NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Myotonia Congenita

, PhD and , MD.

Author Information

Initial Posting: ; Last Update: August 6, 2015.

Summary

Clinical characteristics.

Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. 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 symptoms 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 pathogenic variants causing both the autosomal recessive and autosomal dominant forms of myotonia congenita.

Management.

Treatment of manifestations: Muscle stiffness may respond to sodium channel blockers such as mexiletine (currently the medication with best documented effect), carbamazepine, or phenytoin. Beneficial effects have also been reported with quinine, dantrolene, and acetazolamide.

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 of 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) or an autosomal dominant manner (Thomsen disease); the same pathogenic variant may occur in families with both types of inheritance. In the autosomal dominant form, the proportion of cases caused by de novo pathogenic variants is unknown; each child of an individual with autosomal dominant myotonia congenita has a 50% chance of inheriting the pathogenic variant. 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. 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 pathogenic variants in CLCN1, in which case inheritance can be assumed to be autosomal recessive. Testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.

Diagnosis

Suggestive Findings

Myotonia congenita should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

  • 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
  • Family history consistent with either autosomal dominant or autosomal recessive inheritance

Laboratory findings

  • Serum creatine kinase concentration that may be slightly elevated (≤3-4x the upper limits of normal)
  • Electromyography (EMG) performed with needle electrodes that discloses characteristic showers of spontaneous electrical activity (myotonic bursts)

Note: Guidelines for molecular genetic testing based on electrophysiologic tests in myotonic disorders have been formulated [Tan et al 2011]; however, in most cases the clinical features provide sufficient guidance.

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.

Note: Muscle biopsy is not required to consider or establish the diagnosis of myotonia congenita.

Establishing the Diagnosis

The diagnosis of myotonia congenita is established in a proband with identification of a heterozygous pathogenic variant or biallelic pathogenic variants in CLCN1 (see Table 1).

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 some pathogenic variants can occur in both autosomal recessive myotonia congenita and autosomal dominant myotonia congenita.

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Table 1.

Summary of Molecular Genetic Testing Used in Myotonia Congenita

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
CLCN1Sequence analysis 2>95%
Gene-targeted deletion/duplication analysis 31%-5% 4
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Gene-targeted deletion/duplication analysis detects intragenic CLCN1 deletions or duplications. Examples of methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

4.

A single study of 60 preselected patients revealed larger deletions/duplications in four [Raja Rayan et al 2012].

Clinical Characteristics

Clinical Description

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.

Muscle stiffness. Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and 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 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 more severe symptoms than seen in the autosomal dominant form.

Muscle weakness. 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 or distal myopathy has been reported [Nagamitsu et al 2000].

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

Genotype-Phenotype Correlations

The phenotypic manifestations of the pathogenic variants in CLCN1 can be variable even within the same family [Sun et al 2001, Colding-Jørgensen 2005]. Cases of semi-dominant inheritance, in which a homozygote is more severely affected than a heterozygote, have been reported [Kuo et al 2006, Lin et al 2006].

Some individuals with the pathogenic variants 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 pathogenic variant have been reported as having a phenotype reminiscent of paramyotonia congenita [Wu et al 2002].

Occasionally, proximal weakness (in individuals with the p.Thr550Met pathogenic variant) or distal myopathy (in individuals with the p.Pro932Leu pathogenic variant) has been reported [Nagamitsu et al 2000]. However, the association of these features with CLCN1 pathogenic variants has been challenged [Simpson et al 2004, Colding-Jørgensen 2005].

