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Myotonia Congenita

Includes: Autosomal Dominant Myotonia Congenita, Autosomal Recessive Myotonia Congenita

, PhD and , MD.

Author Information
, PhD
Molecular Genetic Laboratory
Department of Clinical Genetics
University Hospital Copenhagen
Copenhagen, Denmark
, MD
International Clinical Research – Neurology
H Lundbeck A/S
Copenhagen, Denmark

Initial Posting: ; Last Update: April 12, 2011.

Summary

Disease characteristics. Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and the tongue may be involved. Men are more severely affected than women. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic. The autosomal recessive form of myotonia congenita is often associated with more severe stiffness of muscles than the autosomal dominant form. Individuals with the autosomal recessive form may have progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest. The age of onset is variable: in autosomal dominant myotonia congenita, onset of symptoms is usually in infancy or early childhood; in the autosomal recessive form, the average age of onset is slightly older. In both, onset may be as late as the third or fourth decade of life.

Diagnosis/testing. Myotonia congenita is diagnosed clinically by the presence of episodes of myotonia beginning in early childhood, alleviation of stiffness by brief exercise, myotonic contraction elicited by percussion of muscles, electromyography revealing myotonic bursts, elevated serum creatine kinase concentration, and family history consistent with autosomal dominant or autosomal recessive inheritance. CLCN1, encoding a chloride channel, is the only gene known to be associated with myotonia congenita. Sequence analysis of CLCN1 detects more than 95% of mutations causing both the autosomal recessive and autosomal dominant forms of myotonia congenita.

Management. Treatment of manifestations: Muscle stiffness may respond to mexiletine (the most effective medication); tocainide (can cause bone marrow suppression); procainamide, quinine, or phenytoin. Beneficial effects have also been reported with carbamazepine, dantrolene (associated with hepatotoxicity), and acetazolamide (associated with nausea, anorexia, paresthesias, and kidney stone formation). Myotonia is alleviated temporarily by exercise.

Agents/circumstances to avoid: Depolarizing muscle relaxants (e.g., suxamethonium), adrenaline, beta-adrenergic agonists, propranolol, and colchicine may aggravate myotonia.

Evaluation of relatives at risk: Because individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, testing at-risk individuals during childhood to clarify their genetic status is appropriate.

Genetic counseling. Myotonia congenita is inherited in either an autosomal recessive (Becker disease) and an autosomal dominant manner (Thomsen disease); the same mutation may occur in families with both types of inheritance. In the autosomal dominant form, the proportion of cases caused by de novo mutations is unknown; each child of an individual with autosomal dominant myotonia congenita has a 50% chance of inheriting the mutation. In autosomal recessive myotonia congenita, heterozygotes are usually asymptomatic; at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier; once an at-risk sib is known to be unaffected, the risk to that sib of being a carrier is 2/3. Establishing the mode of inheritance in a simplex case (i.e., a single occurrence in a family) may not be possible unless molecular genetic testing reveals two disease-causing mutations in CLCN1, in which case inheritance can be assumed to be autosomal recessive. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the two disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

The diagnosis of myotonia congenita is suggested in individuals with the following:

  • Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood (Myotonia is defined as impaired relaxation of skeletal muscle after voluntary contraction.)
  • Alleviation of stiffness by brief exercise (known as the "warm-up effect")
  • Myotonic contraction elicited by percussion of muscles
  • Electromyography (EMG) performed with needle electrodes that discloses characteristic showers of spontaneous electrical activity (myotonic bursts) seen only in myotonic conditions

    Note: In autosomal recessive myotonia congenita and in individuals with certain mutations (p.Pro480Leu, p.Arg894X) causing autosomal dominant myotonia congenita, 10-Hz repetitive nerve stimulation elicits a decrement of the evoked muscle response [Colding-Jørgensen et al 2003]. A similar effect is produced by ten seconds of voluntary contraction (short exercise test). Guidelines for molecular genetic testing based on electrophysiologic tests in myotonic disorders have been formulated [Tan et al 2011; see Image guidelines.jpg]; however, in most cases the clinical features provide sufficient guidance.
  • Family history consistent with either autosomal dominant or autosomal recessive inheritance

Testing

Routine blood tests are not helpful in establishing the diagnosis.

Serum creatine kinase concentration may be slightly elevated (≤3-4 times the upper limits of normal).

Muscle biopsy is usually normal, although absence of type 2B fibers is sometimes noted. In very severe cases of autosomal recessive myotonia congenita, myopathic changes may be found.

Molecular Genetic Testing

Gene. CLCN1, encoding a chloride channel, is the only gene known to be associated with myotonia congenita.

