DiagnosisClinical DiagnosisThe diagnosis of myotonia congenita is suggested in individuals with the following:Episodes of muscle stiffness (myotonia) or cramps beginning in early childhood (Myotonia is defined as impaired relaxation of skeletal muscle after voluntary contraction.)Alleviation of stiffness by brief exercise (known as the "warm-up effect")Myotonic contraction elicited by percussion of musclesElectromyography (EMG) performed with needle electrodes that discloses characteristic showers of spontaneous electrical activity (myotonic bursts) seen only in myotonic conditions
Note: In autosomal recessive myotonia congenita and in individuals with certain mutations (p.Pro480Leu, p.Arg894X) causing autosomal dominant myotonia congenita, 10-Hz repetitive nerve stimulation elicits a decrement of the evoked muscle response [Colding-Jørgensen et al 2003]. A similar effect is produced by ten seconds of voluntary contraction (short exercise test). Guidelines for molecular genetic testing based on electrophysiologic tests in myotonic disorders have been formulated [Tan et al 2011; see ]; however, in most cases the clinical features provide sufficient guidance.Family history consistent with either autosomal dominant or autosomal recessive inheritanceTestingRoutine blood tests are not helpful in establishing the diagnosis.Serum creatine kinase concentration may be slightly elevated (≤3-4 times the upper limits of normal).Muscle biopsy is usually normal, although absence of type 2B fibers is sometimes noted. In very severe cases of autosomal recessive myotonia congenita, myopathic changes may be found.Molecular Genetic TestingGene. CLCN1, encoding a chloride channel, is the only gene known to be associated with myotonia congenita. Clinical testingSequence analysis. Sequence analysis detects the majority of mutations that cause both autosomal recessive myotonia congenita and autosomal dominant myotonia congenita.
Note: Distinguishing between autosomal dominant and autosomal recessive myotonia congenita depends mainly on the family history (i.e., the presence of an affected parent), as the same mutations can occur in both autosomal recessive myotonia congenita and autosomal dominant myotonia congenita.Deletion/duplication analysis. Only a single gross deletion involving exon 9 of CLCN1 has been reported in recessive myotonia congenital [Modoni et al 2011]. No exonic or whole-gene deletions have been reported for dominant MC. The proportion of gross deletions/duplications in patients with myotonia congenita is currently unknown and thus the usefulness of such testing is unknown. Table 1. Summary of Molecular Genetic Testing Used in Myotonia CongenitaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCLCN1Sequence analysisSequence variants 2>95%ClinicalDeletion / duplication analysis 3Exon(s) or whole-gene deletions/duplications Unknown 41. The ability of the test method used to detect a mutation that is present in the indicated gene 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.4. A single homozygous deletion comprising exon 9 of CLCN1 has been reported in a patient with myotonia congenita. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyCarrier testing of at-risk relatives for autosomal recessive myotonia congenita requires prior identification of the disease-causing mutations in the family.Predictive testing for at-risk, asymptomatic adult family members requires prior identification of the disease-causing mutation(s) in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersA single CLCN1 mutation, c.1283T>C, has been associated with a paramyotonia-like phenotype in one individual [Weiss & Mayer 1997, Wu et al 2002]. This finding is unique and should be interpreted with caution [Colding-Jørgensen 2005]. Paramyotonia congenita usually results from mutations in SCN4A.}

Natural HistoryMyotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, the facial muscles, and the tongue may be involved. The physician may note that the individual cannot extend the fingers after shaking hands, or a myotonic contraction may be elicited by percussion of muscles (e.g., the tongue, finger extensors, or thenar muscles).The age of onset is variable. In autosomal dominant myotonia congenita, onset of symptoms is usually in infancy or early childhood. In autosomal recessive myotonia congenita, the average age of onset is slightly older. In both conditions, onset may be as late as the third or fourth decade of life.The stiffness can be relieved by repeated contractions of the muscle, a feature known as the "warm-up" phenomenon. Muscles are usually hypertrophic.The autosomal recessive form is often associated with a more severe stiffness of muscles than that seen in the autosomal dominant form. Men are more severely affected than women.Individuals with the autosomal recessive form may have progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest. Occasionally, proximal weakness and distal myopathy have been reported [Nagamitsu et al 2000].Extramuscular manifestations such as early cataracts, abnormal cardiac conduction, or endocrine dysfunction are absent.

