CHAPTER 87 CHANNELOPATHIES OF MUSCLE (INCLUDING THE MYOTONIC DYSTROPHIES)

Channelopathies are disorders resulting from alterations in function of the ion channels found in cell membranes throughout the body. Disorders such as episodic ataxia types 1 and 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and benign familial neonatal convulsions are examples of channelopathies affecting the central nervous system. These disorders are outside the scope of this chapter.

In muscle cells, several types of voltage-gated ion channels are critical in regulating membrane excitability. Dysfunction of these ion channels causes a variety of muscle symptoms. Ion channels consist of multiple transmembrane glycoprotein subunits that form pores in the membrane. Charged ions may pass selectively through these pores, subject to regulation by voltage gating, thus altering the charged ion distribution across the membrane and hence its excitability.

The muscle cell membrane has a negative resting potential of approximately −60 mV that becomes a positive action potential of approximately +40 mV once the membrane is stimulated. In normal muscle cells, this transient depolarization swiftly returns to the resting state and the muscle relaxes; however, in ion channel disorders depolarization may be prolonged and lead to a longer phase of muscle contraction (myotonia) or to inexcitability (periodic paralysis).

Each ion channel type has a different role in sarcolemmal function (Fig. 87-1). Chloride channels are important in stabilizing the membrane potential at the resting level; inward flow of ions through sodium channels induces membrane depolarization and hence action potential; outflow through a voltage-gated subset of potassium channels is involved in the depolarization of the action potential. Calcium channels may be involved in action potential generation or in the regulation of other channel types. Action potential generation in the membrane is coupled to activation of the contractile machinery in the skeletal muscle and to muscle contraction.

Figure 87-1 Ion flux at the sarcolemma. In the resting state, the negative potential across the muscle cell membrane is maintained through relatively higher extracellular sodium and calcium ion concentrations and relatively higher intracellular potassium and chloride ion concentrations. When the membrane is depolarized, an action potential is generated through sodium ion flow into the cell through voltage-gated sodium channels followed by outflow of potassium ions through potassium channels and inflow of chloride ions through chloride channels, thus repolarizing the membrane.

Myotonia may be detectable clinically by employing certain simple maneuvers, especially after a period of rest. Grip myotonia may be elicited by asking the patient to hold his/her fist tightly closed for 10 seconds and then to release it and extend the fingers; the patient may be unable to do this for 10 to 20 seconds. If asked to repeat the maneuver, the time taken to release the grip may decrease; this is known as the warm-up phenomenon. Paramyotonia is the opposite; that is, grip release becomes progressively more difficult with successive contractions. Percussion myotonia may be evident on tapping the thenar or larger limb muscles with a tendon hammer—these muscles may indent due to sustained contraction. Sometimes tapping the thenar with an abducted thumb may cause it to adduct across the palm. Eyelid myotonia may be seen when the patient is asked to close his or her eyes tightly for about 10 seconds and then to open them wide—some patients cannot open their eyes at all initially.

During episodes of periodic paralysis, weakness may range from focal to generalized paralysis. Respiratory muscle involvement is usually less severe than might be expected and patients rarely need respiratory support. Precipitants are discussed under individual disorders. Recovery time varies from less than an hour for a mild attack to several hours or days in a severe episode.

Electromyography in patients with myotonia congenita or myotonic dystrophy should demonstrate repetitive generation of muscle cell membrane action potentials (Fig. 87-2) in resting muscle, although the test may be unnecessary in clinically evident cases, particularly of myotonic dystrophy. The myotonic discharges are described as high-frequency repetitive biphasic spikes or positive waves with varying frequency or amplitude. Electromyography in periodic paralysis will be normal between attacks in patients without a myopathy. During an attack, features such as reduced compound muscle action potential amplitude are seen.

Figure 87-2 Change in amplitude of muscle fiber compound action potentials in patient with hypokalemic periodic paralysis following long exercise test. Intermittent strong exercise over 5 minutes of the abductor digiti minimi muscle was performed in control subjects and patients. Compound muscle action potentials (CMAPs) in patients showed a greater than normal increase in CMAP amplitude immediately after exercise followed by a decline in CMAP amplitude thereafter. This was seen particularly in those with hypokalemic periodic paralysis but was also seen in the other channelopathy patients, making it a useful test.

(From Kuntzer et al: Muscle Nerve 2000;23:1089-1094.)

NONDYSTROPHIC MYOTONIAS AND PERIODIC PARALYSES

Chloride Channel Disorders (CLCN1)

Epidemiology

Thomsen’s and Becker’s myotonia congenita are allelic disorders due to mutations in the CLCN1 gene, which encodes the voltage-gated chloride channel. Myotonia congenita, Thomsen type, first described in 1876, is an autosomal dominant condition with a prevalence of about 1 : 400,000. Becker’s myotonia congenita, described in 1957, is an autosomal recessive condition, more common than Thomsen’s myotonia, with a prevalence of between 1 : 23,000 and 1 : 50,000.¹

Clinical Features

Thomsen’s myotonia congenita is the less severe of the two disorders, but onset of generalized myotonia is in childhood. Both upper and lower limbs are involved, and the myotonia may be evident on attempting to make rapid movements such as rising from a chair after sitting for 30 minutes. The prolonged sarcolemmal excitation leads to muscle hypertrophy, giving the impression of an athletic physique, even in women. Some of these patients are good at certain sports in their youth, although later the worsening myotonia may limit their ability.