Penetrance

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

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 more than 300 affected individuals from the UK, autosomal dominant pathogenic variants were found in only 37% of individuals in whom a pathogenic variant was identified [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 (OMIM) (caused by SCN4A pathogenic variants) 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 (OMIM) (caused by SCN4A pathogenic variants) is a diverse group of rare sodium channel disorders. Up to 20% of persons suspected of having myotonia congenita may in fact have pathogenic variants 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 CNBP, the gene encoding cellular nucleic acid binding protein (zinc finger protein 9) [Liquori et al 2001]. Inheritance of DM1 and DM2 is autosomal dominant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with myotonia congenita, the following evaluations are recommended:

  • Consultation with a clinical geneticist and/or genetic counselor
  • Consultation with a neurologist or other relevant specialist to evaluate the need for pharmacologic treatment

Treatment of Manifestations

Some individuals with minor complaints may only need to accommodate their activities and lifestyles to reduce symptoms [Shapiro & Ruff 2002]. Myotonic stiffness may respond to sodium channel blockers or other pharmacologic treatment options:

  • Mexiletine, a lidocaine derivative, is the best documented treatment option. In a double-blind randomized trial, mexiletine (200 mg 3x/day) significantly reduced stiffness in a group of 59 patients with myotonia, 34 of whom had myotonia congenita [Statland et al 2012]. In clinical practice, 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 epigastric discomfort, nausea, lightheadedness, dizziness, tremor, and ataxia, are reversible with dose reduction.
  • Other sodium channel blockers such as phenytoin and carbamazepine have been reported to have beneficial effects [Conravey & Santana-Gould 2010].
  • Compounds with other presumed modes of action such as quinine, dantrolene, or acetazolamide may be beneficial in some cases [Shapiro & Ruff 2002].

See review in Conravey & Santana-Gould [2010] for a detailed description of these treatment options.

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

In general, anesthesia should be used with caution [Bandschapp & Laizzo 2013]. Particular 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 appear 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 of 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.

Pregnancy Management

For an affected mother, a comprehensive birth plan is recommended [Gorthi et al 2013] to minimize the risks of muscular spasms due to factors such as medications, intramuscular injections, and cold.

Therapies Under Investigation

A trial with lamotrigine is ongoing (NCT01939561).

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 pathogenic variant 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 de novo CLCN1 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown but presumably very low.
  • If the CLCN1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparently de novo pathogenic variant include electromyography. Alternatively, a methodology developed to detect low-level mosaicism, such as an NGS-based deep sequencing approach, can potentially uncover a low mosaic state in one of the parents.
  • The family history of some individuals diagnosed with autosomal dominant myotonia congenita 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., molecular genetic testing and electromyography) have been performed on the parents of the proband.

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. However, the sibs of a proband with clinically unaffected parents are still at increased risk for autosomal dominant myotonia congenita because of the possibility of reduced penetrance in a parent.
  • If the CLCN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant myotonia congenita has a 50% chance of inheriting the CLCN1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a CLCN1 pathogenic variant, 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 (i.e., carriers of one CLCN1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic. Occasionally, the parents of a proband with autosomal recessive myotonia congenita (the proband has two CLCN1 pathogenic variants) can show subtle evidence of myotonia on EMG testing. However, they are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are mostly asymptomatic. Occasionally, on thorough clinical evaluation, heterozygotes can show subtle evidence of myotonia on EMG testing. However, they are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive myotonia congenita are obligate heterozygotes (carriers of a CLCN1 pathogenic variant).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CLCN1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CLCN1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives.

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 CLCN1 pathogenic variants in trans, demonstrating autosomal recessive inheritance. Confirmation of phase by segregation analysis is important, as a single allele with two pathogenic variants has been described [Brugnoni et al 2013]. It should be noted that cases of semi-dominant inheritance, in which a homozygote is more severely affected than a heterozygote, have been reported [Kuo et al 2006, Lin et al 2006].

Testing of at-risk asymptomatic relatives of individuals with myotonia congenita is possible after molecular genetic testing has identified the specific pathogenic variant(s) in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. Because individuals with myotonia congenita may be at risk for adverse anesthesia-related events, testing of at-risk individuals during childhood is 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CLCN1 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for myotonia congenita are possible options.

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.

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)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 1), which is primarily 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 mutated alleles that reduce functionality, whereas autosomal dominant myotonia congenita is believed to result from a dominant-negative pathogenic variant 'poisoning' the channel. The latter variants are therefore mainly located in the dimer interface, whereas variants associated with recessive MC can be located throughout the protein [Skálová et al 2013].

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’) pathogenic variants are usually asymptomatic.

