Myotonia Congenita (CLCN1) and Nondystrophic Skeletal Muscle Channelopathies

Thomsen and Becker myotonia congenita due to CLCN1 variants, SCN4A-related myotonias and periodic paralyses, CACNA1S-related hypokalaemic periodic paralysis, KCNJ2-related Andersen-Tawil syndrome, and biallelic SCN4A congenital myopathy.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

This article treats myotonia congenita (MC) caused by variants in the CLCN1 gene as its principal entity, in its autosomal dominant (AD, Thomsen disease) and autosomal recessive (AR, Becker disease) forms, and groups the other skeletal muscle channelopathies that enter the differential diagnosis: the SCN4A-related nondystrophic myotonias (NDM) (paramyotonia congenita and sodium channel myotonias), the primary periodic paralyses (PP), and the congenital myopathy caused by biallelic loss of function of SCN4A. Andersen-Tawil syndrome (ATS), myotonic dystrophy and malignant hyperthermia (MH) are addressed insofar as they overlap with the muscle channelopathies [1–3].

0.1. Identification of the entities

Sources for Table 0.1: [1, 3–22].

0.2. Key clinical data

The sources for specific treatment and for the European reference network are the summary of product characteristics (SmPC) of Namuscla®, the 2020 international guideline, and the ERN EURO-NMD (European Reference Network for Rare Neuromuscular Diseases) website [2, 3, 27, 28].

1. Introduction

1.1. Myotonia: definition and first descriptions

Myotonia is delayed muscle relaxation after voluntary contraction or mechanical percussion. The 2020 international guideline on NDM credits Strümpell, in 1881, with describing myotonia after voluntary contraction, and Erb with describing percussion myotonia [2]. Clinically, myotonia manifests as stiffness, cramps, "locking" of a movement, or difficulty releasing a grasped object; electrically, it corresponds to bursts of muscle fibre action potentials that persist after the nerve command has ceased. The distinction between dystrophic myotonia (myotonic dystrophy types 1 and 2, with multisystem involvement and progressive weakness) and nondystrophic myotonia (pure sarcolemmal channelopathies, without progressive atrophy or intrinsic cardiac involvement) frames the entire diagnostic reasoning [1, 2].

1.2. From physiology to gene

The bridge between clinical medicine and physiology came from an animal model. In 1966, Lipicky and Bryant showed in the myotonic goat that reduced chloride conductance was associated with hyperexcitability with afterdischarges, and in 1971 they demonstrated an approximately twofold reduction in chloride permeability in muscle fibres from patients with myotonia [2]. In 1992, Koch and colleagues cloned the complementary DNA of the human skeletal muscle chloride channel (CLC-1), mapped it to chromosome 7 near the TCRB locus, demonstrated tight linkage to both recessive generalised myotonia (Becker) and dominant MC (Thomsen) in German families, and identified, in two families with the Becker form, the phenylalanine→cysteine substitution now designated p.(Phe413Cys); they concluded that different variants in the same gene caused the dominant and recessive forms [29]. Shortly before, the first SCN4A variants had been described in HyperPP in 1991, and in PMC and sodium channel myotonia in 1992 [2]. In 1996, Zhang and colleagues described CLCN1 variants associated with both the dominant and recessive forms, and Koty and colleagues documented dominant variants with variable penetrance and a founder effect [30, 31].

1.3. Nomenclature and reclassification

GeneReviews designates the AD form as Thomsen disease and the AR form as Becker disease; both are also called chloride channel myotonia, and the "myotonia levior" described in the older literature is essentially the same disease [1]. The Oxford Desk Reference summarises the classic clinical difference: the two forms are similar, but transient weakness is seen in Becker disease and not in Thomsen disease, and blepharospasm is more frequent in the recessive variant [32]. Orphanet groups the two forms in a single entry, "Thomsen and Becker disease" (ORPHA:614), within the group of genetic chloride channel defect muscle channelopathies [8, 9]. The Brazilian textbook "Síndromes Genéticas: Reconhecer para Tratar" [Genetic Syndromes: Recognise to Treat], in its box on Steinert myotonic dystrophy, uses "Thomsen disease" for the congenital form of myotonic dystrophy type 1 with more than 1,000 CTG repeats; this designation does not match international usage, in which Thomsen disease is dominant CLCN1-related MC [33].

PMC was described by Eulenburg. Sodium channel myotonia was historically called potassium-aggravated myotonia; Rüdel and colleagues proposed the term sodium channel myotonia because not all patients are potassium-sensitive and because potassium loading rarely demonstrates this [2]. The SCM spectrum includes myotonia fluctuans (stiffness that varies from day to day), myotonia permanens (continuous myotonic activity), and acetazolamide-responsive myotonia [11–13, 19]. The 2020 guideline classifies NDM into two genotypic groups, chloride channelopathies (CLCN1) and sodium channelopathies (SCN4A), subdivided by inheritance and phenotype [2]. For the PP, the 2018 review by Statland and colleagues proposes an SCN4A continuum that runs from pure myotonia to myotonia with episodic weakness (PMC) and to episodic weakness with occasional myotonia (HyperPP and NormoPP); whether a patient is classified as having PMC or HyperPP depends on the predominant symptoms [3].

1.4. Scope

Some listings associate CACNA1S with MC. This association is unsupported: GeneReviews considers CLCN1 the only MC gene and describes no other allelic phenotypes of CLCN1, and CACNA1S causes HypoPP type 1, MH susceptibility type 5, and congenital myopathy, without myotonia [1, 6]. CACNA1S is therefore included only in the differential diagnosis of the PP and of malignant hyperthermia susceptibility. SCN4A-associated congenital myopathy refers to a biallelic loss-of-function entity described by Zaharieva and colleagues in 2016, distinct from the gain-of-function channelopathies, and is treated in its own subsection [22].

The entities are defined as follows. MC is a nondystrophic myotonia caused by loss of function of the ClC-1 channel, with generalised stiffness that improves with repeated movement and, often, muscle hypertrophy [1]. PMC is a myotonia caused by Nav1.4 gain of function that worsens with repeated movement and with cold and may be followed by true weakness [1, 19]. SCM is a myotonia caused by Nav1.4 gain of function, without episodic paralysis, that may worsen with potassium and with vigorous exercise [19]. The primary PP are attacks of flaccid weakness associated with changes in serum potassium, with normal potassium between attacks [3, 19, 20]. Biallelic SCN4A congenital myopathy is a myopathy of fetal or neonatal onset, without myotonia, with fetal hypokinesia in the severe forms [22].

2. Molecular Genetics and Pathophysiology

2.1. The ClC-1 channel and muscle membrane stability

CLCN1 (7q34; HGNC:2019; MANE Select transcript NM_000083.3) encodes ClC-1, the voltage-gated chloride channel of the sarcolemma and transverse (T) tubules [4, 34]. In skeletal muscle, unlike in neurons, where potassium currents dominate, chloride conductance is the main resting conductance: GeneReviews attributes to it about 85% of total resting membrane conductance in one paragraph and about 80% in the next, so the reference value is 80–85% [1, 2]. This conductance stabilises the resting potential and counteracts the depolarising effect of the potassium that accumulates in the narrow lumen of the T tubules during repetitive activity. When chloride conductance falls to about 40% of normal or less, potassium accumulation in the T tubules depolarises the surface membrane enough to generate self-sustaining action potentials, which are the substrate of electrical and clinical myotonia [1, 4]. A reduction to about 50%, such as that of a heterozygote for a nonfunctional allele, does not consistently cause myotonia; pharmacologic studies with ClC-1 blockers indicate that conductance must fall below half of normal [1, 2]. A complementary model proposes that accumulated potassium activates a persistent sodium current that sustains the discharges; neither model explains the spontaneous termination of a myotonic burst or the warm-up phenomenon [2]. In mice exposed to a chloride channel inhibitor, high extracellular calcium and magnesium concentrations reduce myotonia, which underpins lines of therapeutic research [2].

ClC-1 is a homodimer in which each subunit forms its own pore ("protopore"), with its own fast gate and a slow gate common to both subunits; the channel is selective for chloride over thiocyanate, bromide, nitrate, and iodide [4]. The dimeric architecture explains the dual inheritance: an allele with complete loss of function reduces conductance to about half and causes disease only when the second allele is also affected (AR inheritance), whereas a mutant subunit that associates with the normal subunit and inactivates it ("dominant-negative effect") reduces conductance below the critical threshold with a single allele (AD inheritance) [1, 2, 4].

2.2. Dominant and recessive CLCN1 variants

GeneReviews counts more than 318 different pathogenic CLCN1 variants, most associated with the AR form and scattered across the coding sequence, chiefly missense and nonsense variants [1]. The AD-form variants are, with the exception of c.2680C>T p.(Arg894Ter), missense variants and cluster in exon 8, which encodes part of the dimer interface domain; Fialho and colleagues, in a UK cohort, described this "hotspot" of dominant-negative interactions [1, 35]. A subset of presumed loss-of-function variants located downstream of the dimer interface is also associated with AD inheritance, and Skálová and colleagues, in an in silico analysis of Czech patients, linked the dominant variants to effects on dimerisation [1, 36]. Brugnoni and colleagues identified, in a large Italian cohort, a region of high variant frequency in exons 4 and 5 [37]. The 2020 guideline, based on the English and Dutch series, states that most variants are missense, with no predominant exon, and that about 30% are small deletions, duplications, insertions, or frameshift variants [2].

About 20 variants are associated only with the AD form and about 12 with both the AD and AR forms, which makes it difficult to predict the mode of inheritance from the variant [1]. Unequivocal pedigrees with both AR and AD inheritance have been described only for p.(Gly230Glu), p.(Thr310Met), p.(Ala531Val), and p.(Arg894Ter). Proposed explanations include reduced penetrance of dominant-negative variants, incomplete dominance, haplotype background, incomplete detection of a second variant, and differences in allelic expression [1, 30, 31, 38]. Dunø and colleagues demonstrated differences in CLCN1 allelic expression with a possible influence on phenotype [38]. The p.(Arg894Ter) variant is the most frequent of those associated with both forms and requires cautious interpretation, because it is found frequently in presumably healthy individuals in gnomAD, indicating reduced penetrance; most reports on this variant predate gnomAD, and its allele frequency was not checked for this article [1]. Heterozygotes for recessive alleles are generally asymptomatic, although a parent or sibling may show subtle myotonia on EMG without any risk of developing disease [1, 4].

Exon deletions and duplications account for 1–3% of pathogenic CLCN1 variants, mostly large intragenic deletions, with a single large duplication described; they have not been identified in the AD form [1]. In 2026, Helal and colleagues described two sisters with recessive MC who were compound heterozygous for c.871G>A p.(Glu291Lys) and a deep intronic variant, c.697-620T>G, which creates a cryptic donor site, includes an out-of-frame cryptic exon, and leads to partial degradation of the messenger RNA by nonsense-mediated decay, with 70:30 allelic expression; the variant was identified by genome sequencing and confirmed by muscle RNA sequencing [39]. The reference transcript is not stated in the abstract; the nomenclature on NM_000083.3 was verified in VariantValidator [34].

2.3. Normalised reference variants

GeneReviews uses transcript NM_000083.2 for CLCN1 and NM_000069.2 for CACNA1S; the current MANE Select transcripts, confirmed in VariantValidator (GRCh38), are NM_000083.3 (CLCN1), NM_000334.4 (SCN4A), and NM_000069.3 (CACNA1S) [1, 20, 34]. None of these genes has a signal peptide or historical numbering that differs from HGVS for the variants listed; the historical one-letter notation (for example, R894X) corresponds directly to the HGVS codon [34].

Sources for the table: [1, 3, 20, 29, 34, 39–44]. The ClinVar column shows only the classifications actually checked; "not checked" does not mean that no record exists.

2.4. Genotype–phenotype correlation, penetrance, and modifiers in MC

GeneReviews recognises no clear genotype–phenotype correlations in MC beyond the association of loss-of-function variants with the AR form; expression varies within the same family, and AD-form variants may show reduced penetrance [1, 37, 45, 46]. The 2020 guideline confirms the variable severity among relatives carrying the same variant [2]. Nagamitsu and colleagues described a "dystrophic" variant of recessive MC, with weakness, caused by novel CLCN1 variants [47]. An allele carrying two pathogenic variants in cis has also been described, which makes it necessary to confirm phase by segregation analysis [1, 37].

Genes interact. A coexisting CLCN1 variant in patients with SCN4A-related myotonia can modulate and exaggerate the phenotype, as Furby and colleagues showed [1, 48]. In patients with confirmed myotonic dystrophy type 2 (DM2), CLCN1 variants can exaggerate the phenotype, as in the cosegregation with a recessive CLCN1 variant in juvenile-onset DM2 described by Cardani and colleagues [1, 49]. The 2020 guideline notes that a subgroup of patients with DM2 has a modifier variant in CLCN1 or SCN4A [2]. Tugizova and colleagues described a man with severe adult-onset NDM, laryngospasm, and apnoea who carried c.1478C>A p.(Ala493Glu) in CLCN1, inherited from his father without myotonia, and c.5107_5109del p.(Glu1703del) in SCN4A, inherited from his mother with subtle myotonia, which the authors interpreted as an additive digenic effect (section 10) [42].

2.5. Nav1.4 and the gain-of-function sodium channelopathies

SCN4A (17q23.3; MANE NM_000334.4) encodes the pore-forming alpha subunit of Nav1.4, the voltage-gated sodium channel responsible for the depolarisation phase of the muscle action potential [5, 34]. All sodium NDM result from gain of function, through enhanced activation or impaired inactivation [2]. In the normal channel, the persistent current is about 0.2% of the peak transient current; in HyperPP variants, incomplete fast inactivation raises it to 1–4%, a 5- to 20-fold relative increase [19]. Modest depolarisation brings the fibre closer to threshold and produces repetitive firing (myotonia); greater depolarisation inactivates the remaining channels and renders the fibre inexcitable (paralysis) [2, 5]. The normal resting potential is about −85 mV; in HyperPP, repetitive firing raises potassium in the T tubules and, combined with the inactivation defect, holds the fibre depolarised at about −45 mV, by which point it is inexcitable [19]. Changes in serum potassium shift the resting potential and precipitate attacks [5]. Larger persistent currents and slow-inactivation defects are associated with paralysis; smaller persistent currents or transient defects are associated with myotonia [2].

About 20 AD SCN4A missense variants cause PMC or SCM, with hotspots in exons 22 and 24, and fewer than 10 cause HyperPP [2]. The HypoPP GeneReviews chapter groups the variants by phenotype and mechanism (protein on the NP of NM_000334.4) [20]:

The p.(Gly1306Glu) variant causes myotonia permanens with neonatal laryngospasm, and other variants at the same codon, such as p.(Gly1306Ala), can cause neonatal respiratory failure [20]. GeneReviews contains two typos in this list: p.(Arg1451Cys) is listed twice, and the PMC variant is printed as "p.Phe11705Ile," which corresponds to NM_000334.4:c.5113T>A p.(Phe1705Ile) [20, 34]. The p.(Ser906Thr) polymorphism, when it coexists with p.(Ile692Met), is associated with longer attacks, more muscles affected, higher creatine kinase (CK), and permanent weakness [19]. In mouse models, the delay in attack onset until the 1st decade and progression in adolescence depend on the Nav1.4 content of the fibre [19]. Penetrance of HyperPP exceeds 90%, and some carriers have myotonia only on EMG [19]. SCN4A is not an established MH susceptibility gene: anaesthetic complications resembling an MH crisis probably result from severe myotonic reactions [5, 19]. In 2026, D'Ambrosio and colleagues published a review of SCN4A variant interpretation under the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, centred on phenotype and mechanism (pore gain of function, S4 segment gating pore current, reduced channel availability, and biallelic loss of function) [50]. A possible relationship between SCN4A variants and Brugada syndrome or arrhythmogenesis is under discussion, with insufficient data for conclusions [2].

2.6. Cav1.1 and the gating pore current in HypoPP

CACNA1S (1q32.1; MANE NM_000069.3) encodes Cav1.1, the alpha-1S subunit of the L-type calcium channel (dihydropyridine receptor) in the T tubules, which activates RYR1 to release calcium from the sarcoplasmic reticulum [6, 34]. In HypoPP type 1, substitutions of arginines in the S4 voltage-sensor segment create an aberrant current through the sensor, the "gating pore," which, at low extracellular potassium (about 2.5–3.5 mmol/L), holds the fibre paradoxically depolarised and inexcitable [3, 6]. Reported variants include NM_000069.3:c.1583G>A p.(Arg528His), p.(Arg528Gly), p.(Arg528Cys), p.(Val876Glu), p.(Arg897Ser), p.(Arg900Ser), c.3716G>A p.(Arg1239His), and p.(Arg1239Gly); biopsy shows vacuoles with p.(Arg528His) [20, 34]. The contribution of each gene to HypoPP varies with the denominator: GeneReviews attributes 40–60% of cases to CACNA1S, 7–14% to SCN4A, and about 30% to unknown causes; Statland and colleagues report CACNA1S in 60% and SCN4A in 20% of families; GeneGuidance reports CACNA1S in about 70% of familial HypoPP [3, 6, 20]. Penetrance is at least 90% in males and reduced in females, except for arginine-to-glycine substitutions; HypoPP type 1 and type 2 cannot be distinguished clinically [20]. CACNA1S is also an MH susceptibility gene (type 5), and patients with CACNA1S-related HypoPP are considered at risk of MH [6].

2.7. Kir2.1 and other periodic paralysis genes

In ATS, loss of function of Kir2.1, the inward rectifier channel responsible for the IK1 current, usually results from dominant-negative missense variants that affect function, trafficking, or binding to phosphatidylinositol 4,5-bisphosphate; a heterozygous whole-gene deletion has been described as a cause of sudden death [7]. KCNJ2 is identified in about 60% of patients with ATS [3]. KCNJ18 accounts for up to 3% of HypoPP, mainly thyrotoxic, KCNE3 has a disputed association, and KCNJ5 has been described in one family with ATS and in one of 21 patients with ATS without a KCNJ2 variant [3]. The differential diagnosis table in the HyperPP GeneReviews chapter attributes thyrotoxic PP to the "Kir 6.2" channel, but KCNJ18 encodes Kir2.6 (Kir6.2 is the product of KCNJ11) [19].

