Muscle channelopathies: A review

Abstract

Background

Muscle channelopathies are a rare and heterogeneous group of disorders that can be clinically challenging and functionally disabling. These disorders can present in both adult and pediatric age groups. These disorders have been known since the turn of the 20th century, with a steady evolution in terms of understanding the pathophysiology, phenotype, diagnostic, and treatment modalities over the last three decades.

Methods

We present a comprehensive review of muscle channelopathies that includes nondystrophic myotonias and periodic paralyses. The disorders in this review have been classified based on the presence or absence of myotonia on either the clinical exam or on electrophysiological testing. The historical background, genetics, pathophysiology, phenotypic presentations, and treatment modalities of each disorder reveal similarities as well as specific nuances in the disease phenotypes. Neurophysiologic testing shows differences in responses on routine and exercise testing and can narrow the differential within subsets of nondystrophic myotonias and periodic paralyses. The advances in genetics further aid in specifying which of the putative channels are at fault. Management can then be guided by knowledge of the causative gene and involves either avoidance of triggers or channel‐based therapeutics.

Conclusion

Muscle channelopathies are rare, but a high index of suspicion along with a knowledge of the phenotype will help guide neurophysiological and genetic testing. A muscle channelopathy diagnosis, subsequently, can assist in avoiding triggers and directing treatments.

Introduction

Ion channels in the nervous system play an essential role in the initiation, propagation, and suppression of action potentials. These ion channels or pore‐forming proteins are special gateways that route ions across the cell membrane. The ion channel structure consists of a central transmembrane pore and includes an assembly of different subunits that enclose the central pore. In most ion channels, the pore is lined by alpha helixes with four homologous domains, but some channels can be composed of beta barrel structures. ¹ Ion channels are actuated either by voltage or by a ligand (e.g., GABA, glycine, AchR). ² These channels include sodium and calcium, the opening of which causes depolarization as compared with potassium and chloride channel opening, which causes hyperpolarization.

Mutations in these channels, commonly missense, can cause either hyper‐ or hypoexcitability depending on whether there is loss or gain of function. ³ These mutations can therefore lead to diseases along the various anatomical axes of the nervous system ranging from epilepsy to episodic ataxia, erythromelalgia, congenital myasthenic syndromes, nondystrophic myotonias, and periodic paralyses. These ion channel disorders, henceforth referred to as “channelopathies,” can be either inherited or acquired due to autoimmune activation. Hereditary channelopathies are usually autosomal dominant but can be inherited in other ways. Channelopathies that are inherited characteristically manifest early in life, with episodic or paroxysmal symptoms and often triggered by stimuli such as stress, temperature changes, and so on that alter channel homeostasis. ⁴

This review focuses on muscle channelopathies that include nondystrophic myotonias and periodic paralyses. These are a heterogeneous group of disorders that are rare but can be clinically challenging and functionally disabling. Although these disorders have been classified in various ways in the literature, we have used what is previously known about the presence or absence of myotonia, on either clinical exam or electrophysiological testing, as the basis for classification (Table 1). These disorders have been known clinically for over 140 years, starting with myotonia congenita by Julius Thomsen in 1876, who described affected individuals from his own family. ⁵ Similarly, in 1908 Birt laid out a pedigree showing himself as being affected and skipping of generations in his family. ⁶ In 1948, Thomasen reported 64 affected individuals in seven consecutive generations. ⁷ Subsequently, Becker offered a descriptive classification of the myotonias in 1977 that was later found to include Thomsen disease and potassium‐aggravated myotonias. ⁸ , ⁹

Table 1.

Classification of muscle channelopathies.

Disease	Channel	Types	Gene
Presence of myotonia
Myotonia congenita	Chloride	Thomsen disease, Becker disease	CLCN1
Paramyotonia congenita	Sodium		SCN4A
Sodium channel myotonias	Sodium		SCN4A
A. Potassium aggravated myotonias		Myotonia permanens, myotonia fluctuans, acetazolamide‐responsive myotonia
B. Hyperkalemic periodic paralysis	Sodium
C. Severe neonatal episodic laryngospasm	Sodium
Schwartz–Jampel syndrome	Not well known		HSPG2
Absence of myotonia
Hypokalemic periodic paralysis	Calcium	Hypokalemic periodic paralysis type 1	CACNA1S
	Sodium	Hypokalemic periodic paralysis type 2	SCN4A
Andersen–Tawil syndrome	Potassium		KCNJ2
Malignant hyperthermia	Calcium		RYR1, CACNA1S, STAC3
Brody	Calcium		ATP2A1

Pediatric Presentation

Symptoms of nondystrophic myotonias and periodic paralyses in children can resemble those in adults, although the timing, duration, and clinical discernment often differ. These factors cause delays in seeking care and subsequent referral to a neuromuscular physician, both leading to late diagnoses. Children can present with recognizable signs such as myotonia or cramps, but often these presentations can be nonspecific, such as gait abnormality, ankle contractures, strabismus, or scoliosis. ¹⁰ Signs can often present early in the neonatal or infantile period with stridulous breathing, choking issues, or potentially life‐threatening episodes, as seen in cases of SCN4A‐related severe neonatal episodic laryngospasm. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ Matthews et al. recommend that all children with discernible leg cramps or gait abnormality be examined for the presence of myotonia, as early detection may avoid further investigations such as biopsy, imaging, or blood tests.

Channelopathies With Myotonia

Chloride channelopathies

Myotonia congenita

In skeletal muscle, action potentials are generated via the activation of voltage‐gated sodium channels resulting in depolarization of the sarcolemmal membrane. However, unlike neurons, chloride channels are the major drivers of repolarization. Myotonia congenita is a nondystrophic myotonia caused by defects in the CLCN1 gene. CLCN1 encodes the voltage‐gated chloride channel protein 1 (CLC‐1), which is primarily expressed in skeletal muscle and regulates the excitability of the membrane. CLCN1 is the most prominent chloride channel in the sarcolemmal membrane, contributing to 80% of resting muscle membrane conductance. ¹⁶ CLCN1 is located on chromosome 7q34 and contains 23 exons. ¹⁷ Notably, it is found in very low levels in the heart, kidney, and smooth muscle. ¹⁸ , ¹⁹ This chloride channel is composed of a dimer of CLC‐1 subunits. ¹⁶ Single‐channel recordings have shown that the opening of the CLC‐1 channels is unique in that it varies between three states: two pores closed, one pore open and one pore closed, and both pores open.