On a research basis, the functional consequences of a number of CLCN1 pathogenic variants 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 phenotypes of myotonic dystrophy type 1 and type 2 are believed to result from missplicing of CLCN1 mRNA due to an RNA toxic effect of the pathogenic expansion of a CTG repeat in DMPK (DM1) and a CCTG repeat in CNBP (DM2) [Charlet-B et al 2002, Mankodi et al 2002]. A similar effect has recently been proposed for Huntington disease (HD), where a CAG expansion in HTT in a mouse model impairs CLCN1 function which in turn could contribute to the chorea, dystonia, and stiffness seen in HD [Waters et al 2013].

The majority of the more than 275 different CLCN1 pathogenic variants identified to date are associated with autosomal recessive myotonia congenita. Approximately 20 pathogenic variants have solely been associated with autosomal dominant myotonia congenita, whereas approximately 12 pathogenic variants associate with both autosomal recessive and autosomal dominant myotonia congenita, making it difficult to predict mode of inheritance.

Unambiguous autosomal recessive and autosomal dominant pedigrees have been described only for p.Gly230Glu, p.Thr310Met, p.Ala531Val, and p.Arg894Ter. This peculiar phenomenon may be explained by the following [Koty et al 1996, Mailänder et al 1996, Zhang et al 1996, Plassart-Schiess et al 1998, Dunø et al 2004, Bernard et al 2008, Richardson et al 2014]:

Gene structure. CLCN1 spans 36 kb and contains 23 exons with a transcript length of 3093 nucleotides. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 275 different pathogenic variants have been identified, the majority of which are associated with autosomal recessive myotonia congenita. Pathogenic variants (both recessive and dominant) appear to be scattered throughout the coding sequence and are mostly missense or nonsense variants (Table 2). Pathogenic variants causing dominant myotonia congenita are often located in exon 8 [Fialho et al 2007].

The p.Arg894Ter pathogenic variant is probably the most common semi-dominant pathogenic variant with homozygotes being more severely affected than heterozygotes [Kuo et al 2006, Lin et al 2006].

Table 2.

CLCN1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.689G>Ap.Gly230GluNM_000083​.2
NP_000074​.2
c.929C>TpThr310Met
c.1283T>Cp.Phe428Ser
c.1592C>Tp.Ala531Val
c.1649C>Tp.Thr550Met
c.2680C>Tp.Arg894Ter
c.2795C>Tp.Pro932Leu
c.2926C>Tp.Arg976Ter

Note on variant classification: Variants listed in the table have been provided by the authors. 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.

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 pathogenic variants are presumed to cause loss of function of the channel; dominant pathogenic variants presumably act through a dominant-negative mechanism, by primarily affecting dimerization [Skálová et al 2013].

References

Published Guidelines/Consensus Statements

  • 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. Available online. 2011. Accessed 1-19-17. [PMC free article: PMC3051421] [PubMed: 21387378]