2.8. Biallelic SCN4A loss of function: congenital myopathy and myasthenic syndrome

Recessive SCN4A loss-of-function variants cause a distinct group of disorders, as a rule without myotonia: congenital myasthenic syndrome 16 (OMIM 614198), congenital myopathy 22A (OMIM 620351), and severe fetal congenital myopathy 22B (OMIM 620369); ClinGen classifies the association between SCN4A and AR myopathy as "definitive" [2, 5]. Zaharieva and colleagues used exome sequencing to identify homozygous or compound heterozygous SCN4A variants in 11 individuals from 6 unrelated families with congenital myopathy. In HEK293 cells, the variants produced nonfunctional channels or channels with reduced activity; all cases had at least one allele with complete loss of function, and in 5 of the 6 families the second allele, in trans, was also loss-of-function [22]. In congenital myasthenic syndrome, biallelic loss of function manifests as generalised fatigable weakness and recurrent episodes of respiratory and bulbar paralysis from birth [19]. When interpreting a result, therefore, the same gene can account for a dominant gain-of-function disorder and a recessive loss-of-function disorder, and the predicted mechanism of the variant must be consistent with the phenotype [50].

2.9. Myotonia in myotonic dystrophy

In myotonic dystrophy type 1 (DM1), the CTG expansion in DMPK causes splicing alterations in distant genes, including the chloride channel gene, which underlies myotonia in DM1 [51].

3. Clinical Spectrum and Manifestations by System

3.1. Myotonia congenita: clinical picture

MC manifests as muscle stiffness from childhood that can involve all striated muscle groups, including the extraocular muscles, facial muscles, and tongue [1]. Stiffness is greatest on the first movement after a period of rest and eases with repeated contractions, the warm-up phenomenon: the first steps after sitting are stiff, and subsequent steps become progressively easier [1, 52]. On examination, the patient may be unable to extend the fingers after a handshake (grip myotonia), and percussion of the tongue, finger extensors, or thenar eminence elicits a localised myotonic contraction [1, 32]. The muscles are usually hypertrophic, sometimes with a "Herculean appearance," typical of the recessive form but also seen in the sodium channelopathies [1, 2]. The AR form is generally more severe and is associated with mild progressive distal weakness and with episodes of transient weakness lasting seconds on initiating movement after rest (transient paresis), which the AD form does not show [1, 2]. Occasionally there is proximal weakness or distal myopathy [1, 47]. Blepharospasm is common, especially in the Becker form [32]. Extramuscular manifestations are generally absent; arrhythmias and conduction defects were described in a minority of patients in a German cohort, of uncertain clinical significance [1, 53]. The French expert group considers that the cardiac abnormalities described in patients with CLCN1 or SCN4A variants were isolated observations in older patients with comorbidities or benign findings, such as isolated atrial premature beats, and that the NDM population has no increased risk of arrhythmia or conduction disorder compared with the general population [54].

GeneReviews compares the two forms by mode of inheritance [1]:

Factors that aggravate myotonia include cold, pregnancy, menstruation, dietary potassium (especially in SCM), hunger, and emotional stress; most patients with chloride channelopathy report cold sensitivity, though less marked than in PMC [1, 2]. In children, the main symptom of MC is leg stiffness, which translates into running and jumping less, falls, and an "odd gait"; the guideline also describes a child with jaw myotonia and dysphagia, contractures, and a patient with progressive scoliosis who underwent surgery [2]. On examination, strabismus, scoliosis, and contractures occur mainly in children [2].

3.2. Cohorts and the proportion of dominant and recessive forms

In a UK cohort of more than 300 patients with a molecular diagnosis, 70% of families had the AR form and 30% the AD form [1, 35]. Comparable distributions have been described in Italian, Spanish, and German cohorts, whereas in Denmark the AD form is more frequent than the AR form [1, 38, 46, 53, 55]. In northern Finland, Baumann and colleagues identified 58 patients in 23 families, with mean onset at age 11 years (2–45), a mean delay to confirmation of 18 years (standard deviation 14), and a male:female ratio of 2.2:1.0; of the pedigrees, 6 were consistent with AR inheritance, 2 with AD, and 5 with AR inheritance with vertical transmission, explained by consanguinity or variable expression [25]. Subsequent molecular analysis of the same population showed that, even in families with apparent dominant transmission, the actual inheritance was autosomal recessive, with many compound heterozygotes owing to the enrichment of three founder variants [41].

The prospective observational study of the CINCH consortium (Consortium for Clinical Investigation of Neurologic Channelopathies) enrolled 95 participants with definite or suspected NDM at 6 centres in the United States, the United Kingdom, and Canada between March 2006 and March 2009: 32 with chloride channelopathy, 34 with sodium channelopathy, 9 with DM2, 1 with DM1, and 17 with no variant identified [26]. Stiffness was the most prominent symptom (66.7% to 100% depending on the group). Comparing sodium and chloride channelopathies, stiffness began at a mean age of 5 and 10 years, myotonia on eye closure was reported by 73.5% and 25%, paradoxical eyelid myotonia was observed in 50% and 0%, and warm-up in 35.3% and 75%; the INQoL (Individualised Neuromuscular Quality of Life) disability score was 20.0 and 9.44, indicating greater impact in the sodium channelopathies; grip myotonia was present in about three-quarters [26]. Pain was the most prominent symptom in about 15% of patients, regardless of genotype, and pain and fatigue are the symptoms that weigh most on quality of life, which is comparable to that in myotonic dystrophy and lower than that of the healthy population [2].

3.3. Paramyotonia congenita and sodium channel myotonias

In PMC, episodes of generalised stiffness begin in early childhood; the stiffness is severe when cold-induced and is often followed by true weakness, and repeated contractions worsen the stiffness (paradoxical myotonia) rather than relieving it [1]. Inability to reopen the eyes after several rapid forced closures is typical, and the stiffness may give way to flaccid weakness or paralysis with intense exercise and cooling; as a rule, it is neither induced nor aggravated by potassium [19]. In a study cited by the guideline, 17 of 32 patients with PMC had episodic weakness and 4 of 32 fixed weakness, all with strength of at least 4/5 on the Medical Research Council (MRC) scale [2]. The episodic weakness of the sodium channelopathies, triggered by cold or exercise, lasts seconds to minutes and may persist for up to 2 days [2]. Overlap between PMC and HyperPP is extensive, and relatives carrying the same variant may have typical features of one or the other [19].

In the sodium channel myotonias, stiffness is severe after vigorous exercise or potassium ingestion, without paralysis; the spectrum ranges from myotonia fluctuans, with stiffness that fluctuates from day to day or goes unnoticed, to myotonia permanens, with continuous myotonic activity on EMG and generalised hypertrophy that includes the face [19]. Compared with MC, the SCN4A-related myotonias are more often associated with eyelid-closure myotonia and pain, may show delayed-onset myotonia after exercise, and, in PAM, may be associated with episodes of HyperPP; falls are more frequent in MC [1]:

3.4. Paediatric presentations and neonatal laryngospasm

Paediatric presentations are more diverse in the sodium channelopathies and include limb and eyelid myotonia, diplopia or blurred vision, strabismus, stridor, and choking [2]. In newborns with an SCN4A variant, the severe neonatal episodic laryngospasm (SNEL) phenotype combines hypertonia and laryngospasm with stridor and apnoea, triggered by crying or cold, and can be fatal without diagnosis and antimyotonic treatment [2, 54]. Ogueri and colleagues described two sisters aged 7 and 3 years with SNEL and PMC due to heterozygous, paternally inherited p.(Gly1306Glu), one of whom also carried an additional maternally inherited pathogenic CLCN1 variant [44]. Respiratory failure due to laryngospasm can also occur in adults: the patient of Tugizova and colleagues, with variants in CLCN1 and SCN4A, had repeated hospitalisations for sudden hypoxemic and hypercapnic respiratory failure in adulthood (section 10) [42].

3.5. Course over the lifespan and treated disease

NDM do not cause progressive atrophy, and life expectancy is generally normal [2]. Trip and colleagues, cited by the guideline, found that most patients report moderate worsening over their lifetime [2]. Fixed weakness is occasional and rarely below MRC grade 4 [2]. Pregnancy worsens symptoms in most women: in a study of 25 women with NDM and 63 pregnancies, symptoms worsened in 62% of pregnancies, with complete resolution in 66% and partial resolution in 32% after delivery [56]. The available natural history data mix treated and untreated patients: in the CINCH study, 39% of patients were not receiving antimyotonic treatment despite being symptomatic [2, 26]. The mexiletine and lamotrigine trials, described in section 7, measure the effect of treatment on stiffness in the short and medium term, not the natural history.

3.6. Hyperkalaemic periodic paralysis

HyperPP manifests as attacks of flaccid limb weakness, which may involve the ocular, pharyngeal, respiratory, and trunk muscles, with serum potassium above 5 mmol/L or a rise of at least 1.5 mmol/L during the attack, or triggered by oral potassium, with normal potassium between attacks [19]. About half of patients have their first attack in the 1st decade and only 25% after age 10 [3, 19]. The typical spontaneous attack occurs in the morning before breakfast and lasts 15 minutes to 1 hour; in about 20% of patients, attacks last more than 2 days and up to more than a week [19]. Triggers include potassium-rich foods, rest after exercise, fasting, cold, stress, fatigue, alcohol, changes in activity, and pregnancy [3, 19]. Attacks increase in frequency and severity until about age 50 and decrease thereafter [19]. More than half of patients have myotonia, especially around attacks, and about 45% have paramyotonia [19]. More than 80% of patients older than 40 report permanent weakness, and about one-third develop chronic progressive myopathy [3, 19]. In a series cited by GeneReviews (Charles 2013), respiratory muscles were affected during attacks in 26% of patients and the face in 62%, 62% reported muscle pain after attacks, 12% had severe interictal symptoms, and the relative risk of thyroid dysfunction was 3.6 [19]. Magnetic resonance imaging (MRI) showed myopathy as early as the 2nd and 3rd decades, involving the gastrocnemius and the superficial posterior compartment of the leg [19].

3.7. Hypokalaemic periodic paralysis

HypoPP manifests as attacks of flaccid weakness with potassium below 3.5 mmol/L, predominantly proximal and ascending, with normal or reduced reflexes and sparing of the cranial muscles [20]. Onset occurs between ages 2 and 30 (mean 14 years; rarely at birth and unlikely after 30), earlier in girls; attacks last 1 to 72 hours (mean about 24 hours), with a mean frequency of 7 per month, ranging from one a day to one every 4 months [20]. Mean potassium during attacks was 1.8 mmol/L in one series and 2.3 mmol/L in another, with a minimum of 1.2 mmol/L [20]. The most commonly reported triggers are exercise (about 67%), carbohydrate-rich or sweet meals (about 45%), cold (about 24%), stress (about 12%), and salt (about 11%), as well as prolonged immobility, glucocorticoids, anaesthesia, and alcohol [20]. Attack frequency peaks between ages 15 and 35 [3]. Prolonged interictal weakness developed in 28% of patients in one series (mean age 39 years); in a survey of 46 patients with a mean age of 55 years, 90% reported fatigue, 67% falls with injuries, and about half used walking aids [20]. Myopathy may be the only manifestation [20]. In an online survey of 66 patients with PP, 68% reported permanent weakness, 82% pain, 89% fatigue, and 67% fall-related injuries, and 49% used walking aids [3].

Source: Table 1 of Statland and colleagues [3].

3.8. Andersen-Tawil syndrome

ATS combines PP (hypo-, normo-, or hyperkalaemic), ventricular arrhythmias with a prolonged QT or QU interval and prominent U waves, and developmental anomalies such as low-set ears, hypertelorism, micrognathia, fifth-finger clinodactyly, syndactyly, short stature, and scoliosis [7, 51]. The full triad is seen in 58–78% of KCNJ2 variant carriers; attacks are hyperkalaemic in about 15%, normokalaemic in about 20%, and hypokalaemic in the remainder, so the response to oral potassium is unpredictable [3, 51]. The tachyarrhythmias can cause syncope and sudden death and are aggravated by hypokalaemia and digitalis; bidirectional ventricular tachycardia must be distinguished from catecholaminergic polymorphic ventricular tachycardia [7, 51]. Mild learning difficulties with a distinct neurocognitive profile (executive function and abstract reasoning) are common [19].

3.9. Biallelic SCN4A congenital myopathy

In the series of Zaharieva and colleagues, weakness began in utero or in the neonatal period; 7 of the 11 individuals died in the 3rd trimester or shortly after birth, with severe fetal hypokinesia [22]. The 4 survivors had congenital or neonatal hypotonia and weakness, mild to moderate facial and neck weakness, neonatal respiratory and swallowing difficulties, and spinal deformities in childhood, and all improved during the 1st decade [22]. Biopsy showed variability in fibre size and fibroadipose tissue, without specific structural changes, and electrophysiology was myopathic, without myotonia [22].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age and setting

In the fetus and newborn, fetal hypokinesia and congenital hypotonia and weakness with respiratory and swallowing difficulty, without myotonia, should prompt inclusion of biallelic SCN4A loss of function in the workup of congenital myopathy [22]. Episodes of stridor, apnoea, cyanosis, and hypertonia triggered by crying or cold suggest SCN4A-related SNEL, a potentially fatal condition that responds to antimyotonic treatment [2]. In children, MC presents with falls, difficulty running, jumping, or getting up from the floor, an "odd gait" after sitting, and muscle hypertrophy; in the sodium channelopathies, eyelid and facial myotonia, transient diplopia, strabismus, stridor, and choking predominate [2, 52]. In adolescents and adults, suspicion arises with stiffness after rest that eases with repetition (MC) or worsens with repetition and cold (PMC); difficulty releasing objects, opening the eyes after forceful closure, climbing stairs, or getting up quickly; and attacks of flaccid weakness associated with meals, rest after exercise, or potassium-rich foods (PP) [1–3]. The diagnostic delay is long: in northern Finland, the mean interval between onset and confirmation was 18 years [25].

Two settings deserve particular attention. The first is anaesthesia: generalised rigidity or masseter spasm after suxamethonium, with difficult mask ventilation and intubation, may be the presenting feature of the disease, as in the 32-year-old woman reported by Farbu and colleagues, whose MC was unknown both to her and to the anaesthetist [2, 57]. The second is pregnancy, during which most women report worsening and which may unmask a previously mild myotonia [2, 56].

4.2. Focused history

The 2020 guideline proposes a list of questions for the first visit [2]:

4.3. Bedside examination

Observing the patient rise from a chair, walk, and shake hands guides the examination [2]. The bedside tests proposed by the guideline are as follows [2, 32]:

Paradoxical myotonia is virtually 100% specific for sodium channelopathy, and transient paresis is 100% specific for recessive chloride channelopathy [2]. GeneReviews suggests measuring severity with questionnaires such as the Myotonia Behaviour Scale (MBS) and with timed tests: time to open tightly closed eyes, time to open a clenched fist, stair climbing, and the timed up and go test [1, 58].

4.4. Red flags for another diagnosis

Multisystem involvement (arrhythmias, cognitive changes, respiratory weakness, gastrointestinal dysfunction, early cataracts) is not a feature of NDM and should prompt investigation for myotonic dystrophy [1, 2]. Frontal balding, ptosis, temporal wasting, and progressive weakness of the neck flexors, finger flexors, and ankle dorsiflexors (DM1) or proximal weakness (DM2) also point to myotonic dystrophy [2]. A markedly elevated CK calls for investigation of another myopathy [2]. In the PP, onset after age 30, sensory symptoms, pain or dysautonomia, urinary retention, ptosis, diplopia, dysphagia or dysarthria, altered consciousness, preceding fever or back pain, tick bite, and preserved reflexes in a paralysed limb suggest another diagnosis [3, 19]. Onset of PP in adulthood suggests ATS or secondary PP [19].

4.5. Emergencies

Emergencies include laryngospasm with stridor or apnoea, especially in newborns and children with an SCN4A variant [2, 44]; generalised myotonic crisis after suxamethonium, with rigidity that prevents ventilation [2, 57]; PP attacks with respiratory muscle involvement or with extreme potassium levels and electrocardiographic changes [19, 20]; and, in ATS, syncope or ventricular tachycardia [51]. The patient information page of Muscular Dystrophy UK, reviewed in March 2025, states that an anaesthetic myotonic crisis should be treated immediately with intravenous sodium channel blockers such as lidocaine [52].

4.6. Newborn screening

The sources consulted describe no newborn screening programmes for MC or the other skeletal muscle channelopathies.

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Diagnostic criteria

GeneReviews states that no consensus clinical diagnostic criteria for MC have been published and establishes the diagnosis in a proband with findings suggestive of myotonia, sometimes with muscle hypertrophy, and a heterozygous or biallelic pathogenic CLCN1 variant [1]. Suggestive findings are episodes of stiffness or cramps from early childhood, relief with brief exercise, myotonic contraction on percussion, CK usually elevated up to 3–4 times the upper limit of normal, myotonic discharges on EMG, and a family history consistent with AR inheritance (affected siblings, consanguinity) or AD inheritance (several generations); the absence of a family history does not exclude the diagnosis [1]. A heterozygous variant of uncertain significance (VUS) neither establishes nor excludes the AD form, and two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the AR form [1].

The 2020 international guideline proposes criteria for NDM as a whole [2]:

Distinguishing the AD and AR forms of MC depends mainly on the family history, because some variants occur in both: an affected parent indicates AD inheritance, and two variants on different alleles in a proband with unaffected parents establish the AR form [1]. Distinguishing chloride from sodium channelopathy rests on clinical features, EMG, and genetic testing (section 6.2) [2].