Pathogenic variants in CLCN1 lead to reduced chloride conductance, which can cause autosomal recessive (Thomsen myotonia congenita) and/or autosomal dominant forms of myotonia congenita (Becker myotonia congenita). Autosomal recessive myotonia congenita is more common than the dominant form and is caused by loss‐of‐function (missense, nonsense, deletions, and splicing) variants, which can occur anywhere throughout the protein. There have been over 200 pathogenic variants found in the CLCN1 gene resulting in myotonia congenita. ²⁰ Pathogenic variants that cause the dominant form of myotonia congenita are typically located in the dimer interface, with exon 8 being a hot spot for dominant negative interactions. ²¹ , ²² Certain pathogenic variants (such as p.Gly230Glu, pThr310Met, p.Ala531Val, and p.Arg894Ter) appear to be associated with both autosomal recessive and autosomal dominant modes of inheritance, which can be explained by reduced penetrance, incomplete dominance, variable expressivity, and gene dosage effects on chloride conductance. ²³ , ²⁴ The prevalence of myotonia congenita has been estimated to be 1:100000. ²⁵ In northern Scandinavia, the prevalence of both types of myotonia congenita is higher at 1:10000. ²⁶

Mutations in the CLCN1 gene and, subsequently, alteration of the CLC‐1 channel lead to hyperexcitability of the muscle membrane. This results from a reduction of the resting membrane conductance, which allows smaller depolarization currents to trigger an action potential. Due to the instability of the muscle membrane electrically, this hyperexcitability leads to a repetitive action potential to a single stimulus, also known as myotonia. ¹⁶

It has been proposed that in Thomsen myotonia congenita, one mutant subunit interacts with a wild‐type subunit and disrupts the ability of the channel to repolarize the cell. In Becker myotonia congenita, the mutant subunit often cannot interact with a wild‐type subunit. ²⁷

Nondystrophic myotonias usually present in the first decade of life, with sodium channelopathies presenting slightly earlier than chloride channelopathies. ²⁷ Both myotonia congenita syndromes demonstrate muscle stiffness in early childhood that improves with activity called the “warm‐up” phenomenon. Leg myotonia is more common in myotonia congenita than in sodium channel myotonias. ²⁸ While traditionally nondystrophic myotonias are thought to be nonsystemic and static diseases, there have been studies showing that patients report worsening symptoms over time. ²⁹ In a recent study, Wang and colleagues describe additional systemic symptoms, notably that nine patients in their cohort of 20 patients had cardiac abnormalities, including conduction defects. ³⁰ Children often present in early childhood with dysphagia or feeding difficulties, falls, and sustained contraction of their eyes after crying (eyelid myotonia). Men have a more severe phenotype than women with myotonia congenita, though it is unclear what role hormones play in modulation of the channels. Patients typically have normal lifespans.

Thomsen myotonia congenita often presents earlier than Becker myotonia congenita and has a prevalence worldwide of 1:23000. ⁸ Thomsen myotonia congenita tends to have a milder phenotype than Becker myotonia congenita. ³¹ Phenotype–genotype correlation is not robust in Thomsen myotonia congenita, and patients with identical mutations inherited through generations can have vastly different presentations.

The prevalence of Becker myotonia congenita has been reported at 1:50000 ⁸ but more recently, it has been described to occur more frequently than Thomsen myotonia congenita. ³² Becker myotonia congenita is thought to be the more severe phenotype. Becker myotonia congenita patients tend to have transient weakness that can resolve after exercise. ³³ Muscle hypertrophy or a “Herculean” appearance is more common in Becker myotonia congenita. ³²

In general, laboratory testing is unremarkable. Creatine kinase levels can be normal or slightly elevated (three to four times higher than the upper limit of normal). ³⁰

Electrical myotonia is the cardinal feature of all nondystrophic myotonias on electromyography. It occurs in up to 95.8% of muscles tested in some studies. ³⁴ A study in 2015 by Drost and colleagues showed that the inter‐discharge interval of myotonic discharges in the rectus femoris can delineate between myotonia congenita and paramyotonia congenita (PMC) with a sensitivity of >95%. Inter‐discharge intervals of >30 ms correlate with chloride channelopathies whereas intervals <30 ms correlate with sodium channelopathies. ³⁵ Nojszewska and colleagues in 2019 showed that 20% of the patients they examined with myotonia congenita had myopathic units on electromyography (EMG). They also showed that myopathic units were significantly more common in distal limb muscles in Becker myotonia congenita (first dorsal interosseous and tibialis anterior) and more common in upper extremity muscles in Thomsen myotonia congenita (biceps and first dorsal interosseous). ³⁴

Muscle biopsy is now rarely performed given the utility of genetic testing. However, on muscle biopsy in nondystrophic myotonias, there is a reduction or absence of type 2B fibers and variation in fiber size. ³⁰ , ³⁶

Targeted single‐gene sequencing analysis will detect >95% of variants in the CLCN1 gene. ³² Multigene panels may be more helpful clinically given the overlap in clinical picture.

Treatment of myotonia congenita is similar to other nondystrophic myotonias. Most of the evidence revolves around use of mexiletine, a class 1b antiarrhythmic and the only FDA‐approved medication. ³⁷ , ³⁸ Lamotrigine has also been studied and improves myotonia and quality of life scores. Other agents including acetazolamide and carbamazepine have been used. Although no studies have looked at treatment in children, case series have shown a preference for acetazolamide due to its safety profile; however, expert opinion suggests that mexiletine should be considered first‐line. ³⁹

Notably, patients with myotonia congenita should be managed cautiously when undergoing anesthesia, particularly with depolarizing agents. Muscle spasms, worsening of symptoms, and difficulties with ventilation have been documented with suxamethonium, beta‐agonists, and colchicine (can trigger myopathy). ⁴⁰ , ⁴¹

Sodium channelopathies

Dominant mutations in the SCN4A gene can lead to a variety of other skeletal muscle channelopathies, including sodium channel myotonia (also called potassium‐aggravated myotonia), hyper‐, hypo‐, or normokalemic periodic paralysis, and severe neonatal episodic laryngospasm. Recessive mutations in the SCN4A gene are associated with congenital myopathy with fetal hypokinesia, congenital myasthenic syndrome, and heart arrhythmias such as Brugada syndrome. ⁴² , ⁴³ Although symptoms can overlap, there are differences in triggers, electrolyte abnormalities, and the response to medical therapies. ¹⁵

Paramyotonia congenita

Paramyotonia congenita (PMC) is a nondystrophic myotonia caused by a gain‐of‐function mutation in the SCN4A gene. Clinically, it is characterized by myotonia that worsens with cold exposure and persistent exercise.