Clinical testing

  • Sequence analysis. Sequence analysis detects the majority of mutations that cause both autosomal recessive myotonia congenita and autosomal dominant myotonia congenita.

    Note: Distinguishing between autosomal dominant and autosomal recessive myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent), as the same mutations can occur in both autosomal recessive myotonia congenita and autosomal dominant myotonia congenita.
  • Deletion/duplication analysis. Only a single gross deletion involving exon 9 of CLCN1 has been reported in recessive myotonia congenital [Modoni et al 2011]. No exonic or whole-gene deletions have been reported for dominant MC. The proportion of gross deletions/duplications in patients with myotonia congenita is currently unknown and thus the usefulness of such testing is unknown.

Table 1. Summary of Molecular Genetic Testing Used in Myotonia Congenita

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CLCN1Sequence analysisSequence variants 2>95%
Deletion / duplication analysis 3Exon(s) or whole-gene deletions/duplications Unknown 4

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

4. A single homozygous deletion comprising exon 9 of CLCN1 has been reported in a patient with myotonia congenita.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Carrier testing of at-risk relatives for autosomal recessive myotonia congenita requires prior identification of the disease-causing mutations in the family.

Predictive testing for at-risk, asymptomatic adult family members requires prior identification of the disease-causing mutation(s) in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and the tongue may be involved. The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).

The age of onset is variable. In autosomal dominant myotonia congenita, onset of symptoms is usually in infancy or early childhood. In autosomal recessive myotonia congenita, the average age of onset is slightly older. In both conditions, onset may be as late as the third or fourth decade of life.

The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon. Muscles are usually hypertrophic.

The autosomal recessive form is often associated with a more severe stiffness of muscles than that seen in the autosomal dominant form. Men are more severely affected than women.

Individuals with the autosomal recessive form may have progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest. Occasionally, proximal weakness and distal myopathy have been reported [Nagamitsu et al 2000].

Extramuscular manifestations such as early cataracts, abnormal cardiac conduction, or endocrine dysfunction are absent.

Genotype-Phenotype Correlations

CLCN1 encodes the voltage-gated chloride channel ClC-1 (chloride channel protein, skeletal muscle). Each muscle chloride channel comprises two identical protein molecules, each forming a separate ion conduction pathway, the so-called protopore. In autosomal recessive myotonia congenita, both subunits have a disease-causing mutation. Autosomal dominant myotonia congenita is believed to result from the presence of one dominant-negative mutation that modifies either the gating of both protopores [Wu et al 2002] or the selectivity of one of the two protopores [Fahlke et al 1997]:

The majority of the more than 100 different CLCN1 mutations identified to date result in autosomal recessive myotonia congenita [Pusch 2002, Wu et al 2002, Grunnet et al 2003, Colding-Jørgensen 2005, Fialho et al 2007, Lossin & George 2008].

The phenotypic manifestations of these dominant and semi-dominant mutations can be variable even within the same family [Sun et al 2001, Colding-Jørgensen 2005].

Some individuals with mutations p.Gly230Glu and p.Thr310Met have been reported to experience a fluctuating phenotype triggered by pregnancy [Lacomis et al 1999, Wu et al 2002] and some with the p.Phe428Ser (NM_000083.2:c.1283T>C) mutation have been reported as having a phenotype reminiscent of paramyotonia congenita [Wu et al 2002].

Occasionally, proximal weakness (in individuals with the p.Thr550Met [NM_000083.2:c.1649C>T] mutation) or distal myopathy (in individuals with the p.Pro932Leu mutation) has been reported [Nagamitsu et al 2000]. However, the association of these features with CLCN1 mutations has been challenged [Simpson et al 2004, Colding-Jørgensen 2005].

Penetrance

The majority of the autosomal dominant mutations can be associated with reduced penetrance. Family members heterozygous for the same mutation may exhibit variable phenotypes ranging from absence of myotonia to severe myotonia.

Anticipation

Anticipation has not been described in myotonia congenita.

Nomenclature

Autosomal dominant myotonia congenita is also known as Thomsen disease.

Autosomal recessive myotonia congenita is also known as Becker disease.

Myotonia levior is essentially the same as myotonia congenita.

Prevalence

Myotonia congenita was originally estimated to occur with a frequency of 1:23,000 for autosomal dominant myotonia congenita and 1:50,000 for the autosomal recessive form [Becker 1977]. Subsequent studies have suggested that the autosomal recessive form is more common than the autosomal dominant form. In a large cohort of over 300 affected individuals from the UK, autosomal dominant mutations were found in only 37% of mutation-positive persons [Fialho et al 2007].

