Myotonia congenita
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| Myotonia congenita | |
|---|---|
| Classification and external resources | |
| ICD-10 | G71.1 |
| ICD-9 | 359.2 |
| OMIM | 160800 |
| DiseasesDB | 8736 |
| MedlinePlus | 001424 |
| MeSH | D009224 |
Congenital myotonia (also myotonia congenita) (Myo- from greek; muscle, and Tonus from latin; tension), is a genetic, neuromuscular channelopathy that affects skeletal muscles (muscles used for movement). The disease was first described by Dansih/German physician Julius Thomsen in 1876, who himself suffered from the disease.[1] The hallmark of the disease is the failure of initiated contraction to terminate, often refereed to as delayed relaxation of the muscles (myotonia) and rigidity.[2] The disorder is caused by mutations in part of a gene (CLCN1) encoding the ClC-1 Chloride channel, resulting in muscle fiber membranes to have an unusually exaggerated response to stimulation (hyperexcitability). Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some mutations, pain, and cramping. In addition to humans, it is also seen in strains of goat[3]canines (miniature Schnauzer and Austratilian cattle dog),[4][5]cats[6] and one breed of pony.
Disease
Two types of myotonia congenita exist; autosomal dominant myotonia congenita also called Thomsens disease (OMIM 160800), after Julius Thomsen, and recessive generalized myotonia (RGM) or Becker myotonia (OMIM 255700), after the German professor Peter Emil Becker, who discovered the recessive subtype of patients suffering from myotonia congenita.[7] The term congenital, meaning that is present from birth, strictly applies only to Thomsens disease, as the onset of Becker myotonia may be delayed up to the age of 4-6,[8] even though both types are genetic disorders, therefore present from birth.
With the advent of genetic testing, it has recently been found that some recessive mutations may occur in a dominant fashion in some individuals. The reason for this is not known. 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.
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).[9]
Prevalence
In northern Scandinavia, the prevalence of myotonia congenita has been estimated at 1:10,000[9]
Myotonia congenita is estimated to affect 1 in 100,000 people worldwide[10]
Symptoms
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,[8] are often enhanced by inactivity, and in some forms is relieved by repetitive movement known as "the warm up effect". The warm up 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.
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.[11] Even though myotonia in itself is not normally associated with pain cramps or myalgia may develop.[11] 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.[12] This muscle weakness is not observed in people with Thomsen disease. However, in recent times, as more and more of the individual mutations that cause myotonia congenita are identified, these limited disease classifications are becoming less widely used.
Early symptoms in a child may include:
- Difficulty swallowing
- Gagging
- Stiff movements that improve when they are repeated
- Frequent falling
- difficulties opening eyelids after strenuous contraction
Possible complications may include:
- Aspiration pneumonia (caused by swallowing difficulties)
- Frequent choking or gagging in infants (also caused by swallowing difficulties)
- Abdominal muscle weakness
- Chronic joint problems
- Injury due to falls
Phenotypic variability
Both Thomsen and Bercker myotonia has high phenotype variability. Severity of symptoms can vary greatly between individuals and throughout the life of the individuals themselves. Part of this may be 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[13] and the use of diuretics[14] aggravate myotonia, and both these conditions are linked to the loss of divalent cations such as magnesium and calcium.[15] It has further been shown that in pharmacological induced myotonia in isolated rat msucle, myotonia could be dampened by increasing the magnesium and calcium content of the extracellular medium[16]
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.
Due to the invisible nature of the disorder, the fact that those with myotonia congenita often appear very fit and able bodied, general lack of knowledge about the disorder by the general and medical community, and oftentimes 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.
Temperature
Many patients report that temperature may affect the severity of symptoms especially cold as being an aggrevating factor,[17] however there is some scientific debate on this subject, and some even report that cold may alleviate symptoms.[18]
The Warm-Up Phenomenon
This penomenon was described along with the disease by Thomsen in 1876 but its etiology remains unclear. Patients report that repeated contraction of muscle alleviate present myotonia with each contraction, such that myotonia is almost absent after a few contractions of the same muscle. The effect lasts about 5 miutes.[19] There have been several proposed mechanism for this phenomenon, but none have been conclusive; one theory is that the Na+/K+-ATPase is stimulated during the myotonic activity by increased intracellular Na+ in the muscle cell, increasing the activity of the Na+/K+-ATPase. However 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.[20] Another theory is that the few remaining functional chloride channels in msucle may become more active with increased muscle activity,[21] this is however not widely recognized.