The SCN4A gene encodes the alpha subunit of the Nav1.4 channel and is found on chromosome 17q23.3. PMC is inherited in an autosomal dominant fashion and leads to a “gain of channel function” defect, thus impairing channel inactivation. Mutations in exons 22 and 24 are considered hot‐spot regions for PMC. ⁴⁴ To date, over 90 different variants have been reported in the SCN4A gene. Around 20 autosomal dominant, missense mutations in the SCN4A gene have been associated with PMC and sodium channel myotonia. ²⁷ SCN4A mutations are more common in East Asia, whereas CLCN1 mutations are more common in European populations. Rarely, there is incomplete penetrance among family members, with some family members remaining asymptomatic despite harboring the mutation. ⁴⁵

The Na1.4 alpha subunit consists of four homologous but not identical domains (DI‐DIV), each with six transmembrane segments (S1–S6). Depolarization of the channel is responsible for forming and conducting the muscle fiber action potential that leads to muscle contraction. There is a normal fast/slow inactivation mechanism to refrain from myotonia or paralysis. Impairments in the function of this channel can lead to either fast or slow inactivation of the channel and, in turn, to persistently increased sodium current and muscle hyperexcitability. This gain‐of‐function defect leads to clinical myotonia and myotonic discharges on electromyography. The persistently increased sodium current causes sustained sarcolemmal depolarization and increased excitability of the muscle fiber membrane. By contrast, loss of function of the regular fast/slow inactivation process leads to paralysis and is discussed in a later section. ⁴⁵

The clinical characteristics of PMC, first described by von Eulenburg, ⁴⁶ include several features that help to distinguish it from other nondystrophic myotonias. Transient muscle stiffness, often exacerbated by cold temperatures and worsened with exercise, are the hallmark features of PMC. ⁴⁷ As compared to mytonia congenita, there tends to be a younger age of onset of disease, which typically presents with muscle stiffness consistent with myotonia. Cold‐induced myotonia is a prominent feature as well as a “paradoxical” worsening of myotonia with exercise. ⁴⁸ Facial myotonia, including eyelid myotonia, is quite prominent and has a high sensitivity for a sodium channelopathy rather than a chloride channel defect. ²⁷ Men and women tend to be affected equally in PMC. ⁴⁵ They can rarely exhibit intermittent paralysis and worsening of symptoms with a high potassium load. ⁴⁹ Clinical symptoms of PMC often remain unchanged throughout life, with muscle atrophy, hypertrophy, or persistent weakness being atypical of this disease. ⁴⁷

The diagnosis of PMC is primarily made when there is a high clinical suspicion by history and clinical examination. One clue to help distinguish a sodium‐channelopathy from a chloride channelopathy is the presence of prominent eyelid myotonia as well as episodic weakness. Eyelid myotonia has a high sensitivity for a mutation in the SCN4A gene. Prior to the wide availability of genetic testing, diagnosis often required extensive testing on EMG, imaging, and muscle biopsy. In current practice, most cases can be diagnosed with a thorough history, physical examination, and targeted genetic testing for CLCN1 and SCN4A. Additional testing is most helpful in the setting of variants of unknown significance on genetic testing. Myotonia can be demonstrated on clinical examination as delayed relaxation following muscle contraction or on percussion. The clinician can look for cold‐induced myotonia and the lack of a warm‐up phenomenon as hallmarks for PMC. Neurophysiological testing reveals myotonic discharges and repetitive muscle fiber after‐discharges on needle testing. In addition, on exercise testing PMC patients typically have a gradual and prolonged decrement in compound muscle action potential (CMAP) after exercise and with cooling. ⁵⁰ It is important to maintain a high clinical suspicion for nondystrophic myotonias given that there is often a delay in diagnosis of many years. ⁵¹

Management of PMC focuses on avoiding known triggers and considering pharmacologic interventions. Most of the medications used to treat myotonia are sodium channel blockers, as there is little evidence for the utility of chloride channel openers. ⁵² At present the most effective drug treatment targets enhancement of both fast and slow inactivation of sodium channels. Conservative management includes counseling to avoid known triggers of myotonia, including prolonged exercise, cold temperatures, and, if applicable, potassium overload. Exercise should focus on endurance training to improve fitness with frequent rest periods and exercising in warm environments. ⁵² If symptoms persist despite conservative management, multiple medications can be considered for symptomatic relief of myotonia. The only medication with Class I evidence for the treatment of myotonia is mexiletine. Mexiletine is a nonselective voltage‐gated sodium channel blocker that works by enhancing fast‐inactivation of the channel. Two double‐blind, placebo‐controlled trials have shown the efficacy and safety of mexiletine in the treatment of nondystrophic myotonias, although neither study included patients younger than 16 years of age. Lamotrigine, also a voltage‐gated sodium channel blocker, was tested in one double‐blind, crossover randomized placebo‐controlled trial in patients with myotonia congenita and PMC. There was improvement in self‐assessed myotonia severity and improved quality of life. ⁵³ Other sodium channel–blocking medications such as carbamazepine, flecainide, and ranolazine have less evidence but are sometimes considered in clinical practice.

Potassium‐Aggravated Myotonias

Potassium‐aggravated myotonias are disorders that, like hyperkalemic periodic paralysis and PMC, are allelic and caused by mutations in the SCN4A gene. ⁵⁴ Unlike hyperkalemic periodic paralysis, patients with potassium‐aggravated myotonias have myotonia without episodes of weakness. ⁵⁵ One of the types (acetazolamide responsive) was first described in a cohort of 14 patients by Trudell et al. ⁵⁶ In 1993, Lerche et al. reported a phenomenon of permanent myotonia, exercise‐induced myotonia, and fluctuating myotonia that were all distinct from previously known myotonias associated with muscle weakness (hyperkalemic periodic paralysis) or cold (PMC) and furthermore were worsened by oral potassium intake. ⁵⁷ These sodium channel myotonias, distinct from hyperkalemic periodic paralysis and PMC, are now divided into three categories: myotonia fluctuans, myotonia permanens, and acetazolamide‐responsive types.