Becker’s myotonia congenita has more severe myotonia than the Thomsen type, with onset in childhood or adolescence. Severe myotonia in the legs may make walking difficult and painful and can lead to falls as rapid movements are impaired. Muscles are hypertrophied as in the Thomsen variant, although shoulder muscles may be relatively less enlarged than those in the lower limbs. These patients may be quite disabled in later life due to a combination of severe myotonia and limb contractures.

Investigation

Creatine kinase levels may be normal or only mildly raised to twice the upper limit of the normal range in Becker’s patients. Electromyographic studies will show repetitive firing in all muscles of both subsets of patients. Muscle biopsy is not indicated as it shows normal appearances or hypertrophied muscle fibers with alterations of fiber type proportions resulting from muscle overactivity.

Molecular genetic analysis of the CLCN1 gene on chromosome 7q should provide a specific diagnosis, although it is not a trivial undertaking. Depending on the degree of clinical confidence that the patient has myotonia congenita, it may be wise to exclude myotonic dystrophies 1 and 2 first, particularly as these genetic tests are well established and relatively straightforward.

Molecular Pathophysiology

CLCN1 mutations are spread throughout the sequence of the gene (Pusch) and are predicted to produce functional changes in the chloride channel protein (CIC-1) with faulty assembly of subunits, impaired ion channel formation, and channel dysfunction (Fig. 87-3). The resulting reduction in chloride ion conductance lowers the threshold for depolarization through sodium channel activation and hence leads to sustained excitability, that is, myotonia.

Figure 87-3 Schematic drawing of voltage-gated cation channel α subunit structure. (A) Four domains assemble into α subunit with central pore. (B) Representation of secondary structure of each domain of α subunit. The sodium channel consists of the main (α) subunit and an accessory (β) subunit. The α subunit consists of four homologous domains which assemble to form a central pore (A). Each domain comprises six transmembrane helices (S1-6) connected by interlinkers (B). The interlinker between S5 and S6 lines the ion pore. The S4 helix is positively charged and acts as a voltage sensor, moving extracellularly and resulting in channel opening through conformational change. The “gate” for fast inactivation is within the interlinker between domains III and IV; three amino acids move on a “hinge,” the so-called hinged-lid model. The voltage-gated L-type calcium channel complex comprises the α subunit, which is of similar structure to that of the sodium channel as well as accessory subunits.

Studies in the two animal models with chloride channel mutations, the myotonic goat and the myotonic mouse, and studies of in vitro ion channel expression have suggested that mutations have a dominant negative effect; this implies that loss-of-function mutations may result in a greater than 50% reduction in channel function, explaining how mutations in the same gene may cause dominant or recessive disease.

Treatment

To alleviate the myotonia, mexiletine is currently the first-line agent; it acts as a “membrane-stabilizing” agent, reducing sodium channel activation, but it has no direct effect on chloride channels. Mexilitene should be used with care as toxicity may develop at higher doses. If mexilitene is not effective, it may be worth switching to carbamazepine or phenytoin. Acetazolamide is not beneficial (although it may be in sodium channel myotonias, see later) and—along with other diuretics—may worsen symptoms of myotonia. Many patients believe that treatment for their myotonia is not necessary as they have adapted to their condition and manage their activities without undue disruption. However, even mild untreated myotonia may lead to subsequent muscle weakness.

Care should be taken that depolarizing agents and anticholinesterases are avoided during anesthesia.

Sodium Channel Disorders (SCN4A)

Epidemiology

Hyperkalemic periodic paralysis (prevalence, approximately 1 : 200,000) and paramyotonia congenita are autosomal dominant conditions. Cases of myotonia permanens are sporadic, probably partly due to the severity of the condition.

Clinical Features

Hyperkalemic periodic paralysis is characterized by intermittent episodes of weakness following a potassium load, hence the name of the condition. Also, potassium concentration in the serum may rise during a spontaneous attack. Other precipitants include resting after exercise, stress, and pregnancy. Cold exposure may also precipitate an attack of weakness, indicating an overlap between hyperkalemic periodic paralysis and paramyotonia congenita (see later).

Attacks usually start in childhood and tend to worsen during subsequent years. Patients often describe spontaneous attacks of weakness first thing in the morning, which may then either resolve or continue to progress. In later years, some patients develop fixed weakness, usually of the lower limbs, independent of episodes of paralysis.

Paramyotonia congenita refers to a condition in which myotonia increases with repeated muscle contractions instead of diminishing as in the other myotonias; this is termed paradoxical myotonia or paramyotonia. In addition, muscle stiffness in paramyotonia congenita is increased by cold temperatures, a feature sometimes reported in other myotonias but only truly seen in paramyotonia congenita. Some patients may experience weakness of their muscles after the stiffness has resolved, indicating an overlap with hyperkalemic periodic paralysis.