5.2. Diagnostic algorithm

When clinical suspicion is high, the guideline recommends starting with EMG, especially when clinical myotonia is not evident, and proceeding to genetic testing that analyses CLCN1 and SCN4A simultaneously, given the phenotypic overlap [2]. One pathogenic variant (or two, in Becker MC) establishes a definite diagnosis without further testing. A VUS should be supported by the variant type, predicted effect, conservation, family segregation, and, when available, in vitro functional analysis. If no variant is identified, or if genetic testing is unavailable, detailed electrophysiologic evaluation (exercise and cooling tests) and exclusion of myotonic dystrophy follow [2]. GeneReviews proposes two approaches: single-gene testing, sequencing CLCN1 first and, if the AR form is suspected and only one heterozygous variant is found, adding gene-targeted deletion/duplication analysis; or a multigene skeletal muscle channelopathy panel that includes CLCN1 and the differential diagnosis genes, which it considers the approach most likely to identify the cause at reasonable cost and with fewer VUS. When the diagnosis has not been considered, exome or genome sequencing are alternatives [1]. The review by Statland and colleagues recommends genetic testing as the first step in the PP when suspicion is intermediate or high [3].

5.3. Laboratory tests

CK is normal or mildly elevated: the 2020 guideline reports normal values to 1–3 times normal, and the MC GeneReviews chapter up to 3–4 times the upper limit; very high values should prompt investigation of another myopathy [1, 2]. Thyroid function should be assessed, because severe hypothyroidism can cause myotonia and thyrotoxicosis causes PP [2, 19]. In the PP, serum potassium during the attack is the most discriminating finding; in HyperPP, CK may rise 5- to 10-fold during the attack, and transient hypokalaemia may occur at the end of the attack, leading to a misdiagnosis of HypoPP [19].

5.4. Electromyography

Myotonic potentials are repetitive discharges at 20–80 Hz with waxing and waning amplitude and frequency ("dive bomber") [2]. The sensitivity of EMG is 100% in NDM and DM1 when the tibialis anterior, quadriceps, first dorsal interosseous, and biceps are examined bilaterally, with 10 insertions per muscle; in DM2 it was 100% in the largest cohort but lower in small series [2]. The negative predictive value approaches 100%, but electrical myotonia is not specific: it also occurs in Pompe disease (especially in the paraspinal muscles), inflammatory myopathies, congenital myopathies (especially myofibrillar), rippling muscle disease, anti-MuSK antibody–positive myasthenia, severe hypothyroidism, and with drugs (20,25-diazacholesterol, clofibrate, 2,4-dichlorophenoxyacetic acid, chloroquine, colchicine, and statins), often as "pseudomyotonia" with complex repetitive discharges [2]. The first interdischarge interval in the rectus femoris distinguishes sodium (<30 ms) from chloride (>30 ms) channelopathies with a discriminative power above 95% [2]. In myotonic dystrophy, myotonia is more easily elicited in DM1 (except in the proximal leg muscles) and has a waxing-waning pattern, whereas in DM2 it is waning only [2]. Electrically silent cramps suggest Brody disease, and myokymic and neuromyotonic discharges suggest Isaacs syndrome [2]. In HyperPP, about half of affected individuals have no electrical myotonia, and during attacks there is reduced recruitment or electrical silence; between attacks, myotonic activity at 20–150 Hz may be recorded and, in permanent weakness, a myopathic pattern [19].

5.5. Short and long exercise tests

The short exercise test (SET), using the Streib technique, consists of a maximal contraction of the abductor digiti minimi for 10–12 s, with supramaximal stimulation of the ulnar nerve immediately and every 10 s for 50 s, repeated three times; cooling and rewarming increase sensitivity, and a concordant decrement of more than 20% in compound muscle action potential (CMAP) amplitude and area is considered abnormal [2]. The long exercise test (LET), using the McManis technique, consists of a 5-minute contraction (15-s blocks with 3–4 s of rest) with CMAP recording every 1–2 minutes for 40–60 minutes; it is positive if the CMAP decreases by more than 40%, typically after exercise, and is abnormal in more than 70% of patients with PP [2, 3]. In MC and PMC, decrements of more than 40% have been described during the exercise itself [2].

Fournier and colleagues described electromyographic patterns that point to variant subgroups, and Tan and colleagues refined them with precooling and rewarming [2, 59, 60]:

In Fournier, the abnormality threshold was the mean plus two standard deviations of healthy controls; in Tan, a concordant decrement of more than 20% in amplitude and area, with precooling and rewarming. Specificity was calculated among the channelopathies; relative to healthy volunteers, it was 100% in both studies [2]. In the CINCH study, the SET showed a CMAP decrement of at least 10% in 59.3% of patients with chloride channelopathy and in 27.6% of patients with sodium channelopathy, a figure that rose to 57.6% in the latter after cooling [26]. The same patterns occur with CLCN1, KCNJ2, and CACNA1S, so they narrow the differential without resolving it, and they may be indistinguishable between NormoPP and HyperPP [5]. In the PP, patterns IV and V (late decrement on the LET) characterise HypoPP, NormoPP, and HyperPP, and in thyrotoxic PP an initial CMAP increase followed by a decline is observed [19].

5.6. Muscle imaging

On muscle ultrasound in NDM, echo intensity is increased in all muscles except the rectus femoris, with hypertrophy of the arms [2]. On MRI, there is T1 or STIR (short tau inversion recovery) hyperintensity in all muscles, leg oedema mainly in the medial gastrocnemius (18 of 21 patients), and a STIR "central stripe" in 10 of 11 patients with a CLCN1 variant and 3 of 10 with an SCN4A variant, with no similar finding in healthy volunteers [2]. Imaging is not part of the NDM diagnostic algorithm [2]. In HyperPP, GeneReviews suggests STIR MRI of the proximal leg muscles at the initial evaluation [19].

5.7. Genetic testing: yield and limitations

GeneReviews gives the proportions of pathogenic CLCN1 variants detectable by each method [1]:

These percentages describe the fraction of the known variant spectrum that each method detects, not the clinical sensitivity of the test, that is, the proportion of patients with MC in whom the cause is found [1]. Clinical yield data are limited. The 2020 guideline cites false-negative rates of up to 20% in 2007; in the Dutch cohort of Trip and colleagues (54 families), tandem analysis of CLCN1 and SCN4A identified at least one variant in 100% of families, with a true yield, in the worst-case scenario, of 93% (3 recessive and 3 sporadic cases without a second CLCN1 variant) [2, 61]. Among probands with confirmed NDM, the proportion with a CLCN1 variant was 45% in a Japanese cohort, 68.5% in a German cohort, and 89% in a Spanish cohort, and the rest had an SCN4A variant [1, 53, 55, 62]. A significant proportion of patients with clinically suspected MC in fact have an SCN4A variant [1, 61]. Variants are compiled in the LOVD (Leiden Open Variation Database) [2].

In the PP, genetic testing detects a heterozygous pathogenic variant in 60–70% of patients who meet clinical criteria, leaving about 30% without a variant [3]. In HyperPP, SCN4A sequencing identifies the variant in about 66% of probands, no deletions or duplications have been described, and no variant is identified in about one-third of patients with a typical phenotype [19]. In a Chinese cohort of 60 patients with primary PP, 92.5% of those with a genetic diagnosis had variants in CACNA1S, KCNJ2, or SCN4A [19].

The limitations of testing should be stated explicitly in the report and in counselling. Sequencing of exons and intron–exon junctions does not detect deep intronic variants such as c.697-620T>G, which was identified only by genome sequencing and confirmed by muscle RNA sequencing [39]. CLCN1 deletion/duplication analysis should be requested when only one variant is identified in a suspected AR form [1]. Leukocyte DNA may fail to detect parental somatic mosaicism [1]. Variants with reduced penetrance, such as p.(Arg894Ter), do not allow expression in a carrier to be predicted [1]. Two variants in a proband confirm the AR form only after segregation has shown them to be in trans, because an allele carrying two pathogenic variants has been described [1, 37]. A negative result does not exclude NDM when the clinical picture and EMG are typical [2].

The report should state the gene, the versioned transcript (NM_000083.3 for CLCN1, NM_000334.4 for SCN4A, NM_000069.3 for CACNA1S), the HGVS nomenclature at the complementary DNA and protein levels, zygosity, the class under ACMG/AMP criteria, and, when there are two variants, whether phase is known or unknown [1, 34, 50]. When interpreting SCN4A variants, the predicted mechanism (dominant gain of function, gating pore current, or biallelic loss of function) must be consistent with the phenotype [50]. Reclassification of a VUS depends on family segregation and functional data [2].

5.8. Periodic paralysis criteria and provocative testing

Source: Tables 2 and 3 of Statland and colleagues, which reproduce the consensus criteria of the Sansone Cochrane review (2008) cited by GeneReviews [3, 20]. The HyperPP GeneReviews chapter adds, as suggestive findings, normal psychomotor development, no arrhythmia between attacks, and, typically, at least one affected first-degree relative [19]. A provocative test with 2–10 g of oral potassium is justified only when there is uncertainty (no documented ictal potassium and negative genetic testing), with monitoring of potassium and strength every 20 minutes, electrocardiography (ECG), an experienced physician, and an anaesthetist available; the attack usually occurs within 1 hour and lasts 30–60 minutes, and the test is contraindicated in hyperkalaemia or inadequate renal or adrenal function [19]. The availability of genetic testing and electrophysiology makes it largely unnecessary [19].

5.9. Prenatal diagnosis and preimplantation genetic testing

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible [1]. Prenatal identification of CLCN1 variants does not predict age at onset, severity, type of symptoms, or rate of progression [1]. In families with an SCN4A variant, the risk of SNEL in the newborn warrants discussing the delivery plan with obstetrics from the time pregnancy is planned [2].

6. Differential Diagnosis

6.1. Comparison table

Sources for the table: [1–3, 7, 19, 20, 22, 32, 51].

6.2. Chloride or sodium channelopathy

Distinguishing MC from the sodium channelopathies is clinically difficult: a significant proportion of patients with suspected MC have an SCN4A variant, and genetic testing should therefore analyse both genes simultaneously [1, 2, 61]. The 2020 guideline summarises the differences [2, 26]:

Warm-up is classic in MC but also occurs in some sodium channelopathies (35.3% in the CINCH study), and hypertrophy occurs in both groups, so no single sign other than paradoxical myotonia and transient paresis is discriminating [2, 26].

6.3. Myotonic dystrophy types 1 and 2

DM1 (DMPK) and DM2 (CNBP) should always be considered, given the prognostic implications of their extramuscular manifestations [1]. DM1 is much more common than NDM, with an incidence of about 1/8,000 live births and a prevalence of about 5/100,000 in most American and European populations [2, 51]. The pattern of weakness is different, and early cataracts, arrhythmias, and endocrine dysfunction do not occur in MC; the absence of these manifestations does not exclude mild DM1 [1]. DM2 is common in Northern European families (in Germany its prevalence is similar to that of DM1), has no congenital form, and presents with less pronounced clinical myotonia, often subclinical, predominantly proximal weakness, prominent muscle pain, and, on biopsy, preferential type 2 fibre atrophy [2, 32, 51]. The Oxford Desk Reference and the textbook Clinical Cardiogenetics use the historical name ZNF9; the current gene name is CNBP [1, 32, 51]. A subgroup of patients with DM2 has a modifier variant in CLCN1 or SCN4A that accentuates myotonia [2, 49].

6.4. Primary and secondary periodic paralyses

When paralysis dominates the picture, the working diagnosis becomes a primary PP [2]. The HyperPP GeneReviews chapter compares the primary PP and thyrotoxic PP [19]:

Hereditary hyperkalaemia has other causes that must be excluded before attributing attacks to HyperPP: adrenal insufficiency (congenital adrenal hyperplasia due to CYP21A2, X-linked adrenal hypoplasia due to NR0B1, Addison disease), recessive hypoaldosteronism of infancy (OMIM 610600), pseudohypoaldosteronism type I (AR due to SCNN1A, SCNN1B, or SCNN1G, OMIM 264350; AD due to NR3C2, OMIM 177735), and type II (Gordon syndrome, due to CUL3, KLHL3, WNK1, or WNK4) [19]. PP secondary to acquired hyperkalaemia occurs with potassium above 7 mmol/L and is associated with spironolactone, angiotensin-converting enzyme (ACE) inhibitors, trimethoprim, nonsteroidal anti-inflammatory drugs, heparin, and nonselective beta-blockers [19]. In HypoPP, the exclusions include renal and gastrointestinal potassium losses, adrenal and thyroid disease, renal tubular acidosis, diuretics, and laxatives [3]. Thyrotoxic PP has a prevalence below 1/1,000,000 in Europe and adult onset [17].

6.5. Other causes of stiffness and myotonia

Schwartz-Jampel syndrome, a recessive disorder due to HSPG2 (perlecan) variants, combines masklike facies, blepharospasm, and skeletal deformities [2, 32]. Brody disease (ATP2A1), rippling muscle disease (CAV3), Pompe disease, centronuclear and myofibrillar myopathies, and inflammatory myopathies warrant an extended gene panel when the clinical picture is atypical [2]. Isaacs syndrome produces neuromyotonia at 150–300 Hz, is associated with antibodies against potassium channels, and has a hereditary form due to KCNA1 [2]. In dystonia, EMG shows no myotonia [2].

7. Treatment and Risk Management Strategies

7.1. Goals and nonpharmacologic measures

There is no disease-modifying treatment for MC or the other NDM; treatment is symptomatic and targets stiffness, pain, fatigue, and falls [2, 54]. GeneReviews identifies no specific clinical practice guidelines for MC and refers to the general 2020 guideline on NDM [1, 2]. For mild complaints, adapting activities and lifestyle may suffice, and brief exercise before a task takes advantage of warm-up [1]. Modifying triggers, such as cold and dietary potassium, is useful mainly in phenotypes with PP [2]. In a study of aerobic training in 6 patients with MC, physical fitness improved without any change in the severity of clinical myotonia or the MBS, and CK remained stable [2, 58]. The guideline encourages aerobic exercise (swimming, cycling, walking) and considers resistance training probably harmless in the absence of weakness [2]. Muscular Dystrophy UK advises an assessment by a physical therapist before starting an exercise programme, to tailor the plan and prevent falls [52].

7.2. When to start pharmacologic treatment and with which drug

Pharmacologic treatment is warranted when stiffness limits mobility, causes falls, significant pain, or fatigue, or interferes with work and daily activities; the fluctuation of symptoms and the difference between the clinic visit, in a warm environment, and everyday conditions call for an individualised approach [54]. In the CINCH study, 39% of symptomatic patients were not receiving antimyotonic treatment [2, 26]. Mexiletine and lamotrigine are the only two NDM treatments supported by evidence from randomised controlled trials (RCTs) [63, 64]. The 2020 guideline assigns mexiletine the highest level of evidence and considers lamotrigine effective in one RCT [2]. After the guideline, the MEXLAM trial compared the two drugs head to head, and the authors proposed a personalised algorithm (section 7.5) [65].

The 2026 review by Matthews and colleagues summarises the factors that guide the choice [63]:

7.3. Mexiletine

Mexiletine is a Vaughan-Williams class Ib antiarrhythmic, structurally similar to lidocaine, that blocks voltage-gated sodium channels, including Nav1.4, and enhances fast inactivation [2, 54]. The block is more potent during bursts of action potentials (use-dependent block) and during prolonged depolarisation (voltage-dependent block) than during physiologic excitability, which explains its antimyotonic efficacy regardless of the channel affected [54]. It has been used for myotonia for more than 30 years [54].

Formulations and dose units. In the European Union, Namuscla® (Lupin Europe GmbH) is available as 62 mg, 83 mg, and 167 mg hard capsules, with doses expressed as mexiletine base (62.48 mg, 83.31 mg, and 166.62 mg of base, as the hydrochloride) [27]. The SmPC specifies that the 200 mg referred to in the study report corresponds to the amount of hydrochloride equivalent to 166.62 mg of base [27]. Academic trials and the US label express the dose as the hydrochloride: 200 mg of hydrochloride is equivalent to about 167 mg of base, and 600 mg/day of hydrochloride to about 500 mg/day of base [27, 66]. Confusing the two units leads to errors of about 20%.

Adult dosing according to the SmPC. Before starting, a detailed cardiac evaluation by a cardiologist and assessment and correction of electrolytes are required [27]. The starting dose is 167 mg/day (1 capsule); after at least 1 week, depending on response, it may be increased to 333 mg/day (2 capsules) and, after another week, to 500 mg/day (3 capsules); maintenance is 167–500 mg/day, not exceeding 500 mg/day, with regular reassessment and discontinuation if there is no benefit [27]. Capsules are swallowed whole with water, avoiding the supine position, and with a meal if there is gastrointestinal intolerance; opening the capsules has not been studied [27].

Paediatric dosing according to the SmPC (6–17 years). The dose depends on weight [27]:

Below age 6 years or 20 kg, safety and efficacy have not been established and no data are available [27]. In older adults (≥65 years), experience is limited, and no adjustment is recommended. In mild (Child-Pugh 5–6) or moderate (7–9) hepatic impairment, the dose should be increased only after at least 2 weeks, and in severe hepatic impairment mexiletine should not be used; in mild or moderate renal impairment no adjustment is needed, and in severe renal impairment it is not recommended [27].

Dosing in guidelines and trials (as the hydrochloride). The 2020 guideline suggests starting at 150 mg twice daily and titrating to 200 mg three times daily, occasionally 300 mg three times daily, with monitoring by ECG and liver function tests and consideration of a complete blood count, and referral to cardiology before starting if the ECG is abnormal or there is a history of arrhythmia [2]. The guideline does not specify age or weight for this regimen. GeneReviews describes the same practice, starting at 150 mg twice daily and slowly increasing to 200–300 mg three times daily [1]. The Statland trial, in patients aged 16 years or older, used 200 mg three times daily [67], and MEXLAM, in adults, titrated from 100 mg/day (2 weeks) to 200 mg/day (2 weeks), 200 mg twice daily (1 week), and 200 mg three times daily [65]. The 300 mg three-times-daily dose (900 mg/day of hydrochloride, about 750 mg/day of base) exceeds the European SmPC maximum of 500 mg/day of base and constitutes use outside the terms of the marketing authorisation; the 1,200 mg/day limit in the US label refers to the antiarrhythmic indication [27, 66].