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

ManagementTreatment of ManifestationsSome individuals with minor complaints may only need to accommodate their activities and lifestyles to reduce symptoms [Shapiro & Ruff 2002].In a Cochrane Review concerning drug treatment for myotonia, no specific recommendations could be made because of insufficient good-quality data and lack of randomized studies [Trip et al 2006].A more detailed description of some of the following treatment options may be found in a recent review [Conravey & Santana-Gould 2010].Pharmacologic treatment of myotonic stiffness may include the following:Mexiletine, a lidocaine derivative, is probably the most effective treatment for myotonia, although efficacy has not been systematically studied in genetically verified myotonia congenita. Doses generally begin at 150 mg twice a day, increasing slowly as needed up to 200-300 mg three times a day. The most common potential side effects, including gastrointestinal distress, lightheadedness, tremor, and ataxia, are reversible with dose reduction.Tocainide. Although tocainide, another lidocaine derivative, is useful in some individuals, it should be used with extreme caution because of the potential for bone marrow suppression.Procainamide (125-1000 mg/day), quinine (200-1200 mg/day), or phenytoin (300-400 mg/day) can be used with few side effects.Carbamazepine has been reported to have a beneficial effect [Berardinelli et al 2000].Dantrolene may be beneficial in severe cases. However, hepatotoxicity has been reported, and liver function values must be measured at baseline and at appropriate intervals during therapy [Shapiro & Ruff 2002].Acetazolamide is beneficial in some individuals. Doses begin at 125 mg twice a day, slowly increasing to 250 mg three times a day according to effect and tolerance [Shapiro & Ruff 2002]. Common side effects include: nausea, anorexia, and paresthesias; individuals must be warned about the formation of kidney stones. Rash has been reported, and liver function studies, serum concentration of electrolytes, and complete blood count (CBC) and platelet count should be monitored.Prevention of Primary ManifestationsExercise 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 AvoidCare must be taken with the use of depolarizing muscle relaxants during anesthesia because they may cause adverse anesthesia-related events. Because life-threatening muscle spasms and secondary ventilation difficulties occurred following a preoperative injection of suxamethonium, Farbu et al [2003] recommended that suxamethonium be avoided in individuals with myotonia congenita. Note: Non-depolarizing muscle relaxants seem to act normally in individuals with myotonia congenita but do not counteract a myotonic response caused by suxamethonium [Farbu et al 2003].In rare cases, injections of adrenaline or selective beta-adrenergic agonists in high doses may aggravate myotonia.The beta-antagonist propranolol has likewise been reported to worsen myotonia [Blessing & Walsh 1977]. Accordingly, beta-agonists and beta-antagonists should be used with caution and particular care should be taken with the use of intravenous fenoterol or ritodrine.Colchicine may cause a myopathy with myotonia in individuals with renal insufficiency [Rutkove et al 1996] and may thus also, in theory, aggravate the myotonia of individuals with myotonia congenita.Evaluation of Relatives at RiskBecause individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, testing at-risk individuals during childhood to clarify their genetic status is appropriate.