Pathophysiology
Myotonia congenita is caused in humans by loss-of-function mutations in the gene CLCN1. CLCN1 is the gene encoding the protein CLCN1, that forms the ClC-1 chloride chanel, critical for the normal function of skeletal muscle cells. This gene is also associated with the condition in horses and goats.
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.
The dysfunctional Cl- channels are located in the muscle fiber membrane and, does 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, have been subject to heavy debate and results from experiments are inconclusive.[22]
In skeletal muscle fibers a large transverse tubule system with a high surface-area to volume ratio exist. 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 is 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 defect, 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[23] 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).
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, 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.
Animal models
Myotonia can be achieved in preparations of intact isolated muscle by the administration of 9-Anthracenecarboxylic acid a blocker of chloride channels[24][25] . 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.[26]
During the 1970's several murine models of myotona appeared, one in particular have been used widely, the adr mouse or "arresed developmet of righting response".[27] This model is often used in scientific work with Muscular Dystrophy, and displys myotonia due to lack of functional chloride channels.
Related and Similar Disorders
Sodium Channel Myotonias (SCN4A)
- Potassium-aggravated myotonia (Acetazolamide Responsive Myotonia)
- Paramyotonia Congenita
- Hyperkalemic Periodic Paralysis
Dystrophies
- Myotonic dystrophy (Myotonic Muscular Dystropy: Type 1 and Type 2)
Potassium Channel Disorders (KCNJ2)
Other Disorders
- Thyroid Disorders
- Neuromyotonia (Isaac's Syndrome)
- Stiff Person Syndrome
- Brody myopathy(Brody Disease, Brody's Disease, Brody's Myopathy)
References
- ^ Thomsen J. Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer Disposition - Ataxia muscularis? Archiv für Psychiatrie und Nervenkrankheiten 1876; 6:702-718
- ^ Gutmann, James L.; Phillips LH, 2nd (September 1991). "Myotonia congenita.". Seminars in neurology 11 (3): 244–8. PMID 1947487.
- ^ Lipicky, RJ; Bryant, SH (September 1966). "Sodium, potassium, and chloride fluxes in intercostal muscle from normal goats and goats with hereditary myotonia.". The Journal of general physiology 50 (1): 89–111. PMID 5971035.
- ^ Rhodes, TH; Vite, CH; Giger, U; Patterson, DF; Fahlke, C; George AL, Jr (30). "A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.". FEBS letters 456 (1): 54–8. PMID 10452529.
- ^ Finnigan, DF; Hanna, WJ; Poma, R; Bendall, AJ (June 2007). "A novel mutation of the CLCN1 gene associated with myotonia hereditaria in an Australian cattle dog.". Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 21 (3): 458–63. PMID 17552451.
- ^ Hickford, F. H.; Jones, B. R.; Gething, M. A.; Pack, R.; Alley, M. R. (1). "Congenital myotonia in related kittens". Journal of Small Animal Practice 39 (6): 281–285. doi:10.1111/j.1748-5827.1998.tb03651.x.
- ^ Becker P.E. Zur Genetik der Myotonien. In: Kuhn E, editor. Progressive Muskeldystrophie Myotonie -À Myasthenie. Springer Berlin Heidelberg; 1966. p 247-255.
- ^ a b Lossin, Christoph; George AL, Jr (2008). "Myotonia congenita.". Advances in genetics 63: 25–55. PMID 19185184.
- ^ a b Papponen H, Toppinen T, Baumann P, Myllylä V, Leisti J, Kuivaniemi H, Tromp G, Myllylä R (July 1999). "Founder mutations and the high prevalence of myotonia congenita in northern Finland". Neurology 53 (2): 297–302. PMID 10430417.
- ^ Emery, AE (1991). "Population frequencies of inherited neuromuscular diseases--a world survey.". Neuromuscular disorders : NMD 1 (1): 19–29. PMID 1822774.
