Myotonia Congenita 書

8/2/2019 Myotonia Congenita

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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

[email protected]

Eskild Colding-Jrgensen, MD

International Clinical ResearchNeurology

H Lundbeck A/S

Copenhagen, Denmark

[email protected]

Initial Posting: August 3, 2005; Last Update: April 12, 2011.

Summary

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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
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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
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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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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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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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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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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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TopFor current information on availability of genetic testing for disorders included in this section,

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.1999.297


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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

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