Myotonia fluctuans

The term myotonia fluctuans was coined by Ricker et al. in an article describing 17 affected members of three families with myotonia after exercise and potassium intake with muscle weakness that was unaffected by cooling. ⁵⁸ This study together with five individuals in three generations, previously reported by Ricker et al. ⁵⁸ and another group, ⁵⁹ confirmed the existence of myotonia fluctuans as a distinct entity within potassium‐aggravated myotonias.

Myotonia fluctuans is typified by a myotonia (a) with differing severity, (b) of delayed onset after exercise, and (c) worsened by potassium ingestion. There is no weakness on either cold or potassium loading and no myotonia with cold exposure. ⁵⁸ Myotonia severity can range from no stiffness to severe and can affect the muscles of the extremities, extraocular, and the bulbar group. Biopsies of involved muscles can be normal or demonstrate increased internalized nuclei, fiber size variability, or subsarcolemmal vacuoles. Myotonia fluctuans can be prevented by avoiding a potassium‐rich diet and can respond to mexiletine.

Myotonia permanens

Myotonia permanens is due to a mutation in the SCN4A gene coding for the fast Nav1.4 channel. Myotonia in general usually decreases with warming up, but with myotonia permanens the severity of stiffness does not vary. This particular phenotype was originally recognized by Colding‐Jorgensen et al. as a new entity in a patient previously published elsewhere. ⁵⁷ The presentation of myotonia permanens can include stiffness in the muscles of the face, neck, or bulbar group, and involvement of respiratory muscles can lead to ventilatory issues. Cases range in severity from mild to severe laryngospasm. ⁵⁵ EMG typically demonstrates a pattern of continuous myotonia. ⁵⁷ Myotonia permanens has been thought to be a muscle form of Schwartz‐Jampel syndrome. ⁶⁰ , ⁶¹ Although there is paucity in the pediatric literature of myotonia permanens, a high index of suspicion is still recommended as the disorder is treatable but can be lethal if left unrecognized. ⁶²

Acetazolamide‐responsive myotonia

Symptoms of acetazolamide‐resposive myotonia usually start in childhood and can include myotonia of tongue, facial, extremity, and intercostal muscles that is triggered by potassium ingestion. Myotonia can be painful, but paralysis or muscle weakness is never noted. Acetazolamide‐responsive myotonia is due to missense mutations of the SCN4A gene that encodes the alpha subunit of the sodium channel Nav1.4. ⁵⁶ Myotonia is dramatically improved with acetazolamide but when contraindicated in cases of renal calculi, mexiletine has been used as alternative therapy.

Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis is caused by point mutations in the SCN4A gene. Tyler et al. in 1951 published cases of periodic paralysis without hypopotassemia that were the first described cases of hyperkalemic periodic paralysis. ⁶³ The prevalence of hyperkalemic periodic paralysis was approximately 0.17/100000 as reported in England. ⁶⁴ In the Netherlands, prevalence was 0.06/100000 ⁶⁵ whereas in an Italian cohort seven of 80 (8.7%) individuals were affected. ⁶⁶ Vereb noted that 20% of the patients with SCN4A pathogenic variants showed periodic paralysis. ⁵¹

The attacks of hyperkalemic periodic paralysis consist of flaccid muscle weakness in the thighs, calves, or arms lasting from minutes to hours. These episodes usually occur in the mornings before breakfast and on weekends or other holidays when people are resting in bed for longer than usual. The attacks are usually triggered by ingestion of potassium‐rich foods, fasting, resting after physical activity, stress both emotional and environmental (cold), pregnancy, or medication use such as steroids. ⁶⁷ , ⁶⁸ Attacks of periodic paralysis usually begin in the first decade of life and often have a family history of an affected first‐degree relative. The severity and frequency of the episodes varies, and some people report functional disability right after the attack. ⁶⁹ Between attacks, individuals with hyperkalemic periodic paralysis have normokalemia, preserved sensation, deep tendon reflexes, and strength, although progressive weakness over time has been noted. ⁷⁰ The sphincter muscles are usually spared, and most people do not report discomfort. ⁶⁸

Hyperkalemic periodic paralysis can present clinically in three different ways: without myotonia, with clinical or neurophysiologic myotonia, or with paramyotonia. The symptoms of each of these can be similar. ⁷¹ Charles et al. noted that most individuals with hyperkalemic periodic paralysis have myotonia around the time of an episode and that myotonia worsened with cold (paramyotonia) in 45% of affected individuals. They also documented progressive myopathy in some individuals. ⁶⁸ A study reported that, in individuals over 40 years old with hyperkalemic periodic paralysis, more than 80% have fixed muscle weakness, and almost 33% develop a chronic progressive myopathy. ⁷² Muscle biopsy has also demonstrated changes in cases with progressive myopathy. ⁷³ Individuals with hyperkalemic periodic paralysis have a 3.6 times higher risk of thyroid abnormalities than unaffected individuals. ⁶⁸

Electrical myotonia can be demonstrated on the EMG in 50% to 75% of patients with hyperkalemic periodic paralysis, while less than 20% manifest only clinical myotonia. In the latter, the myotonia is mild and can be provoked by percussion or voluntary contraction in the face, tongue, forearms, and thenar eminence.

Diagnosis is based on clinical symptoms, EMG testing, and genetic testing. The diagnosis is established by testing for a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing. Previously, when diagnosis was not certain, provocative testing using potassium administration to induce an attack was used, but the availability of genetic testing has largely replaced the need for such risky testing.

Management of hyperkalemic periodic paralysis depends on the timing of treatment. Acute management during attacks focuses on measures that can decrease potassium concentration extracellularly, such as increasing carbohydrate‐rich food consumption, performing low‐intensity physical activity, and trial of beta agonists such as salbutamol. Preventive measures can include nonpharmacological methods such as avoiding fasting, eating carbohydrate‐rich food more frequently, avoiding excessive physical activity, and limiting ingestion of potassium‐rich foods. Pharmacological prevention has typically consisted of medications such as acetazolamide, hydrochlorothiazide, and dichlorphenamide. ⁷⁰ , ⁷⁴ , ⁷⁵