Literature Cited

  • Bandschapp O, Laizzo PA. Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses. Paediatr Anaesth. 2013;23:824–33. [PubMed: 23802937]
  • 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.
  • Becker PE. Myotonia Congenita and Syndromes Associated with Myotonia. Topics in Human Genetics. Stuttgart, Germany: Georg Thieme. 1977.
  • Bernard G, Poulin C, Puymirat J, Sternberg D, Shevell M. Dosage effect of a dominant CLCN1 mutation: a novel syndrome. J Child Neurol. 2008;23:163–6. [PubMed: 18263754]
  • Blessing W, Walsh JC. Myotonia precipitated by propranolol therapy. Lancet. 1977;1:73–4. [PubMed: 63714]
  • Brugnoni R, Kapetis D, Imbrici P, Pessia M, Canioni E, Colleoni L, de Rosbo NK, Morandi L, Cudia P, Gashemi N, Bernasconi P, Desaphy JF, Conte D, Mantegazza R. A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. J Hum Genet. 2013;58:581–7. [PubMed: 23739125]
  • Cardani R, Giagnacovo M, Botta A, Rinaldi F, Morgante A, Udd B, Raheem O, Penttilä S, Suominen T, Renna LV, Sansone V, Bugiardini E, Novelli G, Meola G. Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2. J Neurol. 2012;259:2090–9. [PubMed: 22407275]
  • Charlet-B N, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10:45–53. [PubMed: 12150906]
  • Chen TT, Klassen TL, Goldman AM, Marini C, Guerrini R, Noebels JL. Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy. Neurology. 2013;80:1078–85. [PMC free article: PMC3662306] [PubMed: 23408874]
  • Colding-Jørgensen E. Phenotypic variability in myotonia congenita. Muscle Nerve. 2005;32:19–34. [PubMed: 15786415]
  • Conravey A, Santana-Gould L. Myotonia congenita and myotonic dystrophy: surveillance and management. Curr Treat Options Neurol. 2010;12:16–28. [PubMed: 20842486]
  • Dunø M, Colding-Jørgensen E, Grunnet M, Jespersen T, Vissing J, Schwartz M. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet. 2004;12:738–43. [PubMed: 15162127]
  • Emery AE. Population frequencies of inherited neuromuscular diseases - a world survey. Neuromuscul Disord. 1991;1:19–29. [PubMed: 1822774]
  • Farbu E, Softeland E, Bindoff LA. Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Acta Anaesthesiol Scand. 2003;47:630–4. [PubMed: 12699527]
  • Fialho D, Schorge S, Pucovska U, Davies NP, Labrum R, Haworth A, Stanley E, Sud R, Wakeling W, Davis MB, Kullmann DM, Hanna MG. Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. Brain. 2007;130:3265–74. [PubMed: 17932099]
  • Furby A, Vicart S, Camdessanché JP, Fournier E, Chabrier S, Lagrue E, Paricio C, Blondy P, Touraine R, Sternberg D, Fontaine B. Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. Neuromuscul Disord. 2014;24:953–9. [PubMed: 25088311]
  • Gorthi S, Radbourne S, Drury N, Rajagopalan C. Management of pregnancy with Thomsen's disease. Eur J Obstet Gynecol Reprod Biol. 2013;170:293–4. [PubMed: 23806446]
  • Koty PP, Pegoraro E, Hobson G, Marks HG, Turel A, Flagler D, Cadaldini M, Angelini C, Hoffman EP. Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. Neurology. 1996;47:963–8. [PubMed: 8857727]
  • Kuo HC, Hsiao KM, Chang LI, You TH, Yeh TH, Huang CC. Novel mutations at carboxyl terminus of CIC-1 channel in myotonia congenita. Acta Neurol Scand. 2006;113:342–6. [PubMed: 16629771]
  • Lacomis D, Gonzales JT, Giuliani MJ. Fluctuating clinical myotonia and weakness from Thomsen's disease occurring only during pregnancies. Clin Neurol Neurosurg. 1999;101:133–6. [PubMed: 10467912]
  • Lin MJ, You TH, Pan H, Hsiao KM. Functional characterization of CLCN1 mutations in Taiwanese patients with myotonia congenita via heterologous expression. Biochem Biophys Res Commun. 2006;351:1043–7. [PubMed: 17097617]
  • Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–7. [PubMed: 11486088]
  • Mailänder V, Heine R, Deymeer F, Lehmann-Horn F. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet. 1996;58:317–24. [PMC free article: PMC1914535] [PubMed: 8571958]
  • Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44. [PubMed: 12150905]
  • Nagamitsu S, Matsuura T, Khajavi M, Armstrong R, Gooch C, Harati Y, Ashizawa T. A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene. Neurology. 2000;55:1697–703. [PubMed: 11113225]
