myotonia. Cessation of spontaneous activity is associated with sodium channel inactivation (Nav1.4).[ citation needed ]

Diagnosis

Types

Two types of myotonia congenita exist, an autosomal dominant form and an autosomal recessive form. Autosomal dominant myotonia congenita (OMIM #160800) is also called Thomsen disease, after Danish/German physician Asmus Julius Thomas Thomsen (1815–1896), who himself had the disease and who wrote the first description of it in the medical literature (in 1876). [18] Autosomal recessive myotonia congenita (OMIM #255700) is also called generalized myotonia, recessive generalized myotonia (RGM), Becker disease, and Becker myotonia, after the German professor Peter Emil Becker, who discovered its recessive nature. [19]

The term congenital in its sense of "clinically apparent from birth" applies only to Thomsen disease, as the clinical onset of Becker myotonia may be delayed up to the age of 4 to 6 years. [2] But in either form of myotonia congenita, the term's strictest sense reflects that the disease is genetically present from birth, although the clinical onset may be delayed.[ citation needed ]

With the advent of genetic testing, it has recently been found that some typically recessive mutations may occur in a dominant fashion in some individuals. The reason for this is not known.[ citation needed ]

Because several CLCN1 mutations can cause either Becker disease or Thomsen disease, doctors usually rely on characteristic signs and symptoms to distinguish the two forms of myotonia congenita. However, myotonia caused by CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel mutations (SCN4A mutations) resulting in the similar disease paramyotonia congenita.[ citation needed ]

A so-called Finnish heritage disease, congenital myotonia is more common in Finland and among ethnic Finns. A molecular study of the CLCN1 gene in 24 families in northern Finland, including 46 affected individuals, showed that although the inheritance appeared to be dominant (Thomsen type), in fact it is recessive (Becker type). [20]

Differential diagnosis

Sodium channel myotonias (SCN4A)

Dystrophies

Potassium channel disorders (KCNJ2)

Other disorders

Treatment

Some cases of myotonia congenita do not require treatment, or it is determined that the risks of the medication outweigh the benefits. If necessary, however, symptoms of the disorder may be relieved with quinine, ranolazine, procainamide, flecainide, phenytoin, carbamazepine, mexiletine and other anticonvulsant drugs. Physical therapy and other rehabilitative measures may also be used to help muscle function. Genetic counseling is available.[ citation needed ]

Epidemiology

In northern Scandinavia, the prevalence of myotonia congenita has been estimated at 1:10,000. [20]

Myotonia congenita is estimated to affect 1 in 100,000 people worldwide. [21]

Research

The name Thomsen’s disease refers to the Danish physician Julius Thomsen (1815–1896) who described the condition in himself and his family. [22]

Myotonia can be achieved in preparations of intact isolated muscle by the administration of 9-Anthracenecarboxylic acid, a blocker of chloride channels. [23] [24] It is also possible to achieve myotonia in preparations of intact isolated muscle by greatly lowering or removing the extracellular content of chloride in the bathing medium. [16]

During the 1970s several murine models of myotonia appeared. One in particular has been used widely, the adr mouse or "arrested development of righting response". [25] This model is often used in scientific work with muscular dystrophy, and displays myotonia due to lack of functional chloride channels.[ citation needed ]

See also

Related Research Articles

Muscular dystrophy Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation of the skeletal muscles after voluntary contraction or electrical stimulation.

Neuromuscular junction Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

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 channel Class of transport proteins

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.

Fainting goat American breed of meat goat

The myotonic goat or Tennessee fainting goat is an American breed of meat goat. It is characterised by myotonia congenita, a hereditary condition that may cause it to stiffen or fall over when 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.

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.

Paramyotonia congenita Medical condition

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.

Mexiletine Pair of enantiomers

Mexiletine (INN) is a medication used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness. Common side effects include abdominal pain, chest discomfort, drowsiness, headache, and nausea. It works as a non-selective voltage-gated sodium channel blocker and belongs to the Class IB group of anti-arrhythmic medications.

Na<sub>v</sub>1.4

Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

Myotonic dystrophy Genetic disorder that impairs muscle function

Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In myotonic dystrophy, 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 an inability to have children. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.