Pharmacokinetics. Bioavailability is about 90%, peak plasma levels occur at 2–3 hours, and food does not affect absorption; the volume of distribution is 5–9 L/kg, protein binding is 55%, elimination is 90% hepatic (mainly CYP2D6, and CYP1A2) and 10% renal as unchanged drug, and the mean half-life is 10 hours (5–15 hours) [27]. At the maximum adult dose (600 mg/day of hydrochloride), the concentration 2 hours after dosing at steady state was 1.10 µg/mL; in children receiving 167 mg three times daily, exposure was comparable [27]. In the Statland trial, the mean concentration was 0.54 µg/mL, below the antiarrhythmic therapeutic range of 0.5–2.0 µg/mL described for 600–1,200 mg/day [67]. MEXLAM describes onset of action within 30–40 minutes in most patients [65]. CYP2D6 poor metabolisers have higher exposure and should wait at least 7 days before each dose increase; smoking increases clearance 1.3- to 1.7-fold [27]. An exploratory Italian pharmacogenetic study (50 patients, 34 with myotonic dystrophy and 16 with NDM, receiving 200–600 mg/day) found 74% responders and nominally associated the CYP2D6*2/*41 diplotype with nonresponse (odds ratio 10.8; P=0.049) [68].

Contraindications. The SmPC contraindicates mexiletine in hypersensitivity to the active substance, the excipients, or any local anaesthetic; ventricular tachyarrhythmia; complete heart block or block with the potential to progress to it (first-degree atrioventricular block with PR ≥240 ms and/or QRS ≥120 ms, second-degree block, bundle branch block, bifascicular or trifascicular block); acute or previous myocardial infarction or abnormal Q waves; symptomatic coronary artery disease; heart failure with mildly reduced (40–49%) or reduced (<40%) ejection fraction; atrial tachyarrhythmia, fibrillation, or flutter; sinus node dysfunction, including a rate below 50/min; and coadministration with drugs that induce torsades de pointes or that have a narrow therapeutic index [27]. The US label contraindicates it in cardiogenic shock and in second- or third-degree atrioventricular block without a pacemaker [66].

Interactions. Antiarrhythmics that induce torsades de pointes are contraindicated: class Ia (quinidine, procainamide, disopyramide, ajmaline), Ic (encainide, flecainide, propafenone, moricizine), and III (amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant); combination with other class Ib agents (lidocaine, phenytoin, tocainide), beta-blockers, and verapamil or diltiazem is not recommended [27]. CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, with a 38% reduction in clearance) and CYP2D6 inhibitors increase exposure, and inducers (omeprazole, phenytoin, which shortens the half-life from 17.2 to 8.4 hours, rifampin) decrease it [27]. Mexiletine strongly inhibits CYP1A2 (theophylline, caffeine, with a 50% reduction in clearance, lidocaine, tizanidine) and interacts with OCT2 substrates (metformin, dofetilide); it is contraindicated with narrow-index substrates such as digoxin, lithium, phenytoin, theophylline, and warfarin [27]. Mexiletine can cause a false-positive urine amphetamine screen [27].

Adverse effects and management. In the SmPC, the most frequent effects are abdominal pain (12%), insomnia (12%), and vertigo (8%); the most serious are drug reaction with eosinophilia and systemic symptoms (DRESS) and arrhythmias [27]. Common effects include somnolence, headache, paraesthesias, blurred vision, tachycardia, flushing, hypotension, nausea, acne, pain in the extremities, fatigue, asthenia, and chest discomfort; uncommon effects include seizures, speech disorders, and bradycardia [27]. DRESS has an incidence of 1/1,000 to 1/10,000, occurs 1 to 8 weeks after exposure, and has a mortality of 10% in severe systemic forms; mexiletine may increase seizures in patients with epilepsy [27]. In the 3-month trials in the US label, upper gastrointestinal distress occurred in 41%, tremor in 12.6%, dizziness in 10.5%, and incoordination in 10.2%, and these led to discontinuation in 40% of patients with arrhythmia [66]. In the NDM RCTs, gastrointestinal effects were the most common adverse event (for example, 21 of 30 patients on mexiletine and 1 on placebo in the N-of-1 trials) [54, 69]. Gastrointestinal effects, dizziness, tremor, and ataxia resolve with dose reduction, and taking the drug with food improves gastrointestinal tolerance [1, 27]. Overdose was fatal with 4.4 g of hydrochloride, and survival has occurred after about 4 g; it presents with paraesthesias, confusion, hallucinations and seizures, sinus bradycardia, hypotension, collapse, and cardiac arrest, and is treated symptomatically, with intravenous atropine for bradycardia with hypotension and benzodiazepines for seizures [27].

Cardiac monitoring. Recommendations differ between sources:

Sources: [2, 27, 54, 65]. The French algorithm excludes mexiletine in the presence of previous myocardial infarction, angina, or nonrevascularised coronary artery disease (revascularised disease without sequelae of infarction is not an absolute contraindication), high-grade atrioventricular block without a permanent pacemaker, drugs that can cause torsades de pointes, ventricular tachycardia (the sustained form is an absolute contraindication; for the nonsustained form, the mode of detection, symptoms, and contributing factors, such as electrolyte abnormalities to be corrected, are weighed), or atrial fibrillation or flutter; in the presence of sinus bradycardia <50/min, PR ≥240 ms, QRS ≥120 ms, bifascicular or trifascicular block, high-grade block (Mobitz II or complete), pathologic Q waves, or repolarisation abnormalities on ECG; and in the presence of an ejection fraction <50% or a regional wall motion abnormality on echocardiography [54]. In patients with an implantable cardioverter-defibrillator or a pacemaker and high-grade block, concomitant ventricular arrhythmia should be sought, and new chest pain, unusual palpitations, or syncope require a cardiology opinion [54]. The French group, funded by Lupin Neuroscience and with all authors declaring consulting fees from the company, drew on 5 studies of 236 patients with NDM treated with 200–600 mg/day for up to 20 years, with no cases of arrhythmia; the only event described in the first RCT was bradycardia that resolved without discontinuation [54]. Matthews and colleagues report that neither the trials nor 302.4 patient-years of real-world follow-up showed significant ECG changes between baseline and the maximum dose [63]. Hypokalaemia, hyperkalaemia, and hypomagnesaemia increase the proarrhythmic effect and should be corrected beforehand and monitored [27]. Mexiletine should be discontinued immediately if a conduction abnormality or a contraindication appears [27].

7.4. Lamotrigine

Lamotrigine is a sodium channel–blocking antiepileptic drug, used off-label for myotonia in all jurisdictions [2, 70]. The 2020 guideline suggests starting at 25 mg/day and titrating slowly to 300 mg/day, without specifying age or weight, with liver function tests and renal function; the adverse effects listed are rash, headache, fatigue, and nausea [2]. In the Danish RCT, in adults, lamotrigine was taken once daily with increases every 2 weeks: 25 mg, 50 mg, 150 mg, and 300 mg [70]. In MEXLAM, titration was 25 mg/day (2 weeks), 25 mg twice daily (2 weeks), 50 mg twice daily (1 week), 100 mg in the morning, 50 mg at midday, and 50 mg in the evening (1 week), and finally 100 mg in the morning, 50 mg at midday, and 100 mg in the evening (250 mg/day) for the last 2 weeks [65]. Slow titration is intended to reduce the risk of rash; the half-life ranges from 24.1 to 35 hours, so the antimyotonic effect takes weeks to develop and an accidentally missed dose has fewer consequences than with mexiletine [65].

In the US label for Lamictal XR® (GlaxoSmithKline), the boxed warning describes serious rashes requiring hospitalisation, including Stevens-Johnson syndrome, in about 0.8% (8/1,000) of children aged 2–16 years and 0.3% (3/1,000) of adults receiving adjunctive therapy for epilepsy; the risk factors are concomitant valproate and exceeding the recommended starting dose or titration rate [71]. Valproate was an exclusion criterion in MEXLAM [65]. The annual population incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis is 1–2 per million, and lamotrigine accounted for just under 10% of cases reported to FAERS (FDA Adverse Event Reporting System) between 1969 and 2024 [63]. The FDA label also includes a warning on cardiac rhythm and conduction abnormalities: lamotrigine has class IB antiarrhythmic activity in vitro and may widen the QRS and be proarrhythmic in patients with clinically relevant structural or functional heart disease, including cardiac channelopathies such as Brugada syndrome [71]. The European Medicines Agency (EMA) has not replicated this warning; the task force of the International League Against Epilepsy and the American Epilepsy Society recommends a baseline ECG only above age 60 or with multiple cardiovascular risk factors, and prior cardiology review in known heart disease (second- or third-degree atrioventricular block, Brugada syndrome, arrhythmogenic cardiomyopathy, complete left bundle branch block, right bundle branch block with hemiblock) [63].

In the prospective cohort of the UK national centre, 37 patients with genetically confirmed NDM (23 with CLCN1 and 14 with SCN4A) received lamotrigine in clinical practice, with a mean follow-up of 26 months; among the 26 patients evaluable for efficacy, the mean MBS fell from 3.3 to 1.8 (P<0.001; Cohen's d 1.2), and 9 of 37 discontinued because of adverse effects, mainly rash and headache, with no serious events [72]. Lamotrigine was chosen mainly because of previous adverse effects of mexiletine or cardiac contraindications [72].

7.5. Mexiletine versus lamotrigine and the MEXLAM algorithm

MEXLAM was a phase 3, double-blind, crossover, noninferiority RCT conducted at the National Hospital for Neurology and Neurosurgery in London in adults with symptomatic, genetically confirmed NDM; 60 participants (24 women, 36 men; mean age 41.6 years; 35 with MC, 17 with PMC, and 8 with SCM) were randomised between August 2021 and December 2022 to mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or the reverse order, with a 7-day washout [65]. The primary outcome was mean stiffness in an interactive voice response (IVR) diary (0–9 scale) over the last 2 weeks of each period, with a noninferiority margin of 0.5. In the primary analysis (53 participants), stiffness was 2.54 (95% CI 1.98–3.10) with mexiletine and 2.77 (2.21–3.32) with lamotrigine, from a baseline of 5.30; the difference was −0.23 (95% CI −0.63 to 0.17), and because the limit of the interval crosses the margin, noninferiority of lamotrigine could not be concluded [65]. Improvements from baseline were similar in both arms for all secondary outcomes (MBS, pain, fatigue, chair-rise test, and SF-36), with no treatment-by-period interaction [65]. Fourteen participants (23%) withdrew, 4 because of mexiletine adverse effects and 3 because of significant myotonia at the low titration doses, which biases the sample against more severe myotonia [65]. The most common adverse event was indigestion-reflux (8 participants and 208 participant-days with mexiletine; 7 and 130 with lamotrigine), followed by headache (4 in each arm), mood changes (5, with mexiletine only), and brief palpitations (3 and 2); there was no serious rash and there were no serious adverse events [65]. At the end of the trial, 30 of 47 participants chose lamotrigine, and 13 of the 25 who had been taking mexiletine before the trial switched to lamotrigine, mainly because of adverse effects [65].

The authors proposed a personalised algorithm: for all symptomatic patients, lamotrigine is the first choice if there is a history of heart disease, a metabolic profile (hypertension, hypercholesterolaemia, diabetes, obesity), a woman of childbearing potential, gastrointestinal problems, or pain-predominant NDM; for the remainder, mexiletine is preferable when lifestyle demands rapid improvement in symptom control, and lamotrigine when the patient prefers to avoid an annual ECG, weighing local economic factors in both cases [65]. In the United Kingdom, the indicative annual cost per patient was £9,450 for mexiletine (167 mg three times daily; £875 per 100 capsules) and £28.93 for lamotrigine (200 mg twice daily) [65]. This algorithm is a proposal by the authors of a single-centre trial and not a recommendation of a scientific society.

7.6. Other drugs

Ranolazine. Approved by the FDA for chronic angina and by the EMA as add-on therapy, it enhances slow inactivation of sodium channels [2]. The guideline suggests 500 mg twice daily, titrating up to 1,000 mg twice daily, with ECG and renal function in renal impairment; it should not be combined with simvastatin >20 mg and should be limited to 500 mg with CYP3A4 inhibitors such as diltiazem or verapamil; adverse effects are constipation, dizziness, and headache [2]. This regimen matches the US label for chronic angina (500 mg twice daily, up to a maximum of 1,000 mg twice daily, and a maximum of 500 mg twice daily with moderate CYP3A inhibitors) [73]. The European SmPC for Ranexa® is more restrictive: starting at 375 mg twice daily, 500 mg twice daily after 2–4 weeks, and a recommended maximum of 750 mg twice daily, with careful titration (no numerical limit) with moderate CYP3A4 or P-glycoprotein inhibitors, contraindication at creatinine clearance < 30 mL/min and in moderate or severe hepatic impairment, and safety and efficacy not established below age 18 [74]. In the European Union, the 1,000 mg twice daily of the guideline and of the Arnold trial exceeds the SmPC maximum and is off-label use, in addition to being outside the indication. In an open-label trial in 13 patients with MC (500 mg twice daily, increased to 1,000 mg twice daily after week 2), self-reported stiffness, weakness, and pain improved, as did eyelid, grip, and electrical myotonia (class IV evidence) [75]. In a 4-week open-label trial in PMC, ranolazine was well tolerated and improved subjective symptoms and clinical myotonia, without a significant reduction in the duration of electrical myotonia in all muscles [76]. A phase 1 study by Ohio State University in MC, PMC, and DM1 was completed in 2017 [77].

Acetazolamide. For myotonia, the guideline suggests 125 mg twice daily, titrating up to 250 mg three times daily, with a metabolic panel (sodium, potassium, bicarbonate), liver function tests, and complete blood count, and renal ultrasound if there is a risk of stones; it is contraindicated in sulfonamide allergy, and adverse effects include nephrolithiasis, paraesthesias, rash, agranulocytosis, electrolyte disturbances, and gastrointestinal discomfort [2]. The evidence consists of nonrandomised open-label trials; in an open-label study from the pre-genetic era there was improvement in MC, but one of two patients with PMC developed severe weakness [2]. Nephrolithiasis occurred in 3 of 20 patients (15%) on long-term acetazolamide for myotonia [3]. No label includes myotonia or the periodic paralyses; for epilepsy, the authorised indication with the closest regimen, the Portuguese SmPC for acetazolamide (Carbinib®, 250 mg tablets) specifies 250–1,000 mg/day in divided doses in adults and 8–30 mg/kg/day in children, not exceeding 750 mg/day, and for glaucoma allows 125–750 mg/day in children [78]. The guideline doses (250–750 mg/day) fall within that adult range; the 5–10 mg/kg/day used for the periodic paralyses in children is at the lower limit of, or below, the paediatric epilepsy range (subsection 7.13).

Flecainide. It has level 3 evidence in NDM [2]. In SNEL, mexiletine and carbamazepine have had some success and flecainide may be the most effective, but a case of flecainide-induced Brugada pattern in an adult with an SCN4A variant has been described, which calls for caution [2]. Ogueri and colleagues used high-dose flecainide, 220–250 mg/m²/day, combined with standard therapies, in two sisters with SNEL and PMC due to p.(Gly1306Glu), without cardiac effects; this is a case report and off-label use [44]. The US flecainide label, for paediatric arrhythmias, specifies a starting dose of about 50 mg/m²/day below 6 months of age and up to 100 mg/m²/day above 6 months, in 2–3 divided doses, with a maximum recommended dose of 200 mg/m²/day, which should not be exceeded because plasma levels may rise disproportionately; the Portuguese SmPC (Apocard®) does not recommend flecainide below age 12 and limits adults to 300 mg/day for supraventricular arrhythmias and 400 mg/day for ventricular arrhythmias [79, 80]. The 220–250 mg/m²/day in the report exceeds the US label maximum and is outside the terms of the label. Flecainide is contraindicated in combination with mexiletine [27].

Others. The guideline assigns level 3 evidence to procainamide (no oral formulation in the US), phenytoin, carbamazepine, and tocainide (withdrawn from the market); lacosamide and rufinamide are antimyotonic in vitro, without clinical studies [2]. GeneReviews reports benefit from phenytoin and carbamazepine and, in some cases, from quinine, dantrolene, and acetazolamide [1, 81]. Quinine was abandoned because of rare serious haematologic effects [2]. Tricyclic antidepressants (DM1 and one series with SCN4A), nifedipine, and taurine (DM1) have only scant data, and botulinum toxin A was ineffective in one case of MC [2]. In the 2025 Cochrane review, phenytoin, imipramine, procainamide, clomipramine, nifedipine, tocainide, diazepam, quinine, and taurine were ineffective or of uncertain effect, and acetazolamide, flecainide, ranolazine, and lacosamide have not been studied in RCTs [64]. The sources consulted do not give doses of carbamazepine, phenytoin, or dantrolene for myotonia.

7.7. Clinical trials in the nondystrophic myotonias

Sources: [27, 54, 65, 67, 69, 70, 75, 76, 82].

Results cannot be compared across trials: the scales (IVR 1–9 or 0–9, VAS, MBS), durations, doses, and populations differ, and all the controlled trials are crossover, short, and small [64]. In the Statland trial, a treatment×period interaction required the periods to be analysed separately, and 64–80% of participants guessed their allocation, which limits blinding [67]. In the RCTs, mexiletine was more effective in the chloride channelopathies (in Statland period 2, −4.18 versus −2.67; P=0.003), but period 1 showed the opposite, and a long-term retrospective cohort also found greater benefit in the sodium channelopathies; MEXLAM considers mexiletine less beneficial in MC [2, 65, 67]. The 2025 Cochrane review (17 RCTs, 392 participants, 173 of whom had NDM) assigns moderate certainty to the reduction in stiffness with mexiletine (mean difference −3.12; 95% CI −3.75 to −2.49; 2 crossover RCTs, 89 participants), low certainty to adverse events (94 with mexiletine versus 29 with placebo in 4 RCTs), and low to moderate certainty to the lamotrigine data, and stresses that not all patients respond [64]. The reduction in stiffness to about half of baseline, observed with both drugs in MEXLAM, conveys the absolute size of the effect [65].