  • Papponen H, Toppinen T, Baumann P, Myllyla V, Leisti J, Kuivaniemi H, Tromp G, Myllyla R. Founder mutations and the high prevalence of myotonia congenita in northern Finland. Neurology. 1999;53:297–302. [PubMed: 10430417]
  • Plassart-Schiess E, Gervais A, Eymard B, Lagueny A, Pouget J, Warter JM, Fardeau M, Jentsch TJ, Fontaine B. Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance. Neurology. 1998;50:1176–9. [PubMed: 9566422]
  • Raja Rayan DL, Haworth A, Sud R, Matthews E, Fialho D, Burge J, Portaro S, Schorge S, Tuin K, Lunt P, McEntagart M, Toscano A, Davis MB, Hanna MG. A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1. Neurology. 2012;78:1953–8. [PMC free article: PMC3369509] [PubMed: 22649220]
  • Richardson RC, Tarleton JC, Bird TD, Gospe SM Jr. Truncating CLCN1 mutations in myotonia congenita: variable patterns of inheritance. Muscle Nerve. 2014;49:593–600. [PubMed: 23893571]
  • Rutkove SB, DeGirolami U, Preston DC, Freeman R, Nardin RA, Gouras GK, Johns DR, Raynor EM. Myotonia in colchicine myoneuropathy. Muscle Nerve. 1996;19:870–5. [PubMed: 8965841]
  • Shapiro B, Ruff R. Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related disorders. In: Katirji B, Kaminski H, Preston D, Ruff R, Shapiro B, eds. Neuromuscular Disorders in Clinical Practice. Philadelphia, PA: Butterworth-Heinemann; 2002:987-1020.
  • Simpson BJ, Height TA, Rychkov GY, Nowak KJ, Laing NG, Hughes BP, Bretag AH. Characterization of three myotonia-associated mutations of the CLCN1 chloride channel gene via heterologous expression. Hum Mutat. 2004;24:185. [PubMed: 15241802]
  • Skálová D, Zídková J, Voháňka S, Mazanec R, Mušová Z, Vondráček P, Mrázová L, Kraus J, Réblová K, Fajkusová L. CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. PLoS One. 2013;8:e82549. [PMC free article: PMC3859631] [PubMed: 24349310]
  • Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, Salajegheh MK, Venance SL, Ciafaloni E, Matthews E, Meola G, Herbelin L, Griggs RC, Barohn RJ, Hanna MG. Consortium for Clinical Investigation of Neurologic Channelopathies. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012;308:1357–65. [PMC free article: PMC3564227] [PubMed: 23032552]
  • Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M. Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet. 2001;9:903–9. [PubMed: 11840191]
  • 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. Ann Neurol. 2011;69:328–40. [PMC free article: PMC3051421] [PubMed: 21387378]
  • Trip J, Drost G, Verbove DJ, van der Kooi AJ, Kuks JB, Notermans NC, Verschuuren JJ, de Visser M, van Engelen BG, Faber CG, Ginjaar IB. In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. Eur J Hum Genet. 2008;16:921–9. [PubMed: 18337730]
  • Waters CW, Varuzhanyan G, Talmadge RJ, Voss AA. Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction. Proc Natl Acad Sci U S A. 2013;2013;110:9160–5. [PMC free article: PMC3670332] [PubMed: 23671115]
  • Weiss MD, Mayer RF. Temperature-sensitive repetitive discharges in paramyotonia congenita. Muscle Nerve. 1997;20:195–7. [PubMed: 9040658]
  • Wu FF, Ryan A, Devaney J, Warnstedt M, Korade-Mirnics Z, Poser B, Escriva MJ, Pegoraro E, Yee AS, Felice KJ, Giuliani MJ, Mayer RF, Mongini T, Palmucci L, Marino M, Rudel R, Hoffman EP, Fahlke C. Novel CLCN1 mutations with unique clinical and electrophysiological consequences. Brain. 2002;125:2392–407. [PubMed: 12390967]
  • Zhang J, George AL Jr, Griggs RC, Fouad GT, Roberts J, Kwieciński H, Connolly AM, Ptácek LJ. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Neurology. 1996;47:993–8. [PubMed: 8857733]

Suggested Reading

  • Imbrici P, Altamura C, Pessia M, Mantegazza R, Desaphy JF, Camerino DC (2015) ClC-1 chloride channels: state-of-the-art research and future challenges. Front Cell Neurosci. 27;9:156. [PMC free article: PMC4410605] [PubMed: 25964741]
  • Jen JC, Ptáček L. Channelopathies: episodic disorders of the nervous system. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 204. McGraw-Hill. Available online.
  • 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

  • 6 August 2015 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2017, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2017 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1355PMID: 20301529

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...