Severe Neonatal Episodic Laryngospasm

Lion‐Francois et al. reported three unrelated male neonates with de novo SCN4A mutations. All three neonates had recurrent episodes of life‐threatening apnea due to laryngospasm. These attacks were associated with stridor and generalized muscles stiffness and were followed by hypotonia, cyanosis, and bradycardia. No apparent triggering factors were noted, and the inter‐episodic exams were normal in two neonates. All of them had feeding difficulties, and one died of respiratory arrest at 2.5 months of age. EMG demonstrated continuous myotonic discharges in all three. The two neonates who survived had marked muscle hypertrophy at age six months. One showed myotonia in the eye, tongue, and muscles of handgrip, whereas the other had worsening of myotonia with cold. Carbamazepine or mexiletine were effective treatments. ¹³

We have managed a child like the ones described by Lion‐Francois et al. This baby girl was born at term, a product of a nonconsanguineous union, with a pregnancy notable for possible decreased fetal movements with no complications during delivery. At day of life 1 she had apnea episodes every 10‐15 minutes that were sometimes associated with cyanosis and bradycardia. She had a normal head ultrasound, echocardiogram, and electroencephalogram and a noncontributory magnetic resonance imaging of the brain. Laryngoscopy revealed bilateral vocal cord paralysis during the episodes and normal movements of the vocal cords at other times. There was mild ptosis, but no stiffness or spasms were noted in other muscles initially. Electrophysiological studies revealed myotonic discharges (Figure 1). Carbamazepine decreased the frequency of apnea episodes during NICU stay. She achieved ambulation at age two years but needed g‐tube feeding until age four due to swallowing difficulties. Targeted testing of the SCN4A gene showed a heterozygous C2110A>G mutation. Another variant in the same gene was homozygous but classified as benign. Episodes became more frequent around age two, manifested as voice change and triggered by cold occasionally. The addition of acetazolamide to the carbamazepine resolved the episodes. Interestingly the child developed increased tone in her neck muscles at baseline but otherwise had normal speech and cognitive development. She was five years old at the time of this report and has responded, somewhat, to the addition of baclofen and physical therapy.

Figure 1.

Myotonic discharges seen in a child with severe neonatal episodic laryngospasm.

Other

Schwartz–Jampel syndrome

Schwartz‐Jampel syndrome (SJS) is a group of disorders characterized by skeletal dysplasia and myotonia. They have also been termed Aberfeld syndrome, Catel‐Hempel syndrome, chondrodystrophic myotonia, and osteochondromuscular dystrophy, among others. ⁷⁶ A study of 81 patients in 1997 differentiated this syndrome into three phenotypes based on clinical and radiographic findings. Type 1A presents in childhood and has only moderate bone dysplasia. Type 1B is similar to type 1A but has more prominent bone dysplasia. Type 2 is the most severe phenotype and the most uncommon of the three. Type 2 presents at birth or in infancy and is genetically distinct from the first two types mapping to chromosome 5p13.1, which encodes the LIFR gene. ⁷⁷ , ⁷⁸ We will only discuss Type 1A and 1B.

SJS is mostly inherited in an autosomal recessive pattern; however, Pascuzzi and others describe cases of SJS with dominant inheritance. ⁷⁹ Type 1A and 1B are due to mutations in the HSPG2 gene on chromosome 1p34‐36.1. ⁸⁰ HSPG2 encodes perlecan, a large heparan sulfate proteoglycan that is found in many tissues, including the basement membrane, as well as bone marrow stromal cells that help with cartilage development and fracture repair. ⁷⁷ , ⁸⁰

There are multiple theories on how perlecan mutations result in peripheral nerve hyperexcitability. Originally, peripheral nerve hyperexcitability was thought to be due to a sodium channel defect that caused a delayed but synchronized opening leading to hyperexcitability and delayed relaxation. ⁸¹ , ⁸² Mutations in the perlecan domain V contribute to SJS as it is complexes with dystroglycan and acetylcholinesterase in the neuromuscular junction. Peripheral nerve hyperexcitability in SJS is thought to be due in part to a deficiency of clustering of acetylcholinesterase due to perlecan. ⁷⁸ , ⁸⁰ , ⁸³ However, further studies have shown that the spontaneous activity seen in perlecan‐deficient mice are sensitive to neuromuscular blockade with curare but not to proximal transection, suggesting a preterminal site for peripheral nerve hyperexcitability. ⁸⁴ , ⁸⁵ A study by Echaniz in 2009 also characterized the peripheral nerve hyperexcitability as electrical neuromyotonia (distinct from electrical myotonia where motor unit action potentials fire at a higher rate—150–300 Hz with an amplitude that wanes instead of waxing and waning). The study also demonstrated that the neuromyotonic discharges originated from the distal axon of the nerve. Additionally, their perlecan‐deficient mouse model had increased levels of impaired functional voltage‐gated K+ channels. Taken all together, these suggest a combined mechanism contributing to peripheral nerve hyperexcitability in SJS, including poor localization of acetylcholinesterase, impaired voltage‐gated K+ channels, and evidence of dysmyelination of the axons themselves. ⁸⁴ Perlecan plays an important role in cartilage and bone marrow stromal cells, which results in skeletal abnormalities and pseudofractures in SJS. ⁷⁷

The constellation of symptoms in SJS includes short stature; bone dysplasia such as kyphoscoliosis, pectus carinatum, bowing of the long bones, and epiphyseal, metaphyseal, and hip dysplasia; joint contractures; and generalized clinical myotonia (with electrical neuromyotonia). ⁷⁷ , ⁸¹ , ⁸⁶ Muscle stiffness in the face leads to “mask‐like” facies with blepharospasm and pursed lips. ⁸² , ⁸⁶ Pascuzzi described 22 patients with SJS in whom electrical myotonia was the most common feature and seen in 95% of patients, clinical myotonia in 85%, short stature in 90%, muscle hypertrophy in 70%, and a small, puckered mouth in 80% of patients. Fixed facies were found in 55% of patients. ⁷⁹

Laboratory testing is usually normal, including creatine kinase levels that are normal or slightly elevated. Nerve conduction studies are normal. While some studies describe electrical myotonia on EMG, ⁷⁷ many suggest that EMG typically shows neuromyotonic discharges. ⁸¹ , ⁸⁴ , ⁸⁵ Muscle biopsy may show diffuse atrophy or nonspecific myopathic changes but is otherwise normal. ⁸¹

Like other channelopathies, care should be taken during anesthesia given the risk of malignant hyperthermia. ⁷⁶ Notably, endotracheal intubation can be difficult due to small laryngeal structures and stiffness of the neck. ⁷⁶ Otherwise, treatment is mainly symptomatic, and myotonia may be alleviated by carbamazepine, phenytoin, procainamide, or mexiletine. ⁸² Surgical intervention for blepharospasm has been found to be helpful. ⁷⁷

