Myotonia is the abnormal delay in muscular relaxation after a vigorous voluntary contraction. Myotonia patients have muscle stiffness following voluntary contractions that gradually improve with exercising (the so-called "warmup" effect). A single stimulus can cause several repeating action potentials, or "myotonic runs," in myotonia, caused by the electrical instability of the muscular membrane itself. Myotonia is principally brought on by an inability of the usual chloride inflow during repolarization to compensate.
Myotonia congenita is a hereditary condition characterized by muscular membrane hyperexcitability induced by decreased sarcolemmal chloride conductance produced by mutations in CLCN1, the gene encoding the primary skeletal muscle chloride channel ClC-1. With nearly 130 identified mutations, the condition can be passed down either as an autosomal-dominant or recessive condition. Despite being an uncommon condition, understanding the pathophysiology of myotonia congenita revealed the significance of sarcolemmal chloride conductance in regulating muscle excitability and provided the first case of a human disease connected to the CLC family of chloride-transporting proteins. When depolarizing muscle relaxants are administered to patients with MC, they are at significant risk of developing a severe myotonic reaction with generalized muscle spasms. The myotonic response could be more pronounced in patients with hypothyroidism and pregnant women. The myotonic response may be impacted by any rise in serum potassium after suxamethonium treatment.
Myotonia congenita is characterized by muscle stiffness that begins in childhood and affects all striated muscle groups, including the extrinsic eye muscles, face muscles, and tongue. Autosomal dominant (AD) myotonia congenita does not frequently have the more severe symptoms that autosomal recessive (AR) myotonia congenita has (such as progressive mild distal weakening and episodes of transient weakness brought on by movement after rest). In AD myotonia congenita, onset typically occurs in infancy or early childhood; in AR myotonia congenita, onset typically occurs when a person is older. Affected individuals report muscle stiffness when starting a movement. Myotonia can coexist with several conditions, such as myotonic muscular dystrophy, Para myotonia congenita, and hyperkalemic periodic paralysis. Myotonia can also be brought on by pharmacological and chemical toxicity exposure.
Following are the major types of myotonia congenital −
Autosomal-dominant MC − Also known as Thomson disease. Myotonia congenita which is dominantly inherited, typically manifests in the first few months of life. The initial sign could be a delayed relaxation of the eyelids after a forceful closure due to crying or sneezing. Exceptionally well-defined muscles in the infant's extremities are another possible symptom. Thomsen Disease frequently goes undiagnosed until late infancy, when the kid shows clumsiness and has trouble moving after resting. When getting out of a chair, the muscles are stiff, especially in the legs, and stair climbing may be difficult.
Recessive Generalized Myotonia − People with RGM have more severe myotonia than those with Thomsen Disease. They sometimes have brief episodes of weakness when starting to move, especially after a lengthy period of inactivity. Transient weakness is characterized by a perceived "wave" of weakness or muscle failure that affects muscles needed to perform a task. It may cause a person to drop an object or have trouble maintaining balance. Severe myotonia may impair postural control to the point where righting movements are "stuck" prematurely in mid-motion, resulting in uncontrollable falling. Although myotonia is typically not accompanied by pain, RGM patients may experience severe muscular cramps or myalgia, especially after intense exercise when they are at rest.
Major methods of treatment are −
Historically, anti-myotonic medications included quinidine and quinine. The well-documented toxic effect known as cinchonism, which can include dizziness, nausea, and other gastrointestinal problems, makes it unwise to continue administering these drugs to reduce myotonic response. Quinine/quinidine use for an extended period also negatively impacts and may cause serious neurological side effects or even death. It is still possible to use these substances temporarily when needed, such as in advance of circumstances where unrestricted motor function is crucial. Unfortunately, the anti-myotonic effects of quinidine and quinine diminish with continued usage. Therefore the benefit of treating myotonia over the long run is poor. Procaine, tocainide, mexiletine, carbamazepine, and phenytoin are some more medications used to treat myotonia with varying degrees of success.
They might be extremely helpful in the management of congenital myotonia. The emotional condition of affected persons may affect phenotypic severity, with stress and mental distress contributing to worsening myotonia. As long as it is not implied that the cause of myotonia is psychological, relaxation techniques may be helpful. Exercises to increase flexibility could be advantageous for preventing muscular strains when movements are made during myotonic episodes.
Myotonia congenita can be inherited in either an autosomal dominant (Thomsen disease) or autosomal recessive (Becker disease) form; the same pathogenic variant may be linked to both types of inheritance. If molecular genetic testing finds two trans CLCN1 pathogenic mutations in a proband with unaffected parents, inheritance can be presumed to be autosomal recessive; otherwise, determining the mode of heredity in a simplex case (i.e., an isolated occurrence in a family) may not be feasible.
Autosomal recessive inheritance: Each sibling of an affected person has a 25% probability of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants at conception if both parents are known to be heterozygous for a CLCN1 pathogenic variant. Autosomal dominant inheritance: Most people with autosomal dominant myotonia congenita have an afflicted parent. If the proband's parent is affected and has the pathogenic variant found in the proband, the likelihood of the sibs acquiring the pathogenic variant is 50%.
Myotonia congenita was the first known hereditary channelopathy involving a ClC chloride channel. Understanding the underlying molecular causes of this condition has shed light on the CLC-1 chloride channel's structure-function interactions and the typical physiology of sarcolemmal excitability. Myotonia congenita needs to be better understood by medical professionals to take advantage of therapeutic prospects that have emerged since the disorder's molecular genetic background was uncovered.
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