7.8. Comparative regulatory status

Sources: [2, 27, 63, 66, 71, 83–86]. The 2021 MC GeneReviews chapter states that mexiletine is "the only FDA-approved drug for this indication"; the US label limits the indication to ventricular arrhythmias, so the statement does not reflect the regulatory status [1, 66]. The 2026 review by Matthews and colleagues still describes Namuscla® as authorised only in adults [63]. The French group reports orphan designation of mexiletine in the US as well and recent authorisation in the United Kingdom, and in France mexiletine has a temporary recommendation for use in adult myotonic dystrophy [54, 87]. In the Netherlands, generic mexiletine is used in adults with NDM and, off-label, in children, and Namuscla® is considerably more expensive [63]. The access situation in Portugal and Brazil was not researched in the sources consulted.

7.9. Treatment of the periodic paralyses

Treatment of the primary PP is symptomatic and not curative, and has three goals: to shorten or abort the attack, to reduce the frequency and intensity of attacks, and to limit the permanent weakness of late myopathy [3, 19, 20]. The first step is to identify each patient's triggers, by recording episodes (time of day and circumstances) and reviewing the diet [20]. Controlled studies are limited to dichlorphenamide and a small crossover trial of acetazolamide; the other measures, including potassium doses, rest on case series, centre experience, and expert consensus [3, 20, 88].

Sources: HyperPP GeneReviews chapter (Table 6 and prevention), HypoPP GeneReviews chapter (Table 5 and prevention), and Table 5 of Statland and colleagues [3, 19, 20]. In the sources consulted, no drug has a centralised marketing authorisation for the PP in the European Union, and in the US only dichlorphenamide has an approved indication for the PP; the others are used off-label (section 7.8).

HypoPP attack. During an attack there is, as a rule, no true potassium depletion, but rather a reversible shift of potassium from the extracellular to the intracellular compartment; the goal is to raise blood potassium only enough to trigger membrane repolarisation and release of the potassium sequestered in the cells [20]. Normalisation of serum potassium may precede recovery of strength, and overcorrection risks rebound hyperkalaemia [3, 20]. Mild to moderate attacks can be treated at home once the diagnosis is established: oral potassium chloride, as capsules or solution (the latter acting faster), is taken at a starting dose of 1 mEq/kg, followed by about 100 mL of water for every 20 mEq, with at least a partial response expected at 30 minutes [20]. If there is no improvement at 30 minutes, a further 0.3 mEq/kg (20 mEq for 60 kg) may be taken, and the total potassium dose to treat an attack should not exceed 200 mEq in 24 hours; the source does not define a minimum age or weight for this regimen [20]. Statland and colleagues describe an alternative regimen of 0.2–0.4 mEq/kg every 30 minutes, not exceeding 200–250 mEq/day [3]. Oral potassium chloride labels refer to hypokalaemia in general and to extended-release forms, which are not used during attacks: the US label specifies 40–100 mEq/day in divided doses, with no more than 40 mEq per dose, and the Portuguese SmPC (Cloreto de Potássio Sandoz®, 750 mg = 10 mEq) generally specifies 2 tablets 2–3 times daily (40–60 mEq/day) for hypokalaemia in adults; neither establishes safety and efficacy in children [89, 90]. The single dose of 1 mEq/kg in GeneReviews (60 mEq for 60 kg) exceeds the US label's maximum per dose and is off-label use, which the source justifies by the intracellular shift of potassium during the attack. If there is no improvement after another 30 minutes, medical evaluation with potassium measurement is required; difficulty breathing, swallowing, or speaking and signs of arrhythmia call for hospital transfer [20]. Intravenous potassium is reserved for very low hypokalaemia with severe symptoms or when the oral route is not possible: the concentration should not exceed 40 mEq/L, because of the risk of thrombophlebitis, and the rate should not exceed 0.3 mEq/kg/h (18 mEq/h for 60 kg), because of the risk of arrhythmia and cardiac arrest [20]; Statland and colleagues give a maximum rate of 20 mEq/h and 200 mEq/day, with 5 mEq potassium chloride boluses as an alternative [3]. ECG and serum potassium are monitored before, during, and for several hours after normalisation, because the large U wave of hypokalaemia increases susceptibility to torsades de pointes and tall, peaked T waves signal hyperkalaemia with a risk of arrest; supplementation is stopped once potassium normalises, even if weakness persists [20]. Patients should keep potassium available in several places (bedside table, pocket or bag, car) to take at the first symptoms, and sustained mild physical activity may abort some attacks [20].

HyperPP attack. Sustained mild exercise and carbohydrate intake at the onset of weakness may prevent or abort the attack; inhaled salbutamol and intravenous glucocorticoids may abort or attenuate it, and intravenous calcium gluconate terminates the attack in some patients [3, 19]. A case report described benefit from intravenous magnesium [19].

Prevention in HypoPP. Oral potassium supplementation (10–20 mmol per dose, three times daily) reduces and shortens attacks, especially when one dose is taken a few hours before the usual time of attacks (for example, in the evening if attacks occur on waking) [20]. Acetazolamide is considered the additional treatment of choice, with no standardised regimen and no consensus on when to start; it is beneficial in about 50% of patients, ineffective in 30%, and may worsen SCN4A-related HypoPP [20]. In an analysis of 74 genotyped patients cited by Statland and colleagues, the overall response was 46%: 56% (31 of 55) with CACNA1S variants and 16% (3 of 19) with SCN4A variants; worsening was described with NM_000334.4 (SCN4A) p.(Arg672Gly) and p.(Arg672Ser) and with NM_000069.3 (CACNA1S) c.3716G>A p.(Arg1239His), and 3 patients who worsened on acetazolamide responded to dichlorphenamide [3]. In a 2-week crossover RCT in 8 patients with HypoPP, acetazolamide 125 mg three times daily improved strength in 7 of 8, with a 10% increase in total strength [3]. Carbonic anhydrase inhibitors promote kaliuresis and a non–anion gap metabolic acidosis through urinary bicarbonate excretion, and the systemic acidosis may reduce susceptibility to attacks; opening of calcium-activated potassium channels and reduced intracellular sodium accumulation have also been proposed, which would explain the effect on prolonged interictal weakness [20]. Common class adverse effects are paraesthesias, fatigue, mild reversible cognitive disturbances, and an increased risk of nephrolithiasis; laboratory and ultrasound surveillance on acetazolamide is given in section 11.2 [20]. When carbonic anhydrase inhibitors are not tolerated or lose efficacy, potassium-sparing diuretics are used, which may be combined with potassium supplementation under regular serum potassium monitoring [20]. Spironolactone, because of its slow breakdown, can cause hyperkalaemia with worsening weakness, arrhythmias, and hair loss, in addition to androgenic effects; eplerenone has fewer androgenic effects and may be preferred [20].

Prevention in HyperPP. In addition to dietary measures, avoiding prolonged bed rest is recommended: attacks are more frequent on holidays and weekends, and patients are advised to get up early and eat a full breakfast [19]. Stress and intense exercise should be avoided, because rest after exertion triggers attacks [19]. Pharmacologic prevention uses a thiazide diuretic or a carbonic anhydrase inhibitor, at modest doses and at intervals ranging from twice daily to twice weekly; GeneReviews prefers thiazides because they have fewer adverse effects [19]. Hydrochlorothiazide can be useful even with normal serum potassium, and its effect is assessed 4 weeks after starting by measuring strength and by MRI of the proximal leg muscles [19]. The potassium and sodium thresholds on diuretics, which differ within GeneReviews itself, are given in section 11.2 [19]. In PMC with attacks of weakness and in normokalaemic PP, the HyperPP strategies are applied, without controlled data [3].

Dichlorphenamide. Dichlorphenamide is an orally administered carbonic anhydrase inhibitor. In the US, the molecule was approved in 1958 for glaucoma (Daranide®, discontinued), and Keveyis® (Xeris) received on 7 August 2015, the indication for the treatment of primary HyperPP, primary HypoPP, and related variants; generics exist, such as Ormalvi® [85]. In the European Union, it has no centralised marketing authorisation for the PP, following withdrawal of the Ekesivy® application in 2019 (section 7.8) [86]. The US label directs starting at 50 mg orally once or twice daily, adjusting the dose at weekly intervals, with a minimum of 50 mg/day and a maximum of 200 mg/day, reassessing response at 2 months, and measuring potassium and bicarbonate before starting and periodically [85]. In the trials, the starting dose was 50 mg twice daily in treatment-naive patients and 20% of the acetazolamide dose in those already taking it, with a mean dose of 82 mg/day at week 9 [3, 20]. The label contraindicates dichlorphenamide in sulfonamide hypersensitivity, with high-dose aspirin, in severe pulmonary disease, and in hepatic insufficiency, and warns of serious sulfonamide-type reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, agranulocytosis), hypokalaemia, hyperchloremic metabolic acidosis, and falls, especially in older adults; safety and efficacy in children have not been established [85]. Reactions with a frequency ≥10% in the trials were paraesthesias (44% versus 14% with placebo), cognitive disorder (14% versus 7%), dysgeusia (14% versus 0%), and confusion (11% versus 0%); they generally did not require discontinuation and resolved when it occurred [20, 85].

Sources: [85, 88]. The two 9-week trials provide class I evidence for HypoPP but lacked the precision to demonstrate efficacy or lack of efficacy in HyperPP; there was no significant effect on strength or muscle mass, and paraesthesias (47% versus 14%) and confusion (19% versus 7%) were the most common adverse events in the two trials combined [88]. The differences between the article (medians) and the label (mean differences in frequency) result from different metrics applied to the same patients and should not be read as independent results. In the 52-week open-label extension, with all participants on dichlorphenamide, the improvement was maintained in both groups [20].

Late myopathy and prevention of complications. It is not known whether preventing attacks prevents myopathy, which can develop in carriers with no previous attacks; there is no curative treatment, acetazolamide may partially reverse prolonged interictal weakness in some patients, and spironolactone or eplerenone may be beneficial [20]. Physical therapy helps maintain strength and motor function, especially after age 40, but sustained exertion worsens weakness in the PP, so self-managed exercise is preferable to imposed physical therapy [20]. Prevention of falls and injuries, reported by 67% of patients with HypoPP older than 40, and informing those around the patient, at school, in sports, and at work, so that the patient has rapid access to potassium and physical assistance during an attack, are part of treatment [20]. A Danish strength training trial in HypoPP and HyperPP is under way (section 7.14) [91].

7.10. Anaesthesia and perioperative care

Anaesthetic complications have been described in children and adults with NDM, and all patients should be informed of the risk and carry an alert card or bracelet stating the diagnosis and contraindications [2]. The anaesthesia and surgical teams should be aware of the diagnosis before the procedure and carry out a focused preoperative assessment [52]. In the muscle channelopathies, disturbed membrane excitability produces a spectrum of perioperative reactions ranging from severe myotonic reactions, with masseter spasm and opisthotonus, to attacks of weakness and paralysis [92]. At-risk relatives who have not had genetic testing or clinical evaluation with EMG should be treated as potentially affected when undergoing anaesthesia [19].

Muscle relaxants. Suxamethonium (suxamethonium) should be avoided in all NDM, because there are numerous reports of myotonic crisis with generalised rigidity that makes mask ventilation and intubation difficult, sometimes as the first manifestation of the disease (section 4.1) [1, 2, 57]. Nondepolarising relaxants appear to act normally in MC but do not reverse a myotonic reaction already triggered by suxamethonium [1, 57]. In HyperPP and the sodium channelopathies, GeneReviews considers reasonable an induction sequence with inhaled oxygen, cricoid pressure, thiopental, and twice the dose effective in 95% of patients (ED95) of an intermediate- or short-acting nondepolarising relaxant, followed by intubation; inhalational induction is also possible and was well tolerated in elective surgery [19]. Shutes and colleagues described a child with Thomsen MC who underwent two extensive spinal surgeries under continuous rocuronium infusion, reversed with sugammadex: relaxation was maintained to reduce myotonic episodes, at the cost of motor evoked potential monitoring, and there was a single presumed myotonic episode, without serious sequelae [93]. This is a case report, not a validated technique.

Perioperative factors that aggravate myotonia. In HyperPP, changes in serum osmolality and pH, shivering due to hypothermia, and mechanical stimuli aggravate the myotonic reaction during general anaesthesia, and opioids, potassium, and anticholinesterases should be avoided because they aggravate the myotonic reaction, with masseter spasm and respiratory muscle rigidity that hinder intubation and mechanical ventilation [19]. In PMC, the narrative review by Chee and colleagues found no consensus on the optimal technique but identified recurring principles: avoid triggers of stiffness, control temperature strictly, and be prepared for complications [94]. Maintaining a warm ambient temperature is particularly important in paramyotonia [5]. Muscular Dystrophy UK prefers local or regional anaesthesia to general anaesthesia and states that a myotonic crisis should be treated immediately with intravenous sodium channel blockers such as lidocaine (section 4.5) [52]. In patients taking mexiletine, the Namuscla® SmPC contraindicates the drug in hypersensitivity to local anaesthetics and advises against combining it with other class Ib antiarrhythmics, including lidocaine, whose clearance mexiletine reduces through CYP1A2 inhibition (section 7.3) [27].

Perioperative weakness in the PP. In HyperPP, generalised and respiratory weakness after anaesthesia is prevented with glucose infusion, normothermia, and keeping serum potassium low [19]. In HypoPP, the risk of paralysis before or after anaesthesia requires strict control of serum potassium, avoidance of large glucose and salt loads, a low-carbohydrate diet, maintenance of body temperature and acid–base balance, careful use of neuromuscular blockers, and no depolarising relaxants; cooling, glucose or mannitol infusions, and fluids with excess sodium should be avoided [3, 20].

Malignant hyperthermia. Generalised rigidity caused by suxamethonium can raise body temperature and mimic an MH crisis, which is why patients with HyperPP were considered susceptible; GeneReviews considers it more likely that complications suggestive of MH result from severe myotonic reactions [19]. The review by Parness and colleagues concluded that the risk of MH in the myotonias is equivalent to that of the general population, with one possible exception, HypoPP, for which there are no clinical reports of MH but the theoretical risk cannot be estimated with the same confidence, although the authors consider it low [96]. The 2020 guideline, which cites this review, acknowledges some reports of MH in patients with myotonia but does not consider it a relevant risk in NDM [2, 96]. The 2007 NORD page mentions two sisters with Becker MC who developed generalised rigidity after suxamethonium, without a rise in temperature, whose significance with respect to MH remained unclear [97]. The HypoPP GeneReviews chapter, by contrast, recommends considering these patients possibly MH-susceptible and using a trigger-free technique, although it notes that general anaesthesia with volatile agents and suxamethonium has been described as safe in a small number of patients [20]. MH susceptibility is associated with variants in RYR1 or CACNA1S in 50–70% of affected families, and in the remainder the genetic basis remains unknown [98]. The 2021 consensus guideline of the European Malignant Hyperthermia Group (EMHG) does not address the myotonias or the sodium and chloride channelopathies; when a trigger-free technique is chosen, as in HypoPP, its recommendations apply: regional or local anaesthesia as a good choice and, if inadequate, general anaesthesia without potent volatile agents or suxamethonium; preparation of the anaesthesia workstation by flushing according to the manufacturer or with licensed activated charcoal filters (vapour concentration <5 ppm), placed on the inspiratory and expiratory limbs and kept in place throughout the procedure; no prophylactic dantrolene; standard monitoring with continuous core temperature; and the option of day-case surgery [99].

7.11. Agents to avoid

The interactions and contraindications of mexiletine, including combination with antiarrhythmics that induce torsades de pointes and with narrow-therapeutic-index substrates, are given in section 7.3, and the combination of flecainide and mexiletine is contraindicated (section 7.6) [27]. The HyperPP GeneReviews chapter lists spironolactone, ACE inhibitors, trimethoprim, nonsteroidal anti-inflammatory drugs, heparin, and nonselective beta-blockers as causes of PP secondary to acquired hyperkalaemia; of these, it expressly recommends avoiding ACE inhibitors [19]. In ATS, QT-prolonging drugs are avoided.

7.12. Pregnancy and lactation

Effect of pregnancy on the disease. In NDM, most women report worsening during pregnancy (section 3.5), probably accentuated by discontinuation of medication, and some women take months to return to baseline [2, 56]. In the cross-sectional study by Snyder and colleagues (25 women with NDM and 63 pregnancies, by questionnaire and record review), there were 53 live births, 8 miscarriages, 4 elective terminations, and 1 stillbirth; reported infertility was 28% and fetal distress 11.7%, versus a US average of 3.6%, and, in pregnancies with worsening, 76% of women recovered within 3 months after delivery, with a range of 2 days to 12 months [56]. The authors and the guideline consider the outcomes broadly benign; the cross-sectional design, small sample, and comparison with national averages limit the interpretation of these rates [2, 56]. In HyperPP, more than 90% of women report an increased frequency of attacks during pregnancy, about 80% report improvement in weakness during attacks, and 75% report worsening stiffness, although there are case reports of improvement [19]. In HypoPP, pregnancy does not appear to increase the risk of attacks [20]. In ATS, data are limited to isolated reports, such as an uneventful pregnancy with more episodes of weakness and less ventricular ectopy, and GeneReviews proposes a multidisciplinary approach similar to that for long QT syndrome [21].

Antimyotonic drugs. The sources differ. The 2020 guideline recommends treating myotonia in pregnancy only when symptoms are very severe, given the lack of safety data (category C), and mentions reports of uneventful use of mexiletine and acetazolamide in pregnancy outside NDM [2]. The Namuscla® SmPC states that data in pregnancy are limited, that mexiletine crosses the placenta, and that animal studies showed no reproductive toxicity, and concludes that, as a precaution, it is preferable to avoid mexiletine during pregnancy [27]. The MEXLAM authors, in UK practice, consider that mexiletine cannot be prescribed in pregnancy and propose lamotrigine as the first choice for women of childbearing potential who wish to continue antimyotonic treatment during pregnancy [65]. The review by Matthews and colleagues summarises the safety of mexiletine in pregnancy as unknown, with case reports showing no harm, and that of lamotrigine as showing no evidence of teratogenicity and supported by an extensive safety database [63]. Pregnancy and breastfeeding were exclusion criteria in MEXLAM, so none of the NDM trials provides data in this population [65]. Drug choice before conception is discussed in section 8.6.