Channelopathies Without Myotonia

Calcium and sodium channelopathies

Hypokalemic periodic paralysis

Hypokalemic periodic paralysis was described in extensive detail by Westphal as early as 1885, ⁸⁷ but it was not until 1994 that the disease‐causing mutation in the CACNA1S gene was identified. ⁸⁸ Hypokalemic periodic paralysis is a form of periodic paralysis typified by episodes of muscle weakness that are frequently caused by high‐intensity exercise or diets rich in carbohydrates and associated with low levels of serum potassium. Hypokalemic periodic paralysis is caused by mutations in either a calcium or sodium channel. The mutations in dihydropyridine‐sensitive, skeletal muscle CACNA1S calcium channel gene is termed “hypokalemic periodic paralysis type 1” and accounts for most of the mutations causing hypokalemic periodic paralysis. Mutations in the voltage‐sensitive skeletal muscle SCN4A gene is termed “hypokalemic periodic paralysis type 2.” ⁸⁹ These mutations are usually familial, and the acquired causes can be secondary to hyperthyroidism. Episodic muscle weakness secondary to hypokalemia can be due to kidney and gastrointestinal losses. Mutations in the KCNJ2 and KCNJ18 genes that code for inward rectifier potassium channels have also been identified. ⁸⁹

Hypokalemic periodic paralysis is a rare disorder and has a prevalence of 0.5–1:100000. ⁹⁰ , ⁹¹ Familial cases are inherited in an autosomal dominant pattern with incomplete penetrance and express much less in females than males. New mutations usually are sporadic. ⁹² , ⁹³

The most common calcium channel mutation causing hypokalemic periodic paralysis is a missense change in the arginine residue in the S4 domain of the alpha subunit of the L‐type calcium channel (Cav1.1) and less often in the voltage‐gated sodium channel (Nav1.4). ⁹⁴ , ⁹⁵ These mutations result in the disruption of ion channelgating characteristics that render the sarcolemmal muscle inexcitable and cause failure of a muscle action potential, clinically manifesting as weakness or paralysis. ⁹⁴ , ⁹⁶ , ⁹⁷ , ⁹⁸ With serum potassium levels lower than 3 mM, the mutated channels make the muscle fibers undergo paradoxical sustained depolarization, leading to muscles being electrically inexcitable to stimuli and causing clinical weakness. ⁷⁵ , ⁹⁵ , ⁹⁶

Episodic attacks of paralysis usually occur during the first and second decades of life and seem to be less frequent at older ages. ⁷⁵ , ⁹⁹ , ¹⁰⁰ Attacks are provoked by triggering factors such as increased physical strain, carbohydrate‐rich diets, stress, glucocorticoid, and alcohol use. ⁹⁰ , ¹⁰¹ Episodes are present as generalized weakness with a proximal more than distal pattern and often involving the lower extremities. ⁷⁵ Respiratory muscles are usually spared, but when involved can often be fatal. ⁹⁰ , ⁹⁹ Frequency, severity, and duration of episodes can be variable and can range from one to two attacks a week lasting minutes to days. ¹⁰⁰ , ¹⁰¹ Females tend to have fewer episodes than men. Myotonia is not a usual presentation with hypokalemic periodic paralysis. ⁹³ , ¹⁰⁰ , ¹⁰²

Hypokalemic periodic paralysis type 1 mutation can increase susceptibility to malignant hyperthermia, and caution should be exercised with use of inhalational anesthetic agents and muscle paralytics with potassium levels monitored before and after surgery. ¹⁰³

Diagnosis is based on a high index of suspicion when episodes of paralysis are combined with a positive history of previous attacks or positive familial history. Low serum potassium level in such a scenario can clinch the diagnosis. Other testing for secondary causes such as hyperthyroidism should prompt thyroid function tests. An electrocardiogram should also be performed to assess the cardiac risk. ⁷⁵ During episodes the EMG and nerve conduction studies may reveal decreased compound muscle action potential (CMAP) amplitude and/or electrical silence. ¹⁰⁰

The diagnosis is often elusive during the inter‐attack interval and often relies on good history taking, lab testing for secondary causes, and a standing order for potassium levels to be done during an attack. Genetic testing can aid diagnosis when a high degree of suspicion exists. EMG and nerve conduction studies in the inter‐attack interval can be helpful in diagnosis. The long exercise test utilizes the principle of causing muscle weakness by exercising a single muscle for two to five minutes and assessing postexercise CMAP. A CMAP decrement of 40% or higher is considered abnormal. ⁷⁵ , ¹⁰⁴ Muscle biopsy may be nonspecific and may not aid in diagnosis.

Treatment involves normalizing serum potassium levels in the acute period that could potentially ameliorate the symptoms. Oral, age‐appropriate potassium dosing can be titrated up by 30% every 30 minutes for response. ¹⁰¹ , ¹⁰³ Dosing is age‐dependent and takes into account the severity of hypokalemia. Close physical exam and electrocardiogram monitoring are essential to determine response to therapy and avoid cardiac complications. Administration of intravenous potassium is usually indicated for cardiac arrhythmias or presence of dysphagia and/or respiratory compromise. ¹⁰³ , ¹⁰⁵ Use of intravenous potassium certainly requires intensive cardiac monitoring. ⁷⁵

Prevention of episodes involves lifestyle management to avoid triggers. Medications are added when attacks are refractory to lifestyle management alone. Potassium supplementation, carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide, and potassium‐sparing diuretics such as spironolactone or triamterene have been used to prevent and treat attacks. Postulated mechanisms on why carbonic anhydrase inhibitors seem to work are related to its ability to decrease potassium loss in urine, opening of potassium channels, and decreasing sodium accumulation. These actions increase serum potassium concentrations and prevent muscle injury, a mechanism that also contributes to preventing onset of permanent weakness. ⁷⁵ Potassium‐sparing diuretics when used alone or with carbonic anhydrase inhibitors can also prevent attacks but require routine monitoring of electrolytes. ¹⁰⁰

Potassium channelopathies

Andersen–Tawil syndrome

Andersen–Tawil syndrome (also known as Andersen syndrome or long QT syndrome 7) was described by Ellen Andersen in 1971 and further detailed by Rabi Tawil. ¹⁰⁶