In northern Scandinavia, the prevalence of myotonia congenita has been estimated at 1:10,000 [Papponen et al 1999, Sun et al 2001], whereas the worldwide prevalence has been estimated at 1:100,000 [Emery 1991].

Differential Diagnosis

The differential diagnosis of myotonia congenita includes other disorders in which myotonia is a prominent finding. Myotonia congenita can usually be distinguished from these disorders based on the following:

  • Factors that provoke or alleviate myotonia
  • Presence or absence of extramuscular manifestations
  • Findings on electrodiagnostic testing

Diseases to consider in the differential diagnosis

  • Paramyotonia congenita (caused by SCN4A mutations) may sometimes be difficult to distinguish from myotonia congenita:
    • Both conditions present with episodes of generalized stiffness in early childhood. Individuals with paramyotonia congenita display extreme cold sensitivity with cold-induced severe stiffness usually followed by true weakness, features not seen in myotonia congenita; however, individuals with myotonia congenita may report some aggravation of stiffness in the cold.
    • Individuals with myotonia congenita display a pronounced warm-up phenomenon, in which myotonia is relieved with repeated muscle contractions. Conversely, in paramyotonia congenita, repeated muscle contractions may aggravate stiffness (also termed paradoxical myotonia).
  • Potassium-aggravated myotonia is a diverse group of rare sodium channel (SCN4A) disorders. Up to 20% of persons suspected of having myotonia congenita may in fact have mutations in SCN4A [Trip et al 2008]. In some cases, the myotonia may be associated with episodes of hyperkalemic periodic paralysis (see Hyperkalemic Periodic Paralysis Type 1). However, if episodes of periodic paralysis are absent, sodium channel (potassium-aggravated) myotonia may be difficult to distinguish from chloride channel myotonia (myotonia congenita) on clinical grounds alone.
    The following clues are helpful [Shapiro & Ruff 2002, Tan et al 2011]:
    • Characteristically, symptoms of sodium channel disorders worsen with potassium ingestion, an aggravation that is not seen in myotonia congenita.
    • Some individuals with sodium channel myotonia have exercise-induced, delayed-onset myotonia, in which muscle contractions induce myotonia after a period of delay. This phenomenon contrasts with the warm-up phenomenon seen in myotonia congenita.
    • Eye closure myotonia is more frequent in sodium channel myotonia, whereas falls are more frequent in chloride channel myotonia [Tan et al 2011].
    • Many individuals with sodium channel myotonia have painful myotonia, whereas pain is uncommon in chloride channel myotonia.
  • Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) should always be considered in the differential diagnosis of myotonia congenita, as the extramuscular manifestations of DM1 and DM2 have important implications for prognosis and management. Although some degree of muscular weakness and wasting may be observed in autosomal recessive myotonia congenita, the pattern of muscle weakness is very different and extramuscular manifestations including early cataracts, abnormal cardiac conduction, or endocrine dysfunction found in DM1 and DM2 are not observed in myotonia congenita. However, the lack of these extramuscular features does not rule out, for example, a mild form of myotonic dystrophy type I.
    DM1 is caused by expansion of a CTG trinucleotide repeat in DMPK1; DM2 is caused by a CCTG repeat expansion in intron 1 of ZNF9, the gene encoding cellular nucleic acid binding protein (zinc finger protein 9) [Liquori et al 2001]. Inheritance of DM1 and DM2 is autosomal dominant.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Treatment of Manifestations

Some individuals with minor complaints may only need to accommodate their activities and lifestyles to reduce symptoms [Shapiro & Ruff 2002].

In a Cochrane Review concerning drug treatment for myotonia, no specific recommendations could be made because of insufficient good-quality data and lack of randomized studies [Trip et al 2006].

A more detailed description of some of the following treatment options may be found in a recent review [Conravey & Santana-Gould 2010].

Pharmacologic treatment of myotonic stiffness may include the following:

  • Mexiletine, a lidocaine derivative, is probably the most effective treatment for myotonia, although efficacy has not been systematically studied in genetically verified myotonia congenita. Doses generally begin at 150 mg twice a day, increasing slowly as needed up to 200-300 mg three times a day. The most common potential side effects, including gastrointestinal distress, lightheadedness, tremor, and ataxia, are reversible with dose reduction.
  • Tocainide. Although tocainide, another lidocaine derivative, is useful in some individuals, it should be used with extreme caution because of the potential for bone marrow suppression.
  • Procainamide (125-1000 mg/day), quinine (200-1200 mg/day), or phenytoin (300-400 mg/day) can be used with few side effects.
  • Carbamazepine has been reported to have a beneficial effect [Berardinelli et al 2000].
  • Dantrolene may be beneficial in severe cases. However, hepatotoxicity has been reported, and liver function values must be measured at baseline and at appropriate intervals during therapy [Shapiro & Ruff 2002].
  • Acetazolamide is beneficial in some individuals. Doses begin at 125 mg twice a day, slowly increasing to 250 mg three times a day according to effect and tolerance [Shapiro & Ruff 2002]. Common side effects include: nausea, anorexia, and paresthesias; individuals must be warned about the formation of kidney stones. Rash has been reported, and liver function studies, serum concentration of electrolytes, and complete blood count (CBC) and platelet count should be monitored.