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposesTherapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCLCN17q34Chloride channel protein, skeletal muscleChloride channel 1, skeletal muscle (CLCN1) @ LOVDCLCN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Myotonia Congenita (View All in OMIM) View in own window 118425CHLORIDE CHANNEL 1, SKELETAL MUSCLE; CLCN1 160800MYOTONIA CONGENITA, AUTOSOMAL DOMINANT 255700MYOTONIA CONGENITA, AUTOSOMAL RECESSIVEMolecular Genetic PathogenesisCLCN1 encodes the voltage-gated chloride channel ClC-1 (chloride channel protein, skeletal muscle), which is solely expressed in the sarcolemma, where its main function is to regulate excitability and to stabilize the resting potential. The channel functions as a homodimer, and autosomal recessive myotonia congenita is believed to result from two mutant alleles that reduce functionality, whereas autosomal dominant myotonia congenita is believed to result from a dominant-negative mutation 'poisoning' the channel.Normally, the chloride conductance contributes 85% to the resting membrane conductance of human muscle, ensuring its electrical stability. The chloride conductance is crucial for countering the depolarizing effect of potassium (K⁺) accumulation in T tubules. If the chloride conductance is reduced to 40% or less, K⁺ accumulation in the T-tubular lumen depolarizes the surface membrane sufficiently to initiate self-sustaining action potentials causing a prolonged (myotonic) contraction [Barchi 2001]. A reduction of chloride conductance to 50% apparently does not cause myotonia, because heterozygous carriers of non-functional (‘autosomal recessive’) mutations are asymptomatic.On a research basis, the functional consequences of a number of CLCN1 mutations have been investigated by expression of the corresponding mutated cDNA sequences in Xenopus oocytes or mammalian cells followed by whole-cell patch-clamp recordings.The myotonic phenotype of myotonic dystrophy type 1 (DM1; caused by mutation in DMPK) is believed to result from mutated DMPK-misregulated splicing of CLCN1, rendering the protein non-functional [Charlet-B et al 2002, Mankodi et al 2002]. Normal allelic variants. CLCN1 spans 36 kb and contains 23 exons with a transcript length of 3093 nucleotides. Twelve normal allelic variants within the coding sequence are known [Pusch 2002].Pathologic allelic variants. More than 150 different mutations have been identified, the majority of which are associated with autosomal recessive myotonia congenita. Mutations (both recessive and dominant) appear to be scattered throughout the coding sequence and are mostly missense or nonsense mutations (Table 2). Mutations causing dominant myotonia congenita are often located in exon 8 [Fialho et al 2007].Table 2. Selected CLCN1 Pathologic Allelic VariantsView in own windowMode of InheritanceDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹) Reference SequenceDominantc.394A>Tp.Ser132CysNM_000083​.2
NP_000074​.2c.592C>Gp.Leu198Valc.577G>Ap.Glu193Lysc.803C>Tp.Thr268Metc.847C>Tp.Leu283Phe c.857T>Cp.Val286Alac.870C>Gp.Ile290Metc.929C>Tp.Thr310Metc.937G>Ap.Ala313Thrc.1412C>Tp.Ser471Phec.1439C>T ^{2p.Pro480Leuc.1438C>Ap.Pro480Thrc.1655A>Gp.Gln552Argc.1667T>Ap.Ile556Asnc.2512_2513insCTCAp.His838Profs*35
(fs872X)Dominant and recessivec.382A>Gp.Met128Valc.689G>Ap.Gly230Gluc.920T>Cp.Phe307Serc.929C>TpThr310Metc.950G>Ap.Arg317Glnc.1013G>Ap.Arg338Glnc.1592C>Tp.Ala531Valc.2680C>Tp.Arg894X 3c.2795C>Tp.Pro932Leuc.2330delGp.Gly777Alafs*17 4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. The mutation present in Dr. Thomsen himself3. Probably the most common semi-dominant mutation4. Kuo et al [2006], Lin et al [2006]Normal gene product. CLCN1 encodes the protein ClC-1, which consists of 988 amino acids and contains numerous transmembrane domains. The functional ClC-1 channel contributes approximately 80% of the total resting conductance and determines membrane excitability.Abnormal gene product. Recessive mutations are presumed to cause loss of function of the channel; dominant mutations presumably act through a dominant-negative mechanism, by affecting either dimerization or ion selectivity of the channel.}