Myotonia Congenita

Etiology

In skeletal muscle, action potentials are generated through the activation of voltage-gated sodium channels, resulting in depolarization of the sarcolemmal membrane. Unlike neurons, chloride channels are the principal drivers of repolarization. ClC-1 is the predominant chloride channel in the sarcolemmal membrane, contributing to 80% of resting muscle membrane conductance.

Myotonia congenita stems from defective ClC-1 channels due to mutations in the CLCN1 gene.[7][8] The resulting defect confers hyperexcitability through impaired repolarization of the muscle membrane. The faulty ClC-1 channels reduce chloride conductance across the sarcolemma, impairing the ability of skeletal muscle to maintain physiological excitability. Since ClC-1 accounts for most of the resting muscle membrane conductance, CLCN1 mutations significantly increase skeletal muscle input resistance.[9]

ClC-1 channels also counteract the depolarizing effect of excessive extracellular potassium accumulation during repeated action potentials. In healthy individuals, this elevated potassium concentration is balanced by functional ClC-1 channels. Loss of this stabilizing effect, as in myotonia congenita, renders the membrane highly sensitive to even minor potassium fluctuations. These small variations can trigger spontaneous action potentials, further potentiating myotonic symptoms. This mechanism explains why sodium channel blockade is a major therapeutic strategy in myotonia congenita.

Epidemiology

The frequency of myotonia congenita was historically estimated at 1 in 23,000 for the autosomal dominant form and 1 in 50,000 for the autosomal recessive type. More recent data indicate that the dominant form is less common than the recessive type. In a U.K. cohort of 300 patients, only 37% carried autosomal dominant mutations.[10] Both forms occur with higher prevalence in Northern Scandinavia, reaching 1 in 10,000, which is approximately 10 times greater than the worldwide prevalence.[11][12][13]

History and Physical

The cardinal feature of myotonia congenita is delayed relaxation of contracted skeletal muscle.[14] Considerable phenotypic variability occurs in both autosomal dominant and autosomal recessive forms, which can hinder timely diagnosis and management. Identical CLCN1 mutations may produce markedly different clinical presentations, reflecting the complexity of genotype-phenotype correlations in these channelopathies.[15] Conversely, some mutations give rise to highly consistent phenotypes. Detailed family history may help clarify the inheritance pattern, although this information may be absent in sporadic cases.

In early childhood, symptoms may include feeding difficulties such as dysphagia, reflux, gagging, and choking. Children may appear clumsy and fall frequently even after walking is established. Difficulty opening the eyes after prolonged contraction, such as crying, may also be observed. These signs may be subtle, making careful history from patients and caregivers, as well as clinical examination, essential. Symptoms often progress after onset and then plateau.[16]

Muscle stiffness in myotonia congenita often improves with exercise or repetitive movement, a phenomenon termed the “warm-up effect,” which is rapidly lost after cessation of activity. Men appear to be more severely affected than women. Symptoms also often worsen during pregnancy and menstruation, suggesting that sex hormones influence ClC-1 channel function.[17][18]

Myotonia congenita is classically divided into distinct clinical entities based on the mode of inheritance, with Becker and Thomsen disease being the 2 primary forms. Despite subtle differences between these conditions, the phenotypic variability discussed above means that the ultimate diagnosis is confirmed with genetic testing.

Becker disease is inherited in an autosomal recessive manner and associated with moderate-to-severe myotonia and transient weakness, which may become progressive in some cases.[19] The disease generally presents later in childhood than Thomsen disease.[20] Muscle hypertrophy is more prominent in Becker disease, particularly in the larger muscle groups of the lower limbs.

Thomsen disease is inherited in an autosomal dominant pattern and typically associated with an earlier onset of symptoms, although the manifestations are milder than in Becker disease. The mild, progressive, permanent weakness often described in Becker disease does not occur in Thomsen disease.[21] Autosomal dominant mutations responsible for Thomsen disease demonstrate reduced penetrance, and identical mutations inherited across generations can result in markedly different phenotypes.

Evaluation

Clinical examination often reveals myotonia, which may be elicited by asking patients to open and close their eyes or fists repeatedly. Repeated tapping of a muscle can similarly induce myotonia, and patients may have difficulty extending the fingers immediately after a handshake. The warm-up effect, where stiffness improves with repeated activity, may also be demonstrable.

Biochemical investigations are usually unremarkable, although mild elevations of creatine kinase up to 3 to 4 times the upper limit of normal have been described. Electromyography (EMG) is useful in evaluating patients with myotonia, but the technique is time-consuming, uncomfortable, and may yield overlapping findings across different skeletal muscle channelopathies.[22] Diffuse myotonic discharges with spontaneous bursts of electrical activity are typically demonstrated. EMG does not distinguish between autosomal dominant and autosomal recessive myotonia congenita. Given the widespread availability of molecular diagnostics, muscle biopsy is now rarely performed. When obtained, biopsies may show heterogeneous fiber size, increased central nuclei, and absence of type 2B fibers, but these findings are not required to establish the diagnosis.[23]

Genetic testing is considered the gold standard for diagnosis. The most commonly implicated gene is CLCN1, which encodes the skeletal muscle chloride channel ClC-1. However, no pathogenic CLCN1 variants are identified in many patients with a convincing clinical phenotype.