Prevention of Primary Manifestations

Exercise temporarily alleviates myotonia (the warm-up effect). A long-term beneficial effect of gymnastics is sometimes reported by affected individuals; the effect has not been systematically studied.

Agents/Circumstances to Avoid

Care must be taken with the use of depolarizing muscle relaxants during anesthesia because they may cause adverse anesthesia-related events. Because life-threatening muscle spasms and secondary ventilation difficulties occurred following a preoperative injection of suxamethonium, Farbu et al [2003] recommended that suxamethonium be avoided in individuals with myotonia congenita.

Note: Non-depolarizing muscle relaxants seem to act normally in individuals with myotonia congenita but do not counteract a myotonic response caused by suxamethonium [Farbu et al 2003].

In rare cases, injections of adrenaline or selective beta-adrenergic agonists in high doses may aggravate myotonia.

The beta-antagonist propranolol has likewise been reported to worsen myotonia [Blessing & Walsh 1977]. Accordingly, beta-agonists and beta-antagonists should be used with caution and particular care should be taken with the use of intravenous fenoterol or ritodrine.

Colchicine may cause a myopathy with myotonia in individuals with renal insufficiency [Rutkove et al 1996] and may thus also, in theory, aggravate the myotonia of individuals with myotonia congenita.

Evaluation of Relatives at Risk

Because individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, testing at-risk individuals during childhood to clarify their genetic status is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Myotonia congenita can be inherited in either an autosomal recessive (Becker disease) or an autosomal dominant manner (Thomsen disease). A clear distinction can be difficult because the same mutation may occur in families with autosomal recessive inheritance and families with autosomal dominant inheritance.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent.
  • A proband with autosomal dominant myotonia congenita may potentially have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown but presumably very low.

Note: Although the majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with autosomal dominant myotonia congenita has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an individual with autosomal recessive myotonia congenita are obligate heterozygotes and therefore each carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic. Occasionally, the parents of a proband with autosomal recessive myotonia congenita (the proband has two CLCN1 mutations) show subtle evidence of myotonia on EMG testing.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are mostly asymptomatic. Occasionally, on thorough clinical evaluation, heterozygotes show subtle evidence of myotonia on EMG testing.

Offspring of a proband. The offspring of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (carriers) for a disease-causing mutation in CLCN1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives. Because individuals with myotonia congenita may be at risk for adverse anesthesia-related events, testing of at-risk individuals may be appropriate.

Establishing the mode of inheritance in a simplex case (i.e., the occurrence of a single individual with myotonia congenita in a family) may not be possible unless molecular genetic testing reveals two disease-causing mutations in CLCN1, in which case inheritance can be assumed to be autosomal recessive.

Testing of at-risk asymptomatic relatives for myotonia congenita is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur or, if they do, what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for myotonia congenita, an affected family member should be tested first to confirm that the mutation in the family can be identified using currently available techniques. Because individuals with myotonia congenita may be at risk for adverse anesthesia-related events, testing at-risk individuals during childhood may be appropriate.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as myotonia congenita are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 00-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Library of Medicine Genetics Home Reference
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Myotonia Congenita: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Myotonia Congenita (View All in OMIM)

118425CHLORIDE CHANNEL 1, SKELETAL MUSCLE; CLCN1
160800MYOTONIA CONGENITA, AUTOSOMAL DOMINANT
255700MYOTONIA CONGENITA, AUTOSOMAL RECESSIVE

Molecular Genetic Pathogenesis

CLCN1 encodes the voltage-gated chloride channel ClC-1 (chloride channel protein, skeletal muscle), which is solely expressed in the sarcolemma, where its main function is to regulate excitability and to stabilize the resting potential. The channel functions as a homodimer, and autosomal recessive myotonia congenita is believed to result from two mutant alleles that reduce functionality, whereas autosomal dominant myotonia congenita is believed to result from a dominant-negative mutation 'poisoning' the channel.

