Myotonia Congenita

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.

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] (full text); 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 multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of CLCN1 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes CLCN1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of myotonia congenita.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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].

Diseases to Consider in the Differential Diagnosis

Paramyotonia congenita (OMIM 168300) (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 608390) (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.

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.

• If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
• If the pathogenic variant(s) in the family are not known, electromyography can be used to clarify the disease status of at-risk relatives.

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 in the US and EU Clinical Trials Register in Europe 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.