Andersen–Tawil syndrome is delineated into two types based on genes implicated. Type 1 is caused by mutations in the KCNJ2 gene and accounts for 60% of cases. The KCNJ2 gene encodes the inward rectifying potassium channel Kir2.1 that is involved in the transportation of potassium into muscle cells. Type 2 is caused by non‐KCNJ2 mutations and accounts for 40% of cases, most of which are due to KCNJ5 gene mutations. KCNJ5 encodes for the G protein–sensitive inwardly rectifying channel. ¹⁰⁷ , ¹⁰⁸

KCNJ2 mutations disrupt the resting membrane potential of skeletal and cardiac muscle cells and slow the rate of repolarization, causing a longer action potential. In cardiac cells, this results in a prolonged QT interval whereas in skeletal muscles it causes a less excitable membrane and decreased force of muscle contraction. ¹⁰⁷ , ¹⁰⁹

Andersen–Tawil syndrome is characterized by a triad that includes a long QT syndrome, hypokalemic periodic paralysis, and skeletal abnormalities usually presenting in the first or second decade of life. ¹⁰⁸ Individuals may experience episodic weakness that can be triggered by prolonged rest or rest after exercise. Some individuals may experience mild fixed weakness over time. ¹¹⁰

The cardiac manifestations of long QT syndrome can present as bidirectional ventricular tachycardia, polymorphic ventricular tachycardia, and multifocal premature ventricular contractions. Syncope, cardiac arrest, and sudden death can occur as a result. ¹⁰⁹ , ¹¹⁰ Case reports also describe a dilated cardiomyopathy phenotype that may be secondary to chronic tachycardia. ¹⁰⁸

Skeletal abnormalities include micrognathia, low‐set ears, widely spaced eyes, broad forehead, high arched palate, and scaphocephaly as well as clinodactyly, second and third toe syndactyly, short stature, and scoliosis. ¹⁰⁶ , ¹⁰⁸ Mild cognitive delays have also been described. ¹¹¹

Single‐gene or panel testing can lead to the identification of the causative gene. In addition, serum potassium concentration during an episode of weakness may be obtained. EMG and nerve conduction studies are normal between episodes. Long exercise protocol may show an initial postexercise increment with an abnormal decrement in CMAP amplitude or area 20–40 minutes after. ¹¹² , ¹¹³ Aside from QT prolongation, EKG may show prominent U waves, premature ventricular contractions, or bidirectional ventricular tachycardia. 24‐hour Holter is recommended. ¹⁰⁸

Treatment for Andersen‐Tawil syndrome includes control of cardiac arrhythmias with flecainide or beta blockers and occasionally a defibrillator. Medications that prolong QT intervals are to be avoided, such as salbutamol inhalers, thiazide, or potassium‐wasting diuretics. Periodic paralysis can be treated with oral potassium if serum potassium is low. Carbonic anhydrase inhibitors such as acetazolamide are also used to prevent weakness episodes. Monitoring for triggers, including dietary modifications and avoiding intense exercise, is used for prevention. ¹⁰⁷ , ¹⁰⁸

Other

Malignant hyperthermia

Malignant hyperthermia is a condition in which those who are genetically susceptible experience a reaction of skeletal muscle hypermetabolism in response to certain medications. These medications include halogenated anesthetics, depolarizing muscle relaxants (i.e., succinylcholine), and in certain cases, stressors like heat or intense exercise. ¹¹⁴ The incidence of malignant hyperthermia ranges from 1:10000 to 1:250000. ¹¹⁵ Symptoms of malignant hyperthermia include tachypnea (with rising end‐tidal often being the first sign), tachycardia, muscle rigidity, mixed acidosis, rhabdomyolysis, and high fever (can be a late sign). ¹¹⁵ If left untreated, malignant hyperthermia can result in disseminated intravascular coagulation, life‐threatening hyperkalemia due to myocyte death, acute renal failure from myoglobinuria, and so on. ¹¹⁵ Malignant hyperthermia can occur at any time during anesthesia administration and within 60 minutes after. ¹¹⁶ , ¹¹⁷ Malignant hyperthermia can be seen with the first round of anesthetic; however, it is more commonly noted at the time of the third anesthetic event. It is also more common in males than females. ¹¹⁸ , ¹¹⁹ , ¹²⁰ The ryanodine receptor 1 (RYR1) gene is the main source of genetic alterations associated with malignant hyperthermia and accounts for 50%–70% of cases. ¹²¹ , ¹²² At least 34 causative mutations in the RYR1 gene have been discovered. Mutations in the CACNA1S and STAC3 genes have also been found to cause malignant hyperthermia susceptibility. ¹¹⁵ , ¹²³ In these individuals, the triggers listed above cause an uncontrolled release of calcium from myofibers, which in turn causes the myofibers to contract excessively, generating heat and resulting in metabolic acidosis. This further depletes the cells of ATP and causes cellular destruction. ¹²⁴ , ¹²⁵ Diagnosis outside of an acute crisis can be made via caffeine halothane contracture test on muscle biopsy; however, diagnosis is more commonly made using genetic testing. Dantrolene is the treatment if malignant hyperthermia occurs during anesthesia. ¹¹⁵

Brody Disease

Brody disease or myopathy is an autosomal recessive myopathy first described by Dr. Irwin Brody in 1969. ¹²⁶ It is characterized by pronounced exercise‐induced muscle stiffness/contraction in the absence of myotonic discharges on EMG. ¹²⁷ Notably, Brody syndrome is similar phenotypically to Brody disease, but lacks the ATP2A1 mutation. ¹²⁸

Brody myopathy is caused by mutations in the ATP2A1 gene, which encodes the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase type 1 (SERCA1) protein. It is only expressed in type 2 skeletal muscle fibers. The SERCA1 protein helps regulate Ca2+ balance in skeletal muscle by actively transporting it back into the sarcoplasmic reticulum at the end of a muscle contraction cycle. ¹²⁹ Given SERCA1 is only expressed in type 2 fibers, symptoms are mainly induced by short, explosive exercise.