Congenital myopathy is a very broad term for any muscle disorder present at birth. This defect primarily affects skeletal muscle fibres and causes muscular weakness and/or hypotonia. Congenital myopathies account for one of the top neuromuscular disorders in the world today, comprising approximately 6 in 100,000 live births every year. As a whole, congenital myopathies can be broadly classified as follows:

Dents disease Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

Potassium-aggravated myotonia Medical condition

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.

CLCN1

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).

CLCN5 Mammalian protein found in Homo sapiens

The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.

Brody myopathy Medical condition

Brody myopathy is a rare disorder that affects skeletal muscle function. BD was first characterized in 1969 by Dr. Irwin A. Brody at Duke University Medical Center. Individuals with BD have difficulty relaxing their muscles after exercise. This difficulty in relaxation leads to symptoms including cramps, stiffness, and discomfort in the muscles of the limbs and face. Symptoms are heightened by exercise and commonly progress in severity throughout adulthood.

Harald Jockusch is a German biologist and artist with the alias Hal Jos.

A chloride channel blocker is a type of drug which inhibits the transmission of ions (Cl) through chloride channels.

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.

References

  1. Gutmann, Laurie; Phillips Lh, Lawrence (2008). "Myotonia Congenita". Seminars in Neurology. 11 (3): 244–8. doi:10.1055/s-2008-1041228. PMID   1947487.
  2. 1 2 Lossin, Christoph; George, Alfred L. (2008). "Myotonia Congenita". In Rouleau, Guy; Gaspar, Claudia (eds.). Advances in Genetics. Vol. 63. pp. 25–55. doi:10.1016/S0065-2660(08)01002-X. ISBN   978-0-12-374527-9. PMID   19185184.
  3. 1 2 Rüdel, Reinhardt; Ricker, Kenneth; Lehmann-Horn, Frank (1988). "Transient weakness and altered membrane characteristic in recessive generalized myotonia (Becker)". Muscle & Nerve. 11 (3): 202–11. doi:10.1002/mus.880110303. PMID   3352655. S2CID   25778532.
  4. Becker, Peter Emil; Knussmann, Rainer; Kühn, Erich (1977). Myotonia congenita and syndromes associated with myotonia: clinical-genetic studies of the nondystrophic myotonias. Thieme. ISBN   978-3-13-224801-4.[ page needed ]
  5. Wakeman, Bradley; Babu, Deepti; Tarleton, Jack; MacDonald, Ian M. (2008). "Extraocular muscle hypertrophy in myotonia congenita". Journal of American Association for Pediatric Ophthalmology and Strabismus. 12 (3): 294–6. doi:10.1016/j.jaapos.2007.12.002. PMID   18313341.
  6. Basu, A.; Nishanth, P.; Ifaturoti, O. (2010). "Pregnancy in Women with Myotonia Congenita". Obstetric Anesthesia Digest. 30 (2): 62–3. doi:10.1097/01.aoa.0000370558.44941.91. PMID   19368920.
  7. Bretag, A.H.; Dawe, S.R.; Kerr, D.I.B.; Moskwa, A.G. (1980). "Myotonia As a Side Effect of Diuretic Action". British Journal of Pharmacology. 71 (2): 467–71. doi:10.1111/j.1476-5381.1980.tb10959.x. PMC   2044474 . PMID   7470757.
  8. Raman, Leela; Yasodhara, P.; Ramaraju, L.A. (1991). "Calcium and magnesium in pregnancy". Nutrition Research. 11 (11): 1231–6. doi:10.1016/S0271-5317(05)80542-1.
  9. Skov, Martin; Riisager, Anders; Fraser, James A.; Nielsen, Ole B.; Pedersen, Thomas H. (2013). "Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle". Neuromuscular Disorders. 23 (6): 489–502. doi:10.1016/j.nmd.2013.03.009. PMID   23623567. S2CID   6032429.