Drugs for the PP. Women on long-term diuretics may continue treatment during pregnancy [19]. Prenatal exposure to acetazolamide caused limb defects in rodents, but human data have not shown an increased risk of malformations [19, 20]. Human data on oral dichlorphenamide in pregnancy are limited, and the US label describes teratogenicity in the rat, with limb reduction defects at an exposure 17 times the maximum human dose [19, 85]. Eplerenone taken during pregnancy may cause hirsutism in the newborn [20].

Lactation. Mexiletine is excreted in breast milk, and the SmPC requires a decision between breastfeeding and continuing treatment [27]. The sources consulted do not describe lactation data for lamotrigine, acetazolamide, or dichlorphenamide in the context of the muscle channelopathies.

Delivery and obstetric anaesthesia. The MC GeneReviews chapter recommends, based on the report by Gorthi and colleagues, a comprehensive delivery plan that minimises muscle spasms provoked by drugs, intramuscular injections, and cold [1, 95]. The intravenous beta-adrenergic tocolytics fenoterol and ritodrine call for particular care in MC, because high-dose beta-agonists can worsen myotonia (section 7.11) [1]. The anaesthetic rules in section 7.10 apply to caesarean delivery and labour analgesia, with a preference for local or regional anaesthesia [52]. In families with an SCN4A variant, the risk of SNEL in the newborn warrants preparing for delivery with obstetrics and neonatology from the time pregnancy is planned (sections 5.9 and 8.6) [2].

7.13. Children and transition to adult care

Evidence and guideline positions. At the time of the 2020 guideline, there were no completed trials in children with NDM, but there were reports and series with the drugs used in adults, including mexiletine, acetazolamide, carbamazepine, and dantrolene [2]. A series of 3 children suggested acetazolamide as first choice because of its safety and neurologists' experience with the drug, but the guideline authors consider, on expert opinion, that mexiletine should probably also be first choice in children [2]. The 2023 paediatric care recommendations of Matthews and colleagues stress that there are almost no epidemiologic data, longitudinal natural history data, or RCTs of efficacy or tolerability in children, so there are no trial-based good practice recommendations; the lack of data contributes to physicians' hesitancy to prescribe and parents' hesitancy to accept medication, and diagnostic delay causes avoidable morbidity and sometimes mortality [101]. The authors argue that specialised neurophysiologic studies should not delay genetic testing and that management should be holistic, including school, physical activity, pain, and fatigue [101].

Mexiletine in children. Since the European Commission decision of 28 May 2026, Namuscla® has been authorised from age 6 and 20 kg, with weight-based dosing (section 7.3), based on the open-label MEX-NM-301 trial (section 7.7) [27, 84]. Below age 6 or 20 kg there are no data, and the prospective PEGASUS registry, started in September 2025 as a post-authorisation measure, is collecting 24-month safety data on children younger than 6 treated with mexiletine [82, 83]. In the Netherlands, generic mexiletine is used off-label in children with NDM [63]. In the French MEXI-PEDI survey of paediatric neuromuscular centres in the FILNEMUS network, 16 of the 34 respondents had treated children with mexiletine; the drug was used in about one-third of children with NDM, prior cardiac evaluation was routine, and practices for initiation, titration, and assessment were heterogeneous; more than half of the centres reported high efficacy and 3 reported moderate adverse effects (dyspepsia, anorexia, asthenia) [87].

Lamotrigine and other drugs. The MEXLAM authors consider lamotrigine a possible option in children, given the long experience of its use in childhood epilepsy, although it has not been studied in children with NDM [65]. The US label assigns children aged 2–16 years a higher frequency of serious rash than adults (section 7.4) [71]. In SNEL, treatment may require serum drug level monitoring; mexiletine and carbamazepine have had some success, and flecainide may be the most effective in this phenotype (section 7.6) [2].

Periodic paralyses in children. Acetazolamide is used in children at 5–10 mg/kg/day, in 3 doses with meals [3, 20]. The dichlorphenamide trials were conducted in adults; the HypoPP GeneReviews chapter states that the same approach applies to children, with age-adjusted dosing, whereas the US label states that paediatric safety and efficacy have not been established [20, 85]. Children with HypoPP and the adults who care for them should be informed of the risk of attacks, especially at school and during sports, so that potassium and help are rapidly available, and school and sports accommodations are useful [20].

Transition. The sources consulted do not describe a structured protocol for transition from paediatric to adult care in the muscle channelopathies. In England, the highly specialised national muscle channelopathy service, based at the National Hospital for Neurology and Neurosurgery in London, sees children and adults, with video consultations for those unable to travel [52, 65]. The elements that change with age follow from the sources already cited: weight-based paediatric mexiletine dosing coincides with adult dosing from 60 kg, and cardiac surveillance follows the SmPC (sections 7.3 and 11.2) [27]; the choice of antimyotonic drug should be reviewed in girls reaching childbearing age, in light of the MEXLAM algorithm and the pregnancy data in section 7.12 [65]; and information on anaesthetic risk, the alert card, and genetic counselling of the young adult (section 8.6) should be transferred to the patient themself [1, 2].

7.14. Developments in the past 12 months and research

The reference window runs from 17 October 2025 to 17 October 2026; milestones from 2024 and 2025 that postdate the 2020 guideline and have not yet been incorporated into society recommendations are also included.

Sources: [63–66, 72, 82–85, 91, 102–106].

Extended-release formulations. Dosing of mexiletine up to three times daily can compromise adherence, and Lupin is investigating once-daily extended-release formulations in two phase 3 trials, HERCULES in myotonic dystrophy and ACHILLES in NDM [63, 102, 103]. ACHILLES compares the new formulation with immediate-release capsules in patients aged 16 years or older, with primary safety outcomes at 12 weeks and up to week 24, and has no results [102].

Discontinued studies or studies without results. The phase 2 trial of bumetanide in HypoPP (NCT02582476, University College London), based on inhibition of the sodium-potassium-chloride cotransporter (NKCC) in murine models, ended in 2017 with 12 participants because of slow recruitment and loss of funding, with no results posted in the registry [3, 107]. The Danish trial comparing lamotrigine and Namuscla® (NCT05639257, 32 participants planned between December 2022 and April 2024) has "unknown" status in the registry, with no update since December 2022 and no results [108]. The European marketing authorisation application for dichlorphenamide (Ekesivy®) was withdrawn in 2019 (section 7.8) [86]. Retigabine, a potassium channel opener studied as an approach to MC, was withdrawn from the worldwide market in 2017 because of low use and bluish pigmentation [63]. The absence of results in the registry is not equivalent to a negative result.

Preclinical research. No specific activators of the ClC-1 channel are known; niflumic acid, a nonsteroidal anti-inflammatory drug, blocks the channel when applied acutely to transfected cells but increases the expression of mutant channels when applied for 24 hours (chaperone effect), and it is not known whether acute block would be clinically acceptable [63]. Next-generation potassium channel openers are in development [63]. In muscle from mice homozygous for the Scn4a R669H variant (the designation published for the murine model), a model of HypoPP, retigabine (a Kv7 channel agonist) reduced loss of force at extracellular potassium of 4.75 and 1.0 mmol/L (P=0.047 and P=0.007; 4 to 7 muscles per group) [104]. In a mouse model of MC, sodium channel blockers at effective concentrations did not reduce the transient sodium current responsible for the action potential but did reduce the persistent sodium current, and the computational model showed that partial block of this current was enough to abolish myotonic discharges without hypoexcitability; the authors propose directing new drug development towards this target [105]. Safinamide, a blocker of neuronal sodium and calcium channels and a reversible monoamine oxidase B inhibitor, reduced fibre hyperexcitability in vitro in the ADR (arrested development of righting response) mouse, a model of MC, and righting reflex time in vivo, with greater potency than mexiletine [106]. The 2020 guideline also identified as lines of research calcium and magnesium modulators, enhancement of chloride conductance, beta-adrenergic agonists studied in the myotonic rat, variant-specific pharmacogenetics, and aggregated N-of-1 trials [2]. None of these findings has been tested in clinical trials in NDM or the PP.

7.15. Guidelines and divergences between sources

Sources: [1–3, 19, 20, 27, 54, 64, 65, 99, 101]. There is no scientific society guideline dedicated specifically to MC, and the 2020 guideline has not been updated since MEXLAM or the European paediatric extension [1, 2].

Sources: [1–3, 19, 20, 27, 54, 65, 85, 86, 96, 99, 101].

Conflicts of interest weigh on the reading of the sources: the French group was funded by Lupin, the marketing authorisation holder for Namuscla® (section 7.3) [54], and editorial support for the review by Statland and colleagues on the PP was funded by Strongbridge Biopharma, for which the first author declared being a consultant [3]. The MEXLAM algorithm comes from a single-centre academic trial with noncommercial funding [65].

8. Reproductive Options and Family Counselling

8.1. Determining the mode of inheritance

MC has AR (Becker disease) or AD (Thomsen disease) inheritance, and the same CLCN1 variant can be associated with both; the distinction depends mainly on the family history [1]. In a simplex case, the mode of inheritance may not be determinable, except when two variants on different alleles are identified in a proband with unaffected parents, which establishes the AR form [1]. Confirming phase by segregation analysis is important, because an allele containing two pathogenic variants has been described [1, 37]. PMC, the sodium channel myotonias, HyperPP, NormoPP, HypoPP, and ATS have AD inheritance; SCN4A congenital myopathy and congenital myasthenic syndrome 16 have AR inheritance [7, 19, 20, 22].

8.2. Recurrence risks

Sources: [1, 7, 19, 20, 22]. In AD MC, most probands have an affected parent, and the proportion of de novo cases is unknown, presumably very low [1]. In ATS, up to half of cases are de novo [7]. In HyperPP, the risk to siblings of a proband whose variant was not detected in the parents is about 1%, because of germline mosaicism [19].

8.3. Parental testing, mosaicism, and uniparental disomy

In AR MC, the parents are obligate heterozygotes, and molecular testing of both is recommended to confirm carrier status and allow reliable risk assessment [1]. If only one parent carries the variant, a de novo variant in the proband, a postzygotic event in a mosaic parent, or uniparental isodisomy of the chromosome carrying the variant should be considered [1]. In AD MC, parental testing is likewise recommended: if the variant is not detected in either parent, it may be a de novo variant, which is confirmed only by parentage testing (otherwise it is "presumed de novo"), or parental germline or somatic mosaicism, which leukocyte DNA may fail to detect [1]. An apparently negative family history may result from failure to recognise the disease in a relative, reduced penetrance, or early death of the parent; untested but clinically unaffected parents confer an apparently low risk, which is nevertheless higher than that of the general population [1].

8.4. Cascade testing and carriers

Carrier detection requires prior identification of the familial variants [1]. Molecular testing of at-risk relatives during childhood is appropriate, because knowing the diagnosis reduces the risk of anaesthetic events [1]. In the PP, at-risk relatives should undergo molecular testing when the familial variant is known and, otherwise, neurologic examination and EMG; anyone who has not been evaluated should be considered at risk, especially in the anaesthetic setting [19]. In ATS, asymptomatic carriers should have an annual 12-lead ECG and 24-hour Holter monitoring [3]. Occasionally, a heterozygous parent or sibling of a proband with AR MC shows subtle myotonia on EMG without being at risk of developing the disease [1, 4]. Intrafamilial variability between siblings with the same biallelic variants means that severity in one case must not be extrapolated to another [1, 45].

8.5. Prenatal diagnosis and preimplantation genetic testing

Once the pathogenic variants in the family have been identified, prenatal diagnosis and PGT are possible [1]. Prenatal identification of CLCN1 variants does not predict age at onset, severity, type of symptoms, or rate of progression, and this should be stated explicitly in counselling [1]. In the case described by Krovvidi and colleagues, in a family with consanguineous parents, prenatal diagnosis was offered after molecular confirmation [43].

8.6. Content and timing of counselling

The optimal time to determine genetic risk and discuss prenatal diagnosis or PGT is before pregnancy; genetic counselling should be offered to young adults who are affected, carriers, or at risk, and DNA banking of affected individuals should be considered [1]. Counselling should cover the reduced penetrance and variable expressivity of AD MC, the possibility that the same genotype may have different severities within the same family, anaesthetic risk and the need to communicate it to any surgical team, the impact of pregnancy on symptoms, and, in families with an SCN4A variant, the risk of severe neonatal laryngospasm, which requires a delivery plan with obstetrics and neonatology [1, 2, 56]. The choice of antimyotonic drug in a woman of childbearing potential has reproductive implications that should be discussed before conception [63, 65]. In minors, testing is justified by its immediate clinical utility (prevention of anaesthetic complications and treatment decisions), not by anticipation of an adult-onset disease [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each study measures

Frequency estimates for the muscle channelopathies come from three types of source, which are not comparable with one another. The classic estimate of 1:100,000 for MC comes from a worldwide survey of the frequencies of inherited neuromuscular diseases published by Emery in 1991, before the era of molecular diagnosis [1, 23]. The national studies from England and the Netherlands measure minimum point prevalences of genetically confirmed disease in referral services and therefore underestimate the true burden, especially for mild forms that never reach these services [24, 109]. Studies of founder populations measure prevalence in a geographic area enriched for specific variants and cannot be extrapolated [25, 41].

9.2. United States and global estimates

The sources consulted contain no population-based prevalence study in the United States. The review by Statland and colleagues gives estimates of 1/200,000 for HyperPP, 1/100,000 for HypoPP, and 1/1,000,000 for ATS, noting that the UK study obtained lower values [3]. The HypoPP GeneReviews chapter reports a prevalence of about 1:100,000 for HypoPP across all genes [20]. The available North American cohorts are clinical and multinational: the CINCH study enrolled 95 patients at 6 centres in the United States, the United Kingdom, and Canada, and the Statland trial recruited 59 patients at 7 centres in four countries, with 57 of 59 participants White [26, 67].

9.3. Europe

Dutch prevalences are almost double those in England and approach pre-genetic Scandinavian estimates, which the authors attribute to the completeness of their ascertainment [109]. For entry ORPHA:614, Orphanet records a worldwide point prevalence of 1–9/100,000 (value of 1.0, attributed to Emery 1991), a class of 1–9/100,000 for Europe, 7.3/100,000 for Finland, and 0.9/1,000,000 for Italy; for the Dutch and UK studies, it records 0.75/1,000,000 and 0.52/1,000,000, but the primary publications give these values per 100,000, so the Orphanet entry does not match the sources [8, 24, 25, 109]. The same unit discrepancy affects the Orphanet values for PMC, HyperPP, HypoPP, and ATS [10, 14, 16, 18]. This article uses the units of the primary publications. Orphanet has no prevalence data for NormoPP (ORPHA:680) [15].

European genetic cohorts describe the variant spectrum by country: the United Kingdom, with more than 300 patients, 15 of 104 CLCN1 variants accounting for 60% of MC cases, 11 of 22 SCN4A variants accounting for 86% of PMC and SCM pedigrees, and 3 of 17 KCNJ2 variants accounting for 42% of ATS pedigrees [24, 35]; the Netherlands, with 61 different CLCN1 variants (12 novel), 28 SCN4A missense variants (3 novel), 4 CACNA1S variants, and 5 KCNJ2 variants [109]; Italy [37, 46]; Spain [55]; Germany, with 70 patients [53]; Denmark, where the AD form is more frequent than the AR form [38]; and the Czech Republic [36].

9.4. Founder populations

Northern Finland is the best-characterised founder population. Baumann and colleagues found 58 patients in 23 families, most from sparsely populated western Lapland, with a prevalence of 7.3/100,000 [25]. Papponen and colleagues sequenced the 23 exons of CLCN1 in 46 patients and 16 unaffected relatives from 24 families and identified three variants, p.(Phe413Cys) in exon 11, p.(Ala531Val) in exon 15, and p.(Arg894Ter) in exon 23, one of them unique to northern Finland; they showed that, even in families with apparently dominant transmission, the actual inheritance was AR, with many compound heterozygotes resulting from enrichment of the three variants through a founder effect and isolation by distance [41]. GeneReviews summarises these data as "northern Scandinavia" and cites a prevalence of 1:10,000 for that region; the primary sources refer to northern Finland, with 7.3/100,000 [1, 25, 41]. DM2 is common in Northern European families, with a prevalence similar to that of DM1 in Germany, which changes the pretest probability of the differential diagnosis in these populations [51].

9.5. Outside Europe

In a Japanese skeletal muscle channelopathy cohort, 45% of probands with NDM had a CLCN1 variant [1, 62]. In a Chinese cohort of 60 patients with primary PP, 92.5% of cases with a genetic diagnosis had variants in CACNA1S, KCNJ2, or SCN4A [19]. Krovvidi and colleagues described two Indian families with Becker MC, both with parental consanguinity (section 10) [43].

9.6. Data gaps

The sources consulted contain no data on prevalence, variant spectrum, or access to treatment in Portugal or Brazil, nor a population-based study in the United States. The absence of these data in the sources consulted does not show that no published data exist. Trial cohorts are predominantly of European ancestry: 57 of 59 participants were White in the Statland trial and 51 of 60 in MEXLAM, whose authors acknowledge the need to increase diversity in research [65, 67].

9.7. Special populations

In children, presentations are more heterogeneous, and SNEL can be fatal without treatment (section 3.4) [2]. In pregnancy, most women report worsening of symptoms [56]. In older adults, experience with mexiletine is limited, and the French group recommends more frequent cardiac monitoring with age [27, 54]. In patients with hepatic or renal impairment, mexiletine dosing requires specific precautions [27]. In patients with epilepsy, mexiletine may increase seizures [27].

