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8/2/2019 Myotonia Congenita
1/19
Myotonia CongenitaIncludes: Autosomal Dominant Myotonia Congenita, Autosomal Recessive Myotonia Congenita
Morten Dun, PhD
Molecular Genetic Laboratory
Department of Clinical Genetics
University Hospital Copenhagen
Copenhagen, Denmark
Eskild Colding-Jrgensen, MD
International Clinical ResearchNeurology
H Lundbeck A/S
Copenhagen, Denmark
Initial Posting: August 3, 2005; Last Update: April 12, 2011.
Summary
Go to:
TopDisease characteristics. Myotonia congenita is characterized by muscle stiffness present from
childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and thetongue may be involved. Men are more severelyaffectedthan women. Stiffness is relieved by repeated
contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic.
Theautosomal recessiveform of myotonia congenita is often associated with more severe stiffness of
muscles than theautosomal dominantform. Individuals with theautosomal recessiveform may have
progressive, minor distal weakness and attacks of transient weakness brought on by movement after
rest. The age of onset is variable: inautosomal dominantmyotonia congenita, onset of symptoms is
usually in infancy or early childhood; in theautosomal recessiveform, 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, andfamily historyconsistent withautosomal dominantorautosomal
recessiveinheritance. CLCN1, encoding a chloride channel, is the onlygeneknown to be associated
with myotonia congenita.Sequence analysisofCLCN1 detects more than 95% ofmutationscausing
both theautosomal recessiveandautosomal dominantforms of myotonia congenita.
Management.Treatment of manifestations: Muscle stiffness may respond to mexiletine (the mosteffective medication); tocainide (can cause bone marrow suppression); procainamide, quinine, or
mailto:[email protected]:[email protected]:[email protected]:[email protected]://www.ncbi.nlm.nih.gov/books/NBK1355/http://www.ncbi.nlm.nih.gov/books/NBK1355/http://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sequence-analysis/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/family-history/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/books/NBK1355/mailto:[email protected]:[email protected]8/2/2019 Myotonia Congenita
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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.
Testing 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 anautosomal recessive(Becker disease)
and anautosomal dominantmanner (Thomsen disease); the samemutationmay occur in families with
both types of inheritance. In theautosomal dominantform, the proportion of cases caused by de
novomutationsis unknown; each child of an individual withautosomal dominantmyotonia congenita
has a 50% chance of inheriting themutation. Inautosomal recessivemyotonia
congenita,heterozygotesare usually asymptomatic; at conception, each sib of anaffectedindividual
has a 25% chance of beingaffected, a 50% chance of being an asymptomaticcarrier, and a 25% chance
of beingunaffectedand not acarrier; once an at-risk sib is known to beunaffected, the risk to that sib
of being acarrieris 2/3. Establishing themode of inheritancein asimplex case(i.e., a single
occurrence in a family) may not be possible unlessmolecular genetic testingreveals
twodisease-causing mutationsin CLCN1, in which case inheritance can be assumed to beautosomal
recessive.Carrier testingfor at-risk family members and prenatal testing for pregnancies at increased
risk are possible if the twodisease-causing mutationsin the family are known.
Diagnosis
Go to:
TopClinical Diagnosis
The diagnosis of myotonia congenita is suggested in individuals with the following:
Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood (Myotoniais 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: Inautosomal recessivemyotonia congenita and in individuals with
http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genetic-counseling/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/genetic-counseling/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/heterozygote/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/heterozygote/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/heterozygote/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/unaffected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mode-of-inheritance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/simplex-case/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/simplex-case/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/simplex-case/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/disease-causing-mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/disease-causing-mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/disease-causing-mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/carrier-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/ca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Myotonia Congenita
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certainmutations(p.Pro480Leu, p.Arg894X) causingautosomal dominantmyotonia
congenita, 10-Hz repetitive nerve stimulation elicits a decrement of the evoked muscle
response [Colding-Jrgensen et al 2003]. A similar effect is produced by ten seconds of
voluntary contraction (short exercise test). Guidelines formolecular genetic testingbased on
electrophysiologic tests in myotonic disorders have been formulated [Tan et al
2011(see )]; however, in most cases the clinical features provide sufficient
guidance.
Family historyconsistent with eitherautosomal dominantorautosomalrecessiveinheritance
Testing
Routine blood tests are not helpful in establishing the diagnosis.
Serum creatine kinase concentrationmay 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 ofautosomal recessivemyotonia congenita, myopathic changes may be found.
Molecular Genetic Testing
Gene.CLCN1, encoding a chloride channel, is the onlygeneknown to be associated with myotonia
congenita.
Clinical testing
Sequence analysis.Sequence analysisdetects the majority ofmutationsthat causebothautosomal recessivemyotonia congenita andautosomal dominantmyotonia congenita.