  10. Skov, M; De Paoli, FV; Lausten, J; Nielsen, OB; Pedersen, TH (January 2015). "Extracellular magnesium and calcium reduce myotonia in isolated ClC-1 chloride channel-inhibited human muscle". Muscle & Nerve. 51 (1): 65–71. doi:10.1002/mus.24260. PMID   24710922. S2CID   31759926.
  11. Birnberger, K. L.; Rüdel, R.; Struppler, A. (1975). "Clinical and electrophysiological observations in patients with myotonic muscle disease and the therapeutic effect of N-propyl-ajmalin". Journal of Neurology. 210 (2): 99–110. doi:10.1007/BF00316381. PMID   51920. S2CID   10804605.
  12. Van Beekvelt, Mireille C.P.; Drost, Gea; Rongen, Gerard; Stegeman, Dick F.; Van Engelen, Baziel G.M.; Zwarts, Machiel J. (2006). "Na+-K+-ATPase is not involved in the warming-up phenomenon in generalized myotonia". Muscle & Nerve. 33 (4): 514–23. doi:10.1002/mus.20483. PMID   16382442. S2CID   36480234.
  13. Pusch, Michael; Steinmeyer, Klaus; Koch, Manuela C.; Jentsch, Thomas J. (1995). "Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the ClC-1 chloride channel". Neuron. 15 (6): 1455–63. doi: 10.1016/0896-6273(95)90023-3 . PMID   8845168. S2CID   18808219.
  14. Lossin, Christoph (2013). "Nav1.4 slow-inactivation: Is it a player in the warm-up phenomenon of myotonic disorders?". Muscle & Nerve. 47 (4): 483–7. doi:10.1002/mus.23713. PMID   23381896. S2CID   46299644.
  15. Trip J, Faber CG, Ginjaar HB, van Engelen BG, Drost G (2007) Warm-up phenomenon in myotonia associated with the V445M sodium channel mutation. J Neurol 254(2):257-258
  16. 1 2 Rüdel, R; Lehmann-Horn, F (1985). "Membrane changes in cells from myotonia patients". Physiological Reviews. 65 (2): 310–56. doi:10.1152/physrev.1985.65.2.310. PMID   2580324.
  17. Barchi, RL (1975). "Myotonia. An evaluation of the chloride hypothesis". Archives of Neurology. 32 (3): 175–80. doi:10.1001/archneur.1975.00490450055007. PMID   1119960.
  18. Thomsen, J. (1876). "Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer Disposition". Archiv für Psychiatrie und Nervenkrankheiten. 6 (3): 702–18. doi:10.1007/BF02164912. S2CID   46151878.
  19. Becker, P. E. (1966). "Zur Genetik der Myotonien". In Kuhn, Erich (ed.). Progressive Muskeldystrophie Myotonie · Myasthenie. pp. 247–55. doi:10.1007/978-3-642-92920-5_32. ISBN   978-3-642-92921-2.
  20. 1 2 Papponen, H.; Toppinen, T.; Baumann, P.; Myllylä, V.; Leisti, J.; Kuivaniemi, H.; Tromp, G.; Myllylä, R. (1999). "Founder mutations and the high prevalence of myotonia congenita in northern Finland". Neurology. 53 (2): 297–302. doi:10.1212/WNL.53.2.297. PMID   10430417. S2CID   22657247.
  21. Emery, Alan E.H. (1991). "Population frequencies of inherited neuromuscular diseases—A world survey". Neuromuscular Disorders. 1 (1): 19–29. doi:10.1016/0960-8966(91)90039-U. PMID   1822774. S2CID   45648166.
  22. Asmus Julius Thomas Thomsen. Who Named It?
    Thomsen’s disease. Who Named It?
  23. Moffett, R. B.; Tang, A. H. (1968). "Skeletal muscle stimulants. Substituted benzoic acids". Journal of Medicinal Chemistry. 11 (5): 1020–2. doi:10.1021/jm00311a023. PMID   5697062.
  24. Villegas-Navarro, A.; Martinez-Morales, M.; Morales-Aguilera, A. (1986). "Pharmacokinetics of anthracene-9-carboxylic acid, a potent myotonia-inducer". Archives Internationales de Pharmacodynamie et de Thérapie. 280 (1): 5–21. PMID   3718080.
  25. Watts, R. L.; Watkins, J.; Watts, D. C. (1978). "A new mouse mutant with abnormal muscle function: Comparison with the Re‐dy mouse". The Biochemistry of Myasthenia Gravis and Muscular Dystrophy. London: Academic Press. pp. 331–4.