9.8. Reference networks and patient organisations

The relevant European reference network is ERN EURO-NMD, dedicated to rare neuromuscular diseases, one of the 24 European Reference Networks, funded by the EU4Health 2021–2027 programme [28]. In England there is a highly specialised national service for skeletal muscle channelopathies, based in London, which accepts referrals from primary care physicians or other specialists and offers video consultations to those unable to travel [24, 52]. In France, patients are followed by the reference and competence centres of the FILNEMUS network, in three regions [54, 87]. Among patient organisations, the Muscular Dystrophy Association (United States) maintains a page on Thomsen and Becker MC; Muscular Dystrophy UK publishes specialist-reviewed information on NDM, reviewed in March 2025, with the next review due in March 2028, and promotes a cohort study of the Queen Square Centre for Neuromuscular Diseases; and the Periodic Paralysis Association is dedicated to the skeletal muscle channelopathies, including the PP, NDM, and ATS, and provides guides on anaesthesia and genetic testing [52, 110, 111]. GeneReviews also refers to the information pages of the National Institute of Neurological Disorders and Stroke and MedlinePlus Genetics [1]. The National Organization for Rare Disorders page on MC was last updated in 2007 and does not reflect the current state of treatment [97]. Variants are compiled in the LOVD [2].

10. Illustrative Clinical Case

10.1. Becker myotonia congenita in two Indian families

Krovvidi and colleagues described two children from Andhra Pradesh, India [43]. Case 1 was a 9-year-old girl weighing 30.0 kg, born to third-degree consanguineous parents. Symptoms began at age 4, with difficulty rising from a sitting position, which she overcame by pushing up with her hands, leg cramps after prolonged walking, and frequent falls; her father had similar, milder complaints. Case 2 was a 10-year-old girl born to second-degree consanguineous parents (maternal uncle and niece), with facial dysmorphism and hypertelorism and no family history. Both reported easy fatigability and had received vitamin D and calcium supplements without effect. On examination, both had hypertrophy of the shoulders and calves, described by the authors as a "bodybuilder appearance," a negative Gowers sign, 4/5 strength in the extremities, and percussion myotonia of the tongue, calves, and thenar eminences; grip myotonia was present in case 1 and, according to the article's table, absent in case 2. Warm-up and worsening with cold were observed, and one of the children had reduced reflexes. CK was 154 and 184 U/L (reference range 30–135 U/L). Thyroid function, complete blood count, calcium-phosphate studies, liver and renal function, ECG, and echocardiogram were normal. EMG was not performed, a choice the authors justify in the text. The genetic panel identified the homozygous CLCN1 variant c.1667T>A p.(Ile556Asn) in exon 15; on NM_000083.3 the nomenclature was confirmed in VariantValidator, and ClinVar classifies it as pathogenic or likely pathogenic (VCV000021041) [34, 40, 43]. The diagnosis was Becker MC. The children received mexiletine at 200 mg of hydrochloride three times daily for three weeks, with improvement in stiffness and quality of life and good tolerance, in addition to physical therapy, genetic counselling, and an offer of prenatal diagnosis [43].

Figure 2 of the article, accessed on 17 October 2026 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12176253/figure/FIG2/), shows the shoulder muscle hypertrophy of case 1, with the legend describing the bodybuilder appearance due to the prominence of the shoulder girdle as indicative of the Becker form [43].

Two aspects of management in the report do not match recommended practice. The dose of 200 mg of hydrochloride three times daily (about 500 mg/day of base) in a 30-kg child exceeds the European SmPC maximum for the 30–40 kg band, which is about 250 mg/day of base, although the report predates the European paediatric extension of May 2026 [27, 43]. The absence of EMG departs from the 2020 guideline algorithm, which recommends EMG before genetic testing [2]. The article also repeats the statement that mexiletine is the only FDA-approved drug for MC, which does not match the US label [66]. The father's heterozygosity was presumed on clinical grounds and not tested, and Figures 1 and 3 exist in the article but were not consulted [43].

10.2. Adult-onset nondystrophic myotonia with laryngospasm due to digenic inheritance

Tugizova and colleagues described a 35-year-old man with feeding difficulties in childhood, normal motor milestones, and participation in sports in high school [42]. From age 32 he developed leg stiffness with warm-up, grip myotonia, and painless cold-induced stiffness. He had repeated hospitalisations for sudden-onset hypoxemic and hypercapnic respiratory failure due to laryngospasm, resolved by intubation; laryngoscopy showed paradoxical vocal cord motion, with inappropriate adduction interrupting quiet breathing. On examination he had percussion myotonia in the finger extensors, normal strength, and mild hyporeflexia, and EMG revealed dense electrical myotonia in all six muscles tested. Deltoid biopsy showed variation in fibre size, mild endomysial fibrosis, internal nuclei, moth-eaten changes, and minicores and, on electron microscopy, Z-line disorganisation. Testing for DMPK and CNBP expansions was negative, and alpha-glucosidase activity was normal. The genetic panel identified CLCN1 c.1478C>A p.(Ala493Glu), pathogenic, inherited from his father, who had neither clinical nor electrical myotonia, and SCN4A c.5107_5109del p.(Glu1703del), classified as a VUS, inherited from his mother, who had subtle percussion myotonia and mild electrical myotonia; his brother had neither variant. Mexiletine 200 mg of hydrochloride three times daily resolved the myotonia and the laryngospasm, allowing tracheostomy decannulation. The authors interpret the picture as an additive digenic effect and describe it as the first case of adult-onset sodium channelopathy with respiratory failure due to laryngospasm [42].

Figure 1 of the article, accessed on 17 October 2026 (https://pmc.ncbi.nlm.nih.gov/articles/PMC11655165/figure/F1/), shows the laryngoscopic findings: in panel A, laryngeal oedema with normal vocal cord abduction and, in panel B, episodes of inappropriate adduction interrupting quiet breathing [42].

The case illustrates three points of clinical interest: myotonia can begin in adulthood; a CLCN1 variant inherited from a parent with neither clinical nor electrical myotonia can contribute to a severe phenotype when combined with a second variant in another channel, which supports the data on digenic modulation described in section 2.4; and laryngospasm with respiratory failure, described mainly in newborns with an SCN4A variant, can occur in adults and respond to antimyotonic treatment [42, 48]. The interpretation of a VUS as contributing to the phenotype is that of the report's authors and does not constitute formal reclassification under ACMG/AMP criteria [42, 50].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

NDM do not cause progressive muscle atrophy, and life expectancy is generally normal [2]. Morbidity is lifelong and begins early: mean age at symptom onset was 7.7 years (standard deviation 5.5) among the 60 MEXLAM participants, 5 years in the sodium channelopathies and 10 years in the chloride channelopathies in the CINCH study, and 11 years in the northern Finland cohort [25, 26, 65]. Most patients report moderate worsening over their lifetime [2]. Fixed weakness is occasional and rarely below MRC grade 4; proximal weakness is rare in NDM [2]. Quality of life is similar to that in myotonic dystrophy and lower than that of the healthy population, and pain and fatigue are the symptoms that weigh most [2, 26]. Treatment reduces stiffness to about half of baseline in controlled trials, although it has not been shown to alter the natural history [64, 65].

The prognosis of the PP is different, because fixed myopathy is common. In HyperPP, more than 80% of patients older than 40 have permanent weakness and about one-third develop chronic progressive myopathy; MRI shows changes as early as the 2nd and 3rd decades, mainly in the gastrocnemius and the superficial posterior compartment of the leg; attacks increase in frequency and severity until about age 50 and decrease thereafter [19]. In HypoPP, prolonged interictal weakness occurred in 28% of patients in one series, with a mean age of 39 years, and in a survey of patients with a mean age of 55 years, 90% reported fatigue, 67% falls with injuries, and about half used walking aids; myopathy may be the only manifestation [20]. In a survey of 66 patients with PP, 68% reported permanent weakness and 49% used walking aids [3]. In ATS, prognosis is determined by arrhythmic risk [3, 51]. In biallelic SCN4A congenital myopathy, 7 of the 11 individuals in the initial series died in the 3rd trimester or shortly after birth, and the 4 survivors improved during the 1st decade [22].

11.2. Surveillance table

The 2021 version of the MC GeneReviews chapter contains no surveillance section and recommends only an initial evaluation by a neurologist to determine the need for treatment and a genetics consultation [1]. The cardiac surveillance intervals in the table match those described in section 7.3. The arrhythmias and conduction defects described in a minority of patients with MC are of uncertain clinical significance and, in the sources consulted, do not justify periodic ECGs in patients not treated with mexiletine; the French expert group considers that the NDM population has no increased risk compared with the general population [1, 53, 54].

11.3. Long-term treatment outcomes

Long-term information comes from observational cohorts. The French group pooled five studies of 236 patients with NDM treated with 200–600 mg/day of mexiletine for up to 20 years, with no cases of cardiac arrhythmia; in the two retrospective cohorts (63 and 112 patients), heart rate, PR interval, QRS duration, and QTc did not differ significantly between the maximum dose and baseline, and the most frequent adverse effect was dyspepsia [54]. Of the 16 patients in one of these cohorts referred to cardiology for cardiac concerns before or during treatment, all were cleared to start or continue [54]. Matthews and colleagues report 302.4 patient-years of real-world follow-up without significant ECG changes [63]. In the UK prospective lamotrigine cohort, with a mean follow-up of 26 months, the MBS fell from 3.3 to 1.8, and 9 of 37 patients discontinued because of adverse effects [72]. A systematic review of 221 studies and 8,970 patients treated with mexiletine for various indications, cited by the French group, concluded that the drug is effective and safe at doses of 50 to 2,400 mg/day [54]. Long-term paediatric data are limited to the open-label extension of MEX-NM-301, completed in June 2026 with 12 patients and about 24 months of follow-up, whose results have not been posted in the registry, and to the PEGASUS registry, ongoing for children younger than 6 [82, 83].

12. Summary and Concluding Remarks

Myotonia congenita is the most common skeletal muscle channelopathy and results from reduced sarcolemmal chloride conductance caused by CLCN1 variants. Because the ClC-1 channel functions as a homodimer and myotonia appears only when conductance falls below about half of normal, the same molecular architecture explains the dual inheritance: alleles with complete loss of function behave recessively, and alleles that inactivate the normal subunit behave dominantly. The practical consequences for counselling follow: the same variant can be associated with both forms, the penetrance of dominant variants is reduced, determining the mode of inheritance depends on the family history and parental testing, and two variants in a proband confirm the recessive form only after they have been shown to be on different alleles.

Clinically, stiffness that improves with repeated movement, muscle hypertrophy, and, in the recessive form, transient paresis at the start of activity point to chloride channelopathy, whereas myotonia that worsens with repetition and with cold, pain, and facial stiffness point to the sodium channelopathies. Paradoxical myotonia and transient paresis are the only virtually specific signs of each group; all the others overlap, and a significant proportion of patients with clinically suspected myotonia congenita in fact have an SCN4A variant. This overlap justifies simultaneous analysis of both genes, preceded by electromyography when clinical myotonia is not evident. Normal or mildly elevated creatine kinase and the exercise test patterns narrow the differential without resolving it, and a negative genetic result does not exclude the diagnosis: the proportions of variants detectable by each method describe the known variant spectrum, not clinical sensitivity, and deep intronic variants escape exon sequencing.

The essential differential diagnosis includes the myotonic dystrophies, which are much more common and have a different prognosis because of their multisystem manifestations, and the primary periodic paralyses, in which serum potassium during the attack, the supporting criteria, and the gene involved guide preventive treatment. Andersen-Tawil syndrome is distinguished by the triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features and requires its own cardiologic approach. Biallelic loss of function of SCN4A causes a distinct entity, of fetal or neonatal onset and without myotonia, which shows how the same gene produces opposite diseases depending on mechanism and zygosity, and which requires consistency between the predicted mechanism of a variant and the observed phenotype.

Treatment is symptomatic. Mexiletine and lamotrigine are the two drugs with evidence from randomised trials, both reducing stiffness to about half of baseline and with different profiles of tolerability, latency, cost, and safety in pregnancy. Mexiletine is the only authorised therapy for myotonia in the nondystrophic myotonias in the European Union, since December 2018 in adults and, following the European Commission decision of May 2026, also from age 6 and 20 kg, with weight-based paediatric dosing; in the United States it retains an indication only for ventricular arrhythmias, so its use for myotonia is off-label. Doses in the European summary of product characteristics are expressed as mexiletine base, and those in the trials and the US label as the hydrochloride, a difference that must be checked with every prescription. The head-to-head trial of the two drugs did not demonstrate noninferiority of lamotrigine, but improvements were similar, and the choice is now based on patient characteristics, comorbidities, and cardiac contraindications.

Open questions include the absence of disease-modifying therapy, the lack of specific ClC-1 activators, the lack of completed paediatric trials, the scarcity of long-term data, and the absence, in the sources consulted, of population-based epidemiologic studies outside England, the Netherlands, and northern Finland, particularly in Portugal and Brazil. The available data come mainly from populations of European ancestry followed at referral centres, which limits the generalizability of prevalences and genotype proportions.