Symptoms of Brody myopathy usually begin in the first decade of life. Delayed muscle relaxation occurs after exercise, causing stiffness and cramping. Patients sometimes report worsening with cold temperatures. ¹²⁹ , ¹³⁰ In a study of 40 patients with Brody myopathy, roughly one‐third of patients reported muscle weakness, an athletic build was noted in two‐thirds of patients and 23% of patients felt symptoms were progressive but not debilitating. ¹²⁹

EMG shows prolonged involuntary muscle contraction after a voluntary contraction without electrical activity (termed “silent contractures”) with the absence of myotonic discharges. ¹²⁹ , ¹³⁰ Rarely, patients have reported malignant hyperthermia. ¹²⁹ , ¹³⁰ , ¹³¹

Muscle biopsy shows nonspecific variation in fiber size, increased internal nuclei, and type 2 muscle fiber atrophy. ¹²⁹

Dantrolene is effective in treating Brody disease as it blocks Ca2+ release from the sarcoplasmic reticulum. ¹³²

Neurophysiological evaluation of muscle channelopathies

Myotonic discharges on needle EMG correlate with clinical myotonia and are produced as a result of spontaneous repetitive firing of muscle fiber action potentials. These bursts of 10 μV–1 mV potentials occur at 50–150 Hz and resemble a “dive‐bomber” on audio. ¹³³ These are noted in myotonia congenita, paramyotonia congenita, and sodium channel myotonias.

Low‐frequency repetitive stimulation may trigger a CMAP amplitude decrement in paramyotonia congenita and Thomsen and Becker diseases. ¹⁰⁴

Exercise testing is a useful aid in the diagnosis of skeletal muscle channelopathies. This is especially relevant in the setting of equivocal diagnosis and considerations for treatment and management. Several factors can lead to uncertain diagnosis, including patients who experience minimal or transient symptoms and the influence of various environmental factors on the severity of symptomatology. In the nondystrophic myotonias, channel dysfunction leads to mild depolarization of the muscle membrane and subsequent myotonic discharges. In periodic paralysis, the degree of depolarization can render the muscle fiber inexcitable, clinically demonstrated by paralysis of muscles. There is overlap between many of these disorders, with some patients demonstrating multiple phenotypes that allow for specific patterns on electrophysiological exercise testing to aid in diagnosis and guide genetic testing. ²⁸ In children, these tests can be difficult to perform and analyze as they require cooperation from the patient and patience from the provider.

Fournier et al. proposed a standardized protocol for patients with suspected skeletal muscle channelopathies presenting with myotonia or transient paralysis. 133 In both short and long exercise tests, a routine distal compound muscle action potential is evoked with supramaximal stimulation. Typically, the ulnar nerve is stimulated at the wrist with recording at the abductor digiti minimi muscle. The nerve is stimulated at one‐minute intervals for several minutes to ensure a stable baseline is achieved.

The short exercise test was originally described by Streib and colleagues in 1982. ¹³⁴ For the short exercise test, after achieving a stable baseline CMAP, the patient performs voluntary contraction for 10 to 12 seconds with subsequent recording of a CMAP. If a decrement in amplitude is noted, a CMAP is recorded every 10 seconds for 50 seconds until there is a recovery to baseline. The test is repeated two times, with a 60‐second rest period between each trial. The speed of recovery can help differentiate the myotonic syndromes. For example, in myotonic dystrophy and myotonia congenita, the decrement often recovers to baseline in one to two minutes. In myotonia congenita, muscle cooling has no appreciable effect on the exercise test. In the recessive form of myotonia congenita, the initial drop in CMAP amplitude is profound with delayed recovery that can progress over time. In the dominant form of myotonia congenita, the decrement is variable with quick recovery. This contrasts with paramyotonia congenita, where cooling of muscle results in a large drop in CMAP amplitude with delayed recovery. In periodic paralyses, the short exercise test produces no decrement ²⁸ (see Table 2).

Table 2.

Neurophysiological characteristics of muscle channelopathies.

Disease	Postexercise myotonic potentials	Short exercise test	Long exercise test	Fournier pattern
Myotonia congenita
Thomsen	Maybe	Transient ↓ in CMAP amplitude after first trial at room temperature and with cooling	Mild to no ↓ in CMAP amplitude	II
Becker	Maybe	No change in CMAP amplitude after first trial at room temperature or with cooling	Mild to no ↓ in CMAP amplitude	II
Paramyotonia congenita	Yes	↑or ↓ in CMAP amplitude with first trial but gradual decline after second or third trials	↓ in CMAP amplitude during and after exercise persisting for hours	I
		↓↓↓ CMAP amplitude after cooling
Potassium‐aggravated myotonias	No	No change in CMAP amplitude	No change in CMAP amplitude	III
Hyperkalemic periodic paralysis	No	↑ in CMAP amplitude after first trial that ↑↑ with second and third trials	Transient CMAP amplitude ↑ after exercise that ↓ gradually over 30‐40 min	IV
Hypokalemic periodic paralysis
HypoPP type 1	No	No change in CMAP amplitude	Slight to no ↑ in CMAP amplitude that gradually ↓ over time	V
HypoPP type 2	No	No change in CMAP amplitude	Slight ↑ in CMAP amplitude during and after exercise with ↓ over 10‐20 min	V

The long exercise was described by McManis and colleagues in 1986. ¹⁰⁴ The test is performed by instructing the patient to contract the test muscle for a total of 5 minutes with 15‐second intervals of rest. The CMAP is recorded right after the 5 minutes of contraction and then every one to two minutes for the ensuing 45–60 minutes. In most forms of periodic paralyses, the long exercise test showed an initial increase in CMAP amplitude followed by progressive drop over 20–40 minutes with a slow recovery over one hour ²⁸ (See table 2). The decrement is considered abnormal if the CMAP amplitude over time is below 40% of baseline. Due to its duration, the long exercise test is often more technically challenging than the short exercise test, especially in younger children.

Summary

Muscle channelopathies are relatively rare individually and consist of nondystrophic myotonias and periodic paralyses, but together they are group of disorders that can cause substantial disability and loss of quality of life. Recognizing these disorders requires a high index of suspicion that is initially informed by presentations involving distinct triggers and characteristic morphologies. The presence of myotonia, either clinically or on neurophysiological testing, can then help refine the differential. Either targeted or panel genetic testing then helps to confirm the diagnosis in many cases. Treatment involves preventive measures, namely avoiding triggers, or using medications that can modulate channel kinetics. Presentations that are not corroborated by a genetic diagnosis require further study and research and will likely add to the spectrum of these disorders.

Author Contributions

Bridget R. McGowan: Conceptualization; writing—original draft; writing—review and editing. Abigail N. Schwaede: Writing—original draft; writing—review and editing. Lenika De Simone: Writing—original draft. Vamshi K. Rao: Conceptualization; methodology; supervision; writing—original draft; writing—review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.