Note: Distinguishing betweenautosomal dominantandautosomal recessivemyotonia
congenita depends mainly on thefamily history(i.e., the presence of anaffectedparent), as
the samemutationscan occur in bothautosomal recessivemyotonia congenita
andautosomal dominantmyotonia congenita.
Deletion/duplication analysis. Only a single grossdeletioninvolvingexon9 ofCLCN1 hasbeen reported inrecessivemyotoniacongenital[Modoni et al 2011]. No exonic or
whole-genedeletionshave been reported fordominantMC. The proportion of
grossdeletions/duplicationsin patients with myotonia congenita is currently unknown and
thus the usefulness of such testing is unknown.
Table 1. Summary ofMolecular Genetic TestingUsed in Myotonia Congenita
Gene
Symbo
l
Test Method MutationsDetected
MutationDetectio
n Frequency by
Test Method
1
Test
Availabilit
y
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Myotonia Congenita
4/19
CLCN
1
Sequence analysis Sequence variants 2 >95%
Clinical
Deletion/duplicationanalysi
s 3
Exon(s) or
whole-genedeletions/duplicati
ons
Unknown 4
Test Availability refers to availability in theGeneTests Laboratory Directory.GeneReviews designates a
molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory
Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not
verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance.
Clinicians must communicate directly with the laboratories to verify information.
1. The ability of the test method used to detect amutationthat is present in the indicatedgene
2. Examples ofmutationsdetected bysequence analysismay include small
intragenicdeletions/insertionsand missense, nonsense, and splice sitemutations.
3. Testing that identifiesdeletions/duplicationsnot readily detectable bysequence analysisof
genomicDNA; a variety of methods includingquantitative PCR, long-rangePCR, multiplex
ligation-dependentprobeamplification (MLPA), or targeted chromosomal microarray analysis
(gene/segment-specific) may be used. A full chromosomal microarray analysis that
detectsdeletions/duplicationsacross thegenomemay also include thisgene/segment. Seearray GH.
4. A single homozygousdeletioncomprisingexon9 ofCLCN1 has been reported in a patient with
myotonia congenita.
Interpretation of test results. For issues to consider in interpretation ofsequence analysisresults,
clickhere.
Testing Strategy
Carrier testingof at-risk relatives forautosomal recessivemyotonia congenita requires prior
identification of thedisease-causing mutationsin the family.
Predictive testingfor at-risk, asymptomatic adult family members requires prior identification of
thedisease-causing mutation(s) in the family.
Prenatal diagnosisand preimplantation genetic diagnosis (PGD) for at-risk pregnancies require
prior identification of thedisease-causing mutationsin the family.
Note: It is the policy ofGeneReviews to include clinical uses of testing available from laboratories
listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of
such uses by the author(s), editor(s), or reviewer(s).
Genetically Related (Allelic) Disorders
A single CLCN1mutation,c.1283T>C, has been associated with a paramyotonia-likephenotypein one
individual [Weiss & Mayer 1997,Wu et al 2002]. This finding is unique and should be interpreted with
caution [Colding-Jrgensen 2005]. Paramyotonia congenita usually results frommutationsin SCN4A.
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Myotonia Congenita
5/19
Clinical Description
Go to:
TopNatural 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. Inautosomal dominantmyotonia congenita, onset of symptoms is usually
in infancy or early childhood. Inautosomal recessivemyotonia 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.
Theautosomal recessiveform is often associated with a more severe stiffness of muscles than that seen
in theautosomal dominantform. Men are more severelyaffectedthan women.
Individuals with theautosomal recessiveform 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. Inautosomal recessivemyotonia congenita, both subunits
have adisease-causing mutation.Autosomal dominantmyotonia congenita is believed to result from
the presence of onedominant-negativemutationthat 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 CLCN1mutationsidentified to date result inautosomal
recessivemyotonia congenita [Pusch 2002,Wu et al 2002,Grunnet et al 2003,Colding-Jrgensen
2005,Fialho et al 2007,Lossin & George 2008].
More than 15mutationshave been reported to result inautosomal dominantmyotoniacongenita (seeTable 2).
Approximately tenmutationshave been associated with bothautosomalrecessiveandautosomal dominantmyotonia congenita (seeTable 2), making it difficult to
distinguish clearly between the two modes of inheritance. Unambiguousautosomal
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Myotonia Congenita
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recessiveandautosomal dominantpedigreeshave been described only
forp.Gly230Glu, p.Thr310Met,p.Ala531Val, andp.Arg894X. This peculiar phenomenon
may be explained by the following [Koty et al 1996,Mailander et al 1996,Zhang et al
1996,Plassart-Schiess et al 1998,Dun et al 2004,Bernard et al 2008]:
Reducedpenetranceofdominant-negativemutations Incomplete dominance Founder effect Incompletemutationdetection Differences in allelic expression
The phenotypic manifestations of thesedominantand semi-dominantmutationscan be variable even
within the same family [Sun et al 2001,Colding-Jrgensen 2005].