Normally, the chloride conductance contributes 85% to the resting membrane conductance of human muscle, ensuring its electrical stability. The chloride conductance is crucial for countering the depolarizing effect of potassium (K+) accumulation in T tubules. If the chloride conductance is reduced to 40% or less, K+ accumulation in the T-tubular lumen depolarizes the surface membrane sufficiently to initiate self-sustaining action potentials causing a prolonged (myotonic) contraction [Barchi 2001]. A reduction of chloride conductance to 50% apparently does not cause myotonia, because heterozygous carriers of non-functional (‘autosomal recessive’) mutations are asymptomatic.

On a research basis, the functional consequences of a number of CLCN1 mutations have been investigated by expression of the corresponding mutated cDNA sequences in Xenopus oocytes or mammalian cells followed by whole-cell patch-clamp recordings.

The myotonic phenotype of myotonic dystrophy type 1 (DM1; caused by mutation in DMPK) is believed to result from mutated DMPK-misregulated splicing of CLCN1, rendering the protein non-functional [Charlet-B et al 2002, Mankodi et al 2002].

Normal allelic variants. CLCN1 spans 36 kb and contains 23 exons with a transcript length of 3093 nucleotides. Twelve normal allelic variants within the coding sequence are known [Pusch 2002].

Pathologic allelic variants. More than 150 different mutations have been identified, the majority of which are associated with autosomal recessive myotonia congenita. Mutations (both recessive and dominant) appear to be scattered throughout the coding sequence and are mostly missense or nonsense mutations (Table 2). Mutations causing dominant myotonia congenita are often located in exon 8 [Fialho et al 2007].

Table 2. Selected CLCN1 Pathologic Allelic Variants

Mode of InheritanceDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequence
Dominantc.394A>Tp.Ser132CysNM_000083​.2
NP_000074​.2
c.592C>Gp.Leu198Val
c.577G>Ap.Glu193Lys
c.803C>Tp.Thr268Met
c.847C>Tp.Leu283Phe
c.857T>Cp.Val286Ala
c.870C>Gp.Ile290Met
c.929C>Tp.Thr310Met
c.937G>Ap.Ala313Thr
c.1412C>Tp.Ser471Phe
c.1439C>T 2p.Pro480Leu
c.1438C>Ap.Pro480Thr
c.1655A>Gp.Gln552Arg
c.1667T>Ap.Ile556Asn
c.2512_2513insCTCAp.His838Profs*35
(fs872X)
Dominant and recessivec.382A>Gp.Met128Val
c.689G>Ap.Gly230Glu
c.920T>Cp.Phe307Ser
c.929C>TpThr310Met
c.950G>Ap.Arg317Gln
c.1013G>Ap.Arg338Gln
c.1592C>Tp.Ala531Val
c.2680C>Tp.Arg894X 3
c.2795C>Tp.Pro932Leu
c.2330delGp.Gly777Alafs*17 4

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. The mutation present in Dr. Thomsen himself

3. Probably the most common semi-dominant mutation

4. Kuo et al [2006], Lin et al [2006]

Normal gene product. CLCN1 encodes the protein ClC-1, which consists of 988 amino acids and contains numerous transmembrane domains. The functional ClC-1 channel contributes approximately 80% of the total resting conductance and determines membrane excitability.

Abnormal gene product. Recessive mutations are presumed to cause loss of function of the channel; dominant mutations presumably act through a dominant-negative mechanism, by affecting either dimerization or ion selectivity of the channel.

References

Published Guidelines/Consensus Statements

  1. Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D, Sud R, Haworth A, Koltzenburg M, Hanna MG. Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies. 2011. Available online. Accessed 4-5-11. [PMC free article: PMC3051421] [PubMed: 21387378]

Literature Cited

  1. Barchi R. The pathophysiology of excitation in skeletal muscle. In: Karpati G, Hilton-Jones D, Griggs RC, eds. Disorders of Voluntary Muscle. 7 ed. Cambridge, UK: Cambridge University Press. 2001:168-86.
  2. Becker PE. Myotonia Congenita and Syndromes Associated with Myotonia. Topics in Human Genetics. Stuttgart, Germany: Georg Thieme; 1977.
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Suggested Reading

  1. Jen JC, Ptáček L. Channelopathies: episodic disorders of the nervous system. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 204. Available online. Accessed 4-5-11.
  2. Jentsch TJ, Poët M, Fuhrmann JC, Zdebik AA. Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models. Annu Rev Physiol. 2005;67:779–807. [PubMed: 15709978]

Chapter Notes

Revision History

  • 12 April 2011 (me) Comprehensive update posted live
  • 8 July 2008 (me) Comprehensive update posted live
  • 3 August 2005 (me) Review posted to live Web site
  • 14 December 2004 (md) Original submission
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