- ^ a b Rüdel, R; Ricker, K; Lehmann-Horn, F (March 1988). "Transient weakness and altered membrane characteristic in recessive generalized myotonia (Becker).". Muscle & nerve 11 (3): 202–11. PMID 3352655.
- ^ Neuhäuser, Gerhard; Peter Emil Becker (1). "Myotonia congenita and syndromes associated with myotonia. Clinical genetic studies of the nondystrophic myotonias. Peter Emil Becker, with contributions by Rainer Knussmann and Erich Kuhn, translated by Mary F. Passarge. Topics in Human Genetics, Vol III. Stuttgart: Georg Thieme Publishers, 1977. 181 pages, 146 figures, 40 tables. DM 62.40". American Journal of Medical Genetics 2 (1): 99–100. doi:10.1002/ajmg.1320020109.
- ^ Basu A, Nishanth P, Ifaturoti O. Pregnancy in women with myotonia congenita. International Journal of Gynecology & Obstetrics 2009; 106:62-63.
- ^ Bretag AH, Dawe SR, Kerr DIB, Moskwa AG. Myotonia as a side effect of diuretic action. British Journal of Pharmacologuy 1980; 71:467-471.
- ^ Raman L, Yasodhara P, Ramaraju LA. Calcium and magnesium in pregnancy. Nutrition Research 1991; 11:1231-1236.
- ^ Skov, Martin; Riisager, A; Fraser, JA; Nielsen, OB; Pedersen, TH (23). "Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle.". Neuromuscular disorders : NMD. PMID 23623567.
- ^ Nielsen VK, Friis ML, Johnsen T. Electromyographic distinction between paramyotonia congenita and myotonia congenita: effect of cold. Neurology. 1982 Aug;32(8):827-32. PMID 7201578
- ^ Ricker K, Hertel G, Langscheid K, Stodieck G. Myotonia not aggravated by cooling. Force and relaxation of the adductor pollicis in normal subjects and in myotonia as compared to paramyotonia. Jounal of Neurology 1977; 216:9-20.
- ^ Birnberger, K.L. Rüdel, R, Struppler, A. Clinical and electrophysiological observations in patients with myotonic muscle disease and the therapeutic effect of N-propyl-ajmalin. Journal of Neurology 1975 Sep 1;210(2):99-110.
- ^ Van Beekvelt MCP, Drost G, Rongen G, Stegeman DF, Van Engelen BGM, Zwarts MJ. Na+-K+-ATPase is not involved in the warming-up phenomenon in generalized myotonia. Muscle Nerve 2006; 33:514-523.
- ^ Pusch M, Steinmeyer K, Koch MC, Jentsch TJ. Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel. Neuron. 1995 Dec;15(6):1455-63.
- ^ Rüdel, Reinhardt; Lehmann-Horn, F (April 1985). "Membrane changes in cells from myotonia patients.". Physiological reviews 65 (2): 310–56. PMID 2580324.
- ^ Barchi RL. (March 1975). "Myotonia. An evaluation of the chloride hypothesis". Archive of Neurology. 32 (3): 175–180. PMID 1119960.
- ^ Moffett, R.B.; Tang, AH (Sep 1968). "Skeletal muscle stimulants. Substituted benzoic acids.". Journal of medicinal chemistry 11 (5): 1020–2. PMID 5697062.
- ^ Villegas-Navarro A, Martinez-Morales M, Morales-Aguilera A. (March 1986). "Pharmacokinetics of anthracene-9-carboxylic acid, a potent myotonia-inducer.". Arch Int Pharmacodyn Ther. 280 (1): 5–21. PMID 3718080.
- ^ Rüdel, R; Lehmann-Horn, F (April 1985). "Membrane changes in cells from myotonia patients.". Physiological reviews 65 (2): 310–56. PMID 2580324.
- ^ Watts, R.L.; J. Watkins, D.C. Watts (1978). "A new mouse mutant with abnormal muscle function: Comparison with the Re‐dy mouse". The Biochemistry of Myasthenia Gravis and Muscular Dystrophy, Academic Press, London: 331–334.
External links
- NINDS: Myotonia Congenita
- National Library of Medicine: Myotonia Congenita
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