Symptoms are present from early childhood and tend not to worsen. In fact, many patients dismiss their symptoms as innocent family traits so as to reduce the interference of these symptoms with their lifestyles and occupations.

Those patients who do seek medical advice may demonstrate eyelid closure or handgrip paramyotonia even at room temperature, but exposure to a cold environment may accentuate these, particularly in the facial muscles and fingers.

The potassium-aggravated myotonias comprise a group of conditions characterized by myotonia of varying degrees that develops after vigorous exercise or administration of a potassium load. Typically, there is a short delay before the onset of the myotonia, which, in the most severe cases, may then take several hours to resolve.

Myotonia fluctuans is a mild version of potassium-aggravated myotonia in which the muscle stiffness is variable but not generally severe and there is no weakness. The myotonia may show a warm-up phenomenon. Myotonia permanens is at the severe end of the spectrum for potassium-aggravated myotonia and produces a condition of continuous depolarization at the cellular level with consequent sustained muscle contraction, myotonia, and hypertrophy. In severe cases, respiratory muscle compromise and hypoventilation may ensue. The situation may be worsened by exercise or potassium loads. There is an intermediate-severity potassium-aggravated myotonia called potassium- and cold-aggravated myotonia congenita, which clinically resembles Thomsen’s myotonia congenita and probably explains earlier overestimates of its frequency. The two may be distinguishable only on molecular testing.

Investigation

In contrast to the myotonia congenita conditions, creatine kinase levels may be raised up to 5 to 10 times the upper limit of normal. Serum potassium concentration may rise by 1.5 to 3 mM during spontaneous attacks in hyperkalemic periodic paralysis. Interictal sodium and potassium levels are normal.

Muscle biopsy is only occasionally helpful. Older hyperkalemic periodic paralysis patients with fixed weakness may have a vacuolar myopathy, but this may also be seen in those with hypokalemia periodic paralysis. In paramyotonia congenita, muscle biopsy may be normal or show nonspecific changes. In potassium-aggravated myotonia, electron microscopy of biopsies from patients with myotonia fluctuans or permanens may show subsarcolemmal disruption or vacuole formation.

Provocation tests have traditionally been used to assist in making a diagnosis but have been largely superseded by genetic investigations. In suspected hyperkalemic periodic paralysis, the provocation test enhances the likelihood of inducing an attack by having the fasting patient exercise and then rest. If this does not result in an attack, an oral potassium load is given. In suspected paramyotonia congenita, cold immersion of the long finger flexor muscles results in slower relaxation times and reduced compound muscle action potential or contractile force. Oral potassium loading may also be helpful in making the diagnosis of potassium-aggravated myotonia; a strong voluntary contraction followed by short contractions produces a delayed relaxation time. However, provocation tests can be difficult to perform, need careful monitoring, and are contraindicated in myotonia permanens, where there is significant risk of causing life-threatening respiratory muscle stiffness, or in periodic paralyses with preexisting cardiac conduction abnormalities.

Molecular Pathophysiology

The gene encoding the α subunit of the skeletal muscle sodium channel is located on chromosome 17q23-25. The α subunit is responsible for most of the channel’s functionality and comprises four domains, each of which is composed of six transmembrane stretches of α helix. Voltage gating is mediated from within the α subunit and regulates the opening or closing of the channel.

Pathogenic mutations in the SCN4A gene result in impaired inactivation of the sodium channel following generation of the action potential, which results in delayed depolarization of the sarcolemma. This leads to continued muscle cell activation at the cellular level, which is evident clinically as slowed muscle relaxation (myotonia). If the sarcolemma becomes completely depolarized, it is inexcitable and this manifests clinically as (periodic) paralysis.

Hyperkalemic periodic paralysis mutations probably affect binding to and inactivation of the channel, an adverse situation amplified by potassium efflux from the cell. Potassium loading may make depolarization more difficult and precipitate paralysis. The myopathy seen in association with hyperkalemic periodic paralysis seems to occur in patients with the T704M mutation. In paramyotonia congenita, mutations are also believed to impair sodium channel inactivation, an effect enhanced by cold temperatures. Mutations found in potassium-aggravated myotonia patients again affect inactivation of the channel through disrupting binding. This is a graded effect: in functional studies, mutations seen in myotonia fluctuans patients cause less marked changes than the G1306E missense mutation seen in myotonia permanens.

Treatment

Modification of environmental and lifestyle may help to reduce the need for medication. In hyperkalemic periodic paralysis, patients learn to eat regular carbohydrate-rich meals, particularly at breakfast. They should not stop exercising abruptly but rather should “cool down” gradually to prevent the onset of paralysis that occurs with rest after exercise. Patients with potassium-aggravated myotonia should also be advised to avoid sudden bursts of vigorous exercise. In paramyotonia congenita, avoidance of cold temperatures is