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Thomsen disease

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Thomsen disease

Myotonia congenita
Classification and external resources
ICD-10 9 OMIM DiseasesDB MedlinePlus 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 Danish/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 referred 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, and cramping. Though contrary to generic cramping myotonia is not associated with metabolic depletion nor pain.[3] In addition to humans, it is also seen in strains of goat,[4]canines (miniature Schnauzer and Australian cattle dog),[5][6] cats,[7] 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.[8] The term congenital, see Congenital disorder, strictly applies only to Thomsens disease, as the onset of Becker myotonia may be delayed up to the age of 4–6 years,.[9] In Myotonia Congenita, the term reflects that the disease is genetically present from birth, while the onset may be delayed. 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).[10]

Prevalence

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

Myotonia congenita is estimated to affect 1 in 100,000 people worldwide[11]

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,[9] 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.[12] Even though myotonia in itself is not normally associated with pain, cramps or myalgia may develop.[12] 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.[13] 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 or crying (von Graefe's sign)[14]

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 Becker myotonia have 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[15] and the use of diuretics[16] aggravate myotonia, and both these conditions are linked to the loss of divalent cations such as magnesium and calcium.[17] It has further been shown that in pharmacological induced myotonia in isolated rat muscle, myotonia could be dampened by increasing the magnesium and calcium content of the extracellular medium[18]

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 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.

Temperature

Many patients report that temperature may affect the severity of symptoms especially cold as being an aggravating factor,[19] however there is some scientific debate on this subject, and some even report that cold may alleviate symptoms.[20]

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.[21] There have been several proposed mechanisms 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 cytosol of 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.[22] Another theory is that the few remaining functional chloride channels in muscle may become more active with increased muscle activity,[23] this is however not widely recognized.

It has been proposed that inactivation of Na+ channel 1.4 that resides 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 extend that is correlated to warm-up and therefore may provide a plausible cause.[24]

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 channel, 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.[25]

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[26] 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.[27][28] 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.[25]

During the 1970s several murine models of myotona appeared, one in particular have been used widely, the adr mouse or "arrested development of righting response".[29] This model is often used in scientific work with Muscular Dystrophy, and displys myotonia due to lack of functional chloride channels.

See also

Related and Similar Disorders

Sodium Channel Myotonias (SCN4A)

Dystrophies

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

External links

  • YouTube Video of Fainting Goats with Myotonia Cogenita
  • GeneReview/NCBI/NIH/UW entry on Myotonia Congenita
  • YouTube Video of kittens with Myotonia Congenita - Its Not Just About the Goats
  • YouTube Video of Actual Person with Myotonia Congenita
  • Myotonia congenita from Healthdrip
  • NINDS: Myotonia Congenita
  • National Library of Medicine: Myotonia Congenita
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