A multigene panel is generally recommended as the initial approach. Such panels include CLCN1 and other genes of interest, notably SCN4A, which encodes the skeletal muscle sodium channel Nav1.4 and is relevant in the differential diagnosis. Testing should be performed in specialized centers where appropriate methodologies are used to evaluate variants of uncertain significance, correlate identified mutations with clinical features, and limit costs. Broader genomic methods, such as exome sequencing or mitochondrial sequencing, may be pursued if no causative variant is identified on panel testing.[24][25]

Treatment / Management

Pharmacological management of myotonia congenita is not always indicated, and a neurologist should evaluate patients to determine the need for medication before initiation.[26] Lifestyle modifications include avoidance of identified triggers such as stress and cold. Exercise, particularly gymnastics, has been anecdotally reported to relieve myotonia, although this observation requires further investigation.

Medications are generally intended to reduce muscle membrane hypersensitivity by blocking sodium ion flow.[27][28] Mexiletine is the most commonly prescribed drug, but use requires electrocardiographic monitoring of the QT interval before and during treatment.[29] This agent is classified as a class Ib antiarrhythmic and is structurally related to the local anesthetic lidocaine. Mexiletine is primarily used to manage ventricular arrhythmias by blocking the rapid sodium influx responsible for phase 0 of the action potential, thereby shortening the action potential and prolonging the refractory period.[30] Reported adverse effects include tremor, dizziness, ataxia, and gastrointestinal disturbance. These effects are usually dose-dependent and reversible after dose reduction or discontinuation.(A1)

Other sodium channel anticonvulsants such as phenytoin, carbamazepine, oxcarbazepine, and lamotrigine are also commonly used.[31] Acetazolamide is effective as well, particularly in children, because of its favorable safety profile.[32](B3)

Potassium channels have emerged as a novel therapeutic target. The potassium channel activator retigabine has been investigated in murine models of myotonia congenita, where it significantly reduced myotonia severity in vivo. However, evidence to guide pharmacological management is limited.[33](A1)

Special caution is required when treating individuals with myotonia congenita during anesthesia, particularly with depolarizing agents. Muscle spasms and ventilation difficulties have been reported with the use of suxamethonium in patients with this condition.[34](B3)

Differential Diagnosis

Myotonia congenita is the most common nondystrophic myotonia. The condition is termed "nondystrophic" because muscle tissue is not structurally compromised in the disease process. Instead, defective ion channels in skeletal muscle alter ion conductance and produce myotonia. Dysfunction of chloride channels characterizes myotonia congenita, whereas mutations in sodium channel genes cause other nondystrophic myotonias, including paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis. Mutations in the SCN4A gene lead to abnormal function of voltage-gated sodium channels.

Symptoms of myotonia congenita are often most pronounced in the lower limbs, with patients frequently experiencing difficulty rising quickly from a seated position. In contrast, paramyotonia congenita more severely affects the eyes and face. Myotonia associated with hyperkalemic periodic paralysis is generally mild and commonly involves the eyelids and tongue. 

Potassium channel disorders typically worsen after ingestion of potassium-rich foods, and patients often describe their myotonia as painful, a feature not characteristic of myotonia congenita. Careful evaluation of precipitating and relieving factors, associated systemic disease, and EMG findings often permits clinical distinction between myotonia congenita and other channelopathies.

Myotonic dystrophies are another important differential diagnosis in infants and children with muscle weakness and spasticity. Myotonic dystrophy types 1 and 2 are associated with systemic features such as endocrine dysfunction, cardiac conduction defects, and cataract formation. The distribution of muscle weakness in myotonic dystrophy is also distinct from that observed in myotonia congenita.

Prognosis

Neither autosomal nor recessively inherited myotonia congenita is associated with systemic effects or reduced life expectancy. Prognosis differs markedly from that of myotonic dystrophy, which makes accurate diagnosis essential. Symptoms of myotonia congenita generally do not progress once they appear. Becker disease is typically associated with more severe manifestations than Thomsen disease, and permanent weakness may persist. Genetic counseling is important to support informed decisions about family planning.

Complications

Care must be taken during anesthesia, particularly with depolarizing muscle relaxants, which have been associated with adverse events in patients with myotonia congenita, including profound muscle spasm and difficulty with ventilation. Medications that should be avoided, or used only with caution, include the following:

• Suxamethonium: may produce severe muscle spasm and ventilation difficulties
• Adrenaline and β-agonists: may aggravate symptoms
• β-antagonists: may increase symptom severity
• Colchicine: may trigger myopathy, particularly in patients with renal insufficiency

Pregnancy has been associated with worsening of myotonia congenita, which necessitates interprofessional management throughout gestation, delivery, and the postpartum period.