13. References

1. Dunø M, Vissing J. Myotonia Congenita. 2005 Aug 3 [updated 2021 Feb 25]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1355/
2. Stunnenberg BC, LoRusso S, Arnold WD, Barohn RJ, Cannon SC, Fontaine B, et al. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020;62(4):430-444. doi:10.1002/mus.26887. PMID 32270509; PMC8117169.
3. Statland JM, Fontaine B, Hanna MG, Johnson NE, Kissel JT, Sansone VA, et al. Review of the Diagnosis and Treatment of Periodic Paralysis. Muscle Nerve. 2018;57(4):522-530. doi:10.1002/mus.26009. PMID 29125635; PMC5867231.
4. GeneGuidance. CLCN1 — clinical gene curation (version of 2026-09-26).
5. GeneGuidance. SCN4A — clinical gene curation (version of 2026-09-26).
6. GeneGuidance. CACNA1S — clinical gene curation (version of 2026-09-26).
7. GeneGuidance. KCNJ2 — clinical gene curation (version of 2026-09-26).
8. Orphanet. Thomsen and Becker disease (ORPHA:614). Available from: https://www.orpha.net/en/disease/detail/614
9. Orphanet. Neurological muscular channelopathy due to a genetic chloride channel defect (ORPHA:98739, group). https://www.orpha.net/en/disease/detail/98739
10. Orphanet. Paramyotonia congenita of Von Eulenburg (ORPHA:684). https://www.orpha.net/en/disease/detail/684
11. Orphanet. Myotonia fluctuans (ORPHA:99734). https://www.orpha.net/en/disease/detail/99734
12. Orphanet. Myotonia permanens (ORPHA:99735). https://www.orpha.net/en/disease/detail/99735
13. Orphanet. Acetazolamide-responsive myotonia (ORPHA:99736). https://www.orpha.net/en/disease/detail/99736
14. Orphanet. Hyperkalemic periodic paralysis (ORPHA:682). https://www.orpha.net/en/disease/detail/682
15. Orphanet. Normokalemic periodic paralysis (ORPHA:680). https://www.orpha.net/en/disease/detail/680
16. Orphanet. Hypokalemic periodic paralysis (ORPHA:681). https://www.orpha.net/en/disease/detail/681
17. Orphanet. Thyrotoxic periodic paralysis (ORPHA:79102). https://www.orpha.net/en/disease/detail/79102
18. Orphanet. Andersen-Tawil syndrome (ORPHA:37553). https://www.orpha.net/en/disease/detail/37553
19. Weber F. Hyperkalemic Periodic Paralysis. 2003 Jul 18 [updated 2021 Jul 1]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1496/
20. Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis. 2002 Apr 30 [updated 2018 Jul 26]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1338/
21. Veerapandiyan A, Statland JM, Tawil R. Andersen-Tawil Syndrome. 2004 Nov 22 [updated 2018 Jun 7]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1264/
22. Zaharieva IT, Thor MG, Oates EC, van Karnebeek C, Hendson G, Blom E, et al. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain. 2016;139(Pt 3):674-691. doi:10.1093/brain/awv352. PMID 26700687; PMC4766374.
23. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord. 1991;1:19–29. PMID 1822774
24. Horga A, Raja Rayan DL, Matthews E, Sud R, Fialho D, Durran SC, et al. Prevalence study of genetically defined skeletal muscle channelopathies in England. Neurology. 2013;80(16):1472-1475. doi:10.1212/wnl.0b013e31828cf8d0. PMID 23516313; PMC3662361.
25. Baumann P, Myllylä VV, Leisti J. Myotonia congenita in northern Finland: an epidemiological and genetic study. J Med Genet. 1998;35(4):293-296. doi:10.1136/jmg.35.4.293. PMID 9598722; PMC1051276.
26. Trivedi JR, Bundy B, Statland J, Salajegheh M, Rayan DR, Venance SL, et al. Non-dystrophic myotonia: prospective study of objective and patient reported outcomes. Brain. 2013;136(Pt 7):2189-2200. doi:10.1093/brain/awt133. PMID 23771340; PMC3692030.
27. European Medicines Agency. Namuscla 62 mg, 83 mg, 167 mg hard capsules: summary of product characteristics (Annex I–III). Available from: https://www.ema.europa.eu/en/documents/product-information/namuscla-epar-product-information_en.pdf
28. European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Available from: https://ern-euro-nmd.eu/
29. Koch MC, Steinmeyer K, Lorenz C, Ricker K, Wolf F, Otto M, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science. 1992;257(5071):797-800. doi:10.1126/science.1379744. PMID 1379744.
30. Zhang J, George AL Jr, Griggs RC, et al. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Neurology. 1996;47:993–8. PMID 8857733
31. Koty PP, Pegoraro E, Hobson G, et al. Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. Neurology. 1996;47:963–8. PMID 8857727
32. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 497–499.
33. Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar [Genetic Syndromes: Recognise to Treat]. Fortaleza: EdUnichristus; 2021. p. 74–76 (3.3 Distrofia miotónica de Steinert [Steinert myotonic dystrophy]).
34. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. Tool: https://variantvalidator.org/ (GRCh38, MANE Select)
35. Fialho D, Schorge S, Pucovska U, et al. Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. Brain. 2007;130:3265–74. PMID 17932099
36. Skálová D, Zídková J, Voháňka S, et al. CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. PLoS One. 2013;8:e82549. PMID 24349310
37. Brugnoni R, Kapetis D, Imbrici P, et al. A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. J Hum Genet. 2013;58:581–7. PMID 23739125
38. Dunø M, Colding-Jørgensen E, Grunnet M, et al. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet. 2004;12:738–43. PMID 15162127
39. Helal S, Pipko N, Liang Y, Levine A, Carnevale A, Szuto A, et al. Novel deep intronic variant in CLCN1 causing autosomal recessive myotonia congenita. Neurogenetics. 2026;27(1):56. doi:10.1007/s10048-026-00925-z. PMID 42599553.
40. National Center for Biotechnology Information. ClinVar. Bethesda (MD): National Library of Medicine. Available from: https://www.ncbi.nlm.nih.gov/clinvar/ (accessed 17 Oct 2026).
41. Papponen H, Toppinen T, Baumann P, Myllylä V, Leisti J, Kuivaniemi H, et al. Founder mutations and the high prevalence of myotonia congenita in northern Finland. Neurology. 1999;53(2):297-302. doi:10.1212/wnl.53.2.297. PMID 10430417.
42. Tugizova M, Margeta M, Richie M, Pet D, Rosow L, Terrelonge M, et al. Severe Adult-Onset Non-Dystrophic Myotonia With Apnea and Laryngospasm Due to Digenic Inheritance of SCN4A and CLCN1 Variants: A Case Report. Neurol Genet. 2025;11(1):e200223. doi:10.1212/nxg.0000000000200223. PMID 39703462; PMC11655165.
43. Krovvidi S, Nelakurthi S, Gedela M, Singamsetty S, Bhimireddy V. Autosomal Recessive Becker's Form of Myotonia Congenita in Indian Families. Cureus. 2025;17(5):e84373. doi:10.7759/cureus.84373. PMID 40535402; PMC12176253.
44. Ogueri V, Chong J, Fleming M, Simpson K, Sherwin E, Bharucha-Goebel D, et al. High-dose flecainide for symptomatic relief in paramyotonia congenita/severe neonatal episodic laryngospasm due to SCN4A G1306E: a case report. J Med Case Rep. 2025;19(1):224. doi:10.1186/s13256-025-05164-8. PMID 40361141; PMC12070567.
45. Colding-Jørgensen E. Phenotypic variability in myotonia congenita. Muscle Nerve. 2005;32:19–34. PMID 15786415
46. Orsini C, Petillo R, D'Ambrosio P, et al. CLCN1 molecular characterization in 19 South-Italian patients with dominant and recessive type of myotonia congenita. Front Neurol. 2020;11:63. PMID 32117024
47. Nagamitsu S, Matsuura T, Khajavi M, et al. A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene. Neurology. 2000;55:1697–703. PMID 11113225
48. Furby A, Vicart S, Camdessanché JP, et al. Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. Neuromuscul Disord. 2014;24:953–9. PMID 25088311
49. Cardani R, Giagnacovo M, Botta A, et al. Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2. J Neurol. 2012;259:2090–9. PMID 22407275
50. D'Ambrosio P, Cipriano L, Pugliese A, Petillo R, Ricciardi D, Habetswallner F, et al. SCN4A Channelopathies: From Disease Mechanisms to Variant Interpretation. Genes (Basel). 2026;17(9):1116. doi:10.3390/genes17091116. PMID 42793010; PMC13606911.
51. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 371–382.
52. Muscular Dystrophy UK. Non-dystrophic myotonias (NDM). Reviewers: Matthews E, Jayaseelan D. London: Muscular Dystrophy UK; reviewed March 2025. Available from: https://www.musculardystrophyuk.org/conditions/a-z/non-dystrophic-myotonias-ndm/
53. Vereb N, Montagnese F, Gläser D, Schoser B. Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients. J Neurol. 2020 (epub). PMID 33263785
54. Vicart S, Wahbi K, Duchateau J, Sellal JM, Desaphy JF, Deharo JC, et al. Recommendations of an expert group for the cardiac assessment of non-dystrophic myotonia adult patients treated with mexiletine. Neuromuscul Disord. 2024;44:104464. doi:10.1016/j.nmd.2024.104464. PMID 39368428.
55. Milla CP, De Castro CP, Gómez-González C, et al. Myotonia congenita: mutation spectrum of CLCN1 in Spanish patients. J Genet. 2019;98:71. PMID 31544778
56. Snyder Y, Donlin-Smith C, Snyder E, Pressman E, Ciafaloni E. The course and outcome of pregnancy in women with nondystrophic myotonias. Muscle Nerve. 2015;52(6):1013-1015. doi:10.1002/mus.24684. PMID 25900207.
57. Farbu E, Søfteland E, Bindoff LA. Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Acta Anaesthesiol Scand. 2003;47(5):630-634. doi:10.1034/j.1399-6576.2003.00116.x. PMID 12699527.
58. Andersen G, Løkken N, Vissing J. Aerobic training in myotonia congenita: effect on myotonia and fitness. Muscle Nerve. 2017;56:696–9. PMID 28039888
59. Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. 2004;56:650–61. PMID 15389891
60. Tan SV, Matthews E, Barber M, et al. Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies. Ann Neurol. 2011;69:328–40. PMID 21387378
61. Trip J, Drost G, Verbove DJ, et al. In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia. Eur J Hum Genet. 2008;16:921–9. PMID 18337730
62. Sasaki R, Nakaza M, Furuta M, et al. Mutation spectrum and health status in skeletal muscle channelopathies in Japan. Neuromuscul Disord. 2020;30:546–53. PMID 32660787
63. Matthews E, Specterman MJ, Mul K. Treatment updates in myotonic disorders. J Neurol. 2026;273(10):562. doi:10.1007/s00415-026-14073-9. PMID 42698007; PMC13545122.
64. Spillane J, Trip J, Drost G, Faber CG, Hanna MG, Nevitt SJ, et al. Drug treatment for myotonia. Cochrane Database Syst Rev. 2025;4:CD004762. doi:10.1002/14651858.cd004762.pub3. PMID 40197813; PMC11977047.
65. Vivekanandam V, Skorupinska I, Jayaseelan DL, Matthews E, Barohn RJ, McDermott MP, et al. Mexiletine versus lamotrigine in non-dystrophic myotonias: a randomised, double-blind, head-to-head, crossover, non-inferiority, phase 3 trial. Lancet Neurol. 2024;23(10):1004-1012. doi:10.1016/s1474-4422(24)00320-x. PMID 39304240.
66. U.S. Food and Drug Administration / DailyMed. Mexiletine hydrochloride capsules, USP — prescribing information (ANDA214089; label effective 2024-10-18); Drugs@FDA NDA018873 (Mexitil, approved 1985-12-30, discontinued). Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=mexiletine ; https://www.accessdata.fda.gov/scripts/cder/daf/
67. Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012;308(13):1357-1365. doi:10.1001/jama.2012.12607. PMID 23032552; PMC3564227.
68. Brugnoni R, Salvi E, Moresco E, Gallone A, Tufano L, Garibaldi M, et al. Pharmacogenetic pilot study of CYP2D6 and CYP1A2 genes in Italian patients with non-dystrophic myotonia and myotonic dystrophy treated with mexiletine. Gene. 2025;960:149536. doi:10.1016/j.gene.2025.149536. PMID 40324568.
69. Stunnenberg BC, Raaphorst J, Groenewoud HM, Statland JM, Griggs RC, Woertman W, et al. Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials. JAMA. 2018;320(22):2344-2353. doi:10.1001/jama.2018.18020. PMID 30535218; PMC6583079.
70. Andersen G, Hedermann G, Witting N, Duno M, Andersen H, Vissing J. The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study. Brain. 2017;140(9):2295-2305. doi:10.1093/brain/awx192. PMID 29050397.
71. GlaxoSmithKline. LAMICTAL XR (lamotrigine) extended-release tablets — prescribing information (label effective 2025-10-10): boxed warning (serious skin rashes) and 5.4 Cardiac rhythm and conduction abnormalities. Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=lamictal
72. Asad M, Skorupinska I, James N, Jayaseelan D, Hanna MG, Vivekanandam V. Long term safety and efficacy of lamotrigine in patients with non-dystrophic myotonia, a single-centre prospective study. Neuromuscul Disord. 2025;56-57:106222. doi:10.1016/j.nmd.2025.106222. PMID 41202340.
73. Viona Pharmaceuticals. Ranolazine extended-release tablets [prescribing information]. DailyMed set id 00979fb3-d70f-493d-94ca-2914cbadaa9d; version 2026-01-29. ANDA210188. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=00979fb3-d70f-493d-94ca-2914cbadaa9d (accessed 26 Oct 2026).
74. European Medicines Agency. Ranexa (ranolazine) 375 mg, 500 mg, 750 mg prolonged-release tablets — summary of product characteristics. EPAR, product information. Available from: https://www.ema.europa.eu/en/documents/product-information/ranexa-epar-product-information_en.pdf (accessed 26 Oct 2026).
75. Arnold WD, Kline D, Sanderson A, Hawash AA, Bartlett A, Novak KR, et al. Open-label trial of ranolazine for the treatment of myotonia congenita. Neurology. 2017;89(7):710-713. doi:10.1212/wnl.0000000000004229. PMID 28710329; PMC5562961.
76. Lorusso S, Kline D, Bartlett A, Freimer M, Agriesti J, Hawash AA, et al. Open-label trial of ranolazine for the treatment of paramyotonia congenita. Muscle Nerve. 2019;59(2):240-243. doi:10.1002/mus.26372. PMID 30390395; PMC6340713.
77. Ohio State University. Study of ranolazine in myotonia congenita, paramyotonia congenita and myotonic dystrophy type 1. ClinicalTrials.gov NCT02251457. Available from: https://clinicaltrials.gov/study/NCT02251457
78. Carbinib 250 mg comprimidos (acetazolamida) — resumo das características do medicamento [Carbinib 250 mg tablets (acetazolamide) — summary of product characteristics]. INFARMED, Infomed; text approved 29 Oct 2024. Available from: https://extranet.infarmed.pt/INFOMED-fo/ (accessed 26 Oct 2026).
79. Aurobindo Pharma. Flecainide acetate tablets [prescribing information]. DailyMed set id 14e89448-3a18-42e3-8537-2589be1ef94e; version 2024-01-09. ANDA202821. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=14e89448-3a18-42e3-8537-2589be1ef94e (accessed 26 Oct 2026).
80. Laboratório Medinfar. Apocard 100 mg comprimidos (flecainida) — resumo das características do medicamento [Apocard 100 mg tablets (flecainide) — summary of product characteristics]. INFARMED, Infomed (med_id 505); text approved 27 Feb 2024. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=505&tipo_doc=rcm (accessed 26 Oct 2026).
81. Conravey A, Santana-Gould L. Myotonia congenita and myotonic dystrophy: surveillance and management. Curr Treat Options Neurol. 2010;12:16–28. PMID 20842486
82. Lupin Ltd. Steady-state pharmacokinetics, safety and efficacy of mexiletine in adolescents and children with myotonic disorders (MEX-NM-301), NCT04624750; open-label extension NCT04622553; PEGASUS registry NCT07154654; adult observational study NCT04616807. Available from: https://clinicaltrials.gov/study/NCT04624750
83. European Medicines Agency. Namuscla (mexiletine): EPAR — medicine overview and authorisation details. EMEA/H/C/004584. Amsterdam: EMA; page last updated 2026-06-03. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/namuscla
84. European Medicines Agency, CHMP. Summary of opinion (post authorisation): Namuscla (mexiletine), EMADOC-1700519818-3015439. 26 March 2026. Available from: https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-namuscla-x-0000258210_en.pdf
85. Xeris Pharmaceuticals. KEVEYIS (dichlorphenamide) tablets — prescribing information (NDA011366; label effective 2026-03-04); Drugs@FDA NDA011366 (orig. 1958-07-22; efficacy supplement for periodic paralysis 2015-08-07). Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=keveyis
86. European Medicines Agency. Ekesivy (diclofenamide): withdrawal of the marketing authorisation application. EMEA/H/C/005141. Withdrawal 2 October 2019. Available from: https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/ekesivy
87. Barrière S, Manel V, Barnerias C, Wahbi K, Audic F, Cances C, et al. Evaluation of professional practices in the use of mexiletine for the management of childhood myotonia in French pediatric neuromuscular centers (MEXI-PEDI survey). Arch Pediatr. 2025;32(2):107-113. doi:10.1016/j.arcped.2024.10.009. PMID 39875220.
88. Sansone VA, Burge J, McDermott MP, Smith PC, et al. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology. 2016;86:1408-1416. doi:10.1212/wnl.0000000000002416. PMID 26865514.
89. Epic Pharma. Potassium chloride extended-release tablets [prescribing information]. DailyMed set id 00615fad-ad3b-46e8-a89d-48290d937ae2; version 2025-09-23. ANDA209314. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=00615fad-ad3b-46e8-a89d-48290d937ae2 (accessed 26 Oct 2026).
90. Sandoz Farmacêutica. Cloreto de Potássio Sandoz 750 mg comprimidos de libertação prolongada — resumo das características do medicamento [Potassium Chloride Sandoz 750 mg prolonged-release tablets — summary of product characteristics]. INFARMED, Infomed (med_id 704524). Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=704524&tipo_doc=rcm (accessed 26 Oct 2026).
91. Copenhagen University Hospital, Rigshospitalet. Effect of physical training in individuals with hypokalemic and hyperkalemic periodic paralysis. ClinicalTrials.gov NCT07194174. Available from: https://clinicaltrials.gov/study/NCT07194174
92. Bandschapp O, Iaizzo PA. Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses. Paediatr Anaesth. 2013;23(9):824-833. doi:10.1111/pan.12217. PMID 23802937.
93. Shutes TK, McCormick WF, Harris RM, Walters CB. A Novel Anesthetic in Thomsen Myotonia Congenita With Rocuronium and Sugammadex: A Case Report. A A Pract. 2026;20(1):e02137. doi:10.1213/xaa.0000000000002137. PMID 41524695.
94. Chee M, Thangavelautham S, Chen JH, Kothandan H. Anaesthesia for Paramyotonia Congenita: A Narrative Review. Cureus. 2025;17(9):e93393. doi:10.7759/cureus.93393. PMID 41164065; PMC12560062.
95. Gorthi S, Radbourne S, Drury N, Rajagopalan C. Management of pregnancy with Thomsen's disease. Eur J Obstet Gynecol Reprod Biol. 2013;170:293-294. doi:10.1016/j.ejogrb.2013.05.013. PMID 23806446.
96. Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg. 2009;109(4):1054-1064. doi:10.1213/ane.0b013e3181a7c8e5. PMID 19762732.
97. National Organization for Rare Disorders. Myotonia congenita. Rare Disease Report. Quincy (MA): NORD; last updated 17 Sep 2007. Available from: https://rarediseases.org/rare-diseases/myotonia-congenita/
98. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Sensitivity to anaesthetic agents. p. 524–525.
99. Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126(1):120-130. doi:10.1016/j.bja.2020.09.029. PMID 33131754.
100. Blessing W, Walsh JC. Myotonia precipitated by propranolol therapy. Lancet. 1977;1:73-74. doi:10.1016/s0140-6736(77)91083-2. PMID 63714.
101. Matthews E, Palace J, Ramdas S, Sansone V, Tristani-Firouzi M, Vicart S, et al. Care recommendations for the investigation and management of children with skeletal muscle channelopathies. Pediatr Neurol. 2023;145:102-111. doi:10.1016/j.pediatrneurol.2023.05.012. PMID 37315339.
102. Lupin Ltd. Mexiletine PR compared to mexiletine IR in patients with non-dystrophic myotonias (ACHILLES). ClinicalTrials.gov NCT07097701. Available from: https://clinicaltrials.gov/study/NCT07097701
103. Lupin Ltd. Once daily mexiletine PR in myotonic dystrophy type 1 and type 2 (HERCULES). ClinicalTrials.gov NCT06523400. Available from: https://clinicaltrials.gov/study/NCT06523400
104. Denman K, Rich MM. Efficacy of retigabine in treating weakness in a mouse model of hypokalemic periodic paralysis. Muscle Nerve. 2026;73(4):663-667. doi:10.1002/mus.70158. PMID 41550072; PMC12969955.
105. Walker P, Foy B, Wang X, Pham KM, Myers J, Dupont C, et al. Efficacy of sodium channel blockers in treating myotonia is independent of action potential sodium current block. J Physiol. 2026;604(18):7799-7818. doi:10.1113/jp290148. PMID 42700447; PMC13577688.
106. Canfora I, Altamura C, Desaphy JF, Boccanegra B, Vailati S, Caccia C, et al. Preclinical study of the antimyotonic efficacy of safinamide in the myotonic mouse model. Neurotherapeutics. 2024;21(6):e00455. doi:10.1016/j.neurot.2024.e00455. PMID 39322473; PMC11586006.
107. University College London. Bumetanide in hypokalaemic periodic paralysis. ClinicalTrials.gov NCT02582476 (terminated). Available from: https://clinicaltrials.gov/study/NCT02582476
108. Andersen G. Treatment of myotonia — lamotrigine versus Namuscla. ClinicalTrials.gov NCT05639257. Available from: https://clinicaltrials.gov/study/NCT05639257
109. Stunnenberg BC, Raaphorst J, Deenen JCW, Links TP, Wilde AA, Verbove DJ, et al. Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. Neuromuscul Disord. 2018;28(5):402-407. doi:10.1016/j.nmd.2018.03.006. PMID 29606556.
110. Muscular Dystrophy Association. Myotonia Congenita (Thomsen Disease and Becker Type). Available from: https://www.mda.org/disease/myotonia-congenita
111. The Periodic Paralysis Association. Available from: https://www.periodicparalysis.org/