Some individuals withmutationsp.Gly230Gluandp.Thr310Methave been reported to experience a
fluctuatingphenotypetriggered by pregnancy [Lacomis et al 1999,Wu et al 2002] and some with
thep.Phe428Ser(NM_000083.2:c.1283T>C)mutationhave been reported as having
aphenotypereminiscent of paramyotonia congenita [Wu et al 2002].
Occasionally, proximal weakness (in individuals with
thep.Thr550Met[NM_000083.2:c.1649C>T]mutation) or distal myopathy (in individuals with
thep.Pro932Leumutation) has been reported [Nagamitsu et al 2000]. However, the association of these
features withCLCN1mutationshas been challenged [Simpson et al 2004,Colding-Jrgensen 2005].
Penetrance
The majority of theautosomal dominantmutationscan be associated with reducedpenetrance. Family
members heterozygous for the samemutationmay exhibit variablephenotypesranging from absence of
myotonia to severe myotonia.
Anticipation
Anticipationhas not been described in myotonia congenita.
Nomenclature
Autosomal dominantmyotonia congenita is also known as Thomsen disease.
Autosomal recessivemyotonia 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 forautosomal
dominantmyotonia congenita and 1:50,000 for theautosomal recessiveform [Becker 1977].
Subsequent studies have suggested that theautosomal recessiveform is more common than
theautosomal dominantform. In a large cohort of over 300affectedindividuals from the
UK,autosomal dominantmutationswere found in only 37% ofmutation-positive persons [Fialho et al
2007].
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/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/anticipation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/anticipation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.becker.1977.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.becker.1977.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.becker.1977.1http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.fialho.2007.3265http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.becker.1977.1http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/anticipation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/penetrance/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.coldingjorgensen.2005.19http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.simpson.2004.185http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.nagamitsu.2000.1697http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.T.selected_clcn1_pathologic_ahttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=119433676http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.T.selected_clcn1_pathologic_ahttp://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.wu.2002.2392http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http: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Myotonia Congenita
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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
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seeGeneTests Laboratory Directory.ED.
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 SCN4Amutations) may sometimes be difficult todistinguish from myotonia congenita:
Both conditions present with episodes of generalized stiffness in early childhood.Individuals with paramyotonia congenita display extreme coldsensitivitywith
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-upphenomenon, 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
havemutationsin SCN4A[Trip et al 2008]. In some cases, the myotonia may be associated
with episodes of hyperkalemic periodic paralysis (seeHyperkalemic 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]:
http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.papponen.1999.297http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.papponen.1999.297http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.papponen.1999.297http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.sun.2001.903http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.sun.2001.903http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.sun.2001.903http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.emery.1991.19http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.emery.1991.19http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.emery.1991.19http://www.ncbi.nlm.nih.gov/books/NBK1355/http://www.ncbi.nlm.nih.gov/books/NBK1355/http://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.trip.2008.921http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.trip.2008.921http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.trip.2008.921http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.shapiro.2002.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.shapiro.2002.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.shapiro.2002.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.shapiro.2002.1http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/n/gene/hyper-pp/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.trip.2008.921http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/sensitivity/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTestshttp://www.ncbi.nlm.nih.gov/books/NBK1355/#tophttp://www.ncbi.nlm.nih.gov/books/NBK1355/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.emery.1991.19http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.sun.2001.903http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.papponen.1999.2978/2/2019 Myotonia Congenita
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Characteristically, symptoms of sodium channel disorders worsen withpotassium 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 aperiod of delay. This phenomenon contrasts with the warm-up phenomenon seen
in myotonia congenita.
Eye closure myotonia is more frequent in sodium channel myotonia, whereasfalls 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) andmyotonic dystrophy type 2(DM2) should alwaysbe 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
inautosomal recessivemyotonia 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 CTGtrinucleotide repeatinDMPK1; DM2 is caused by a
CCTG repeat expansion inintron1 ofZNF9, thegeneencoding cellular nucleic acid binding
protein (zinc finger protein 9) [Liquori et al 2001].Molecular genetic testingis available for
both disorders. Inheritance of DM1 and DM2 isautosomal dominant.
Note to clinicians: For a patient-specific simultaneous consult related to this disorder, go
to , an interactive diagnostic decision support software tool that provides
differential diagnoses based on patient findings (registration or institutional access required).
Myotonia congenita, autosomal recessive Myotonia congenita, autosomal dominant
Management
Go to:
TopTreatment 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].
http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.tan.2011.1http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d2/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d2/http://www.ncbi.nlm.nih.gov/books/n/gene/myotonic-d2/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-recessive/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/trinucleotide-repeat/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/intron/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/intron/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/intron/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/gene/http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.liquori.2001.864http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.liquori.2001.864http://www.ncbi.nlm.nih.gov/books/NBK1355/#myotonia-c.REF.liquori.2001.864http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/molecular-genetic-testing/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/http://www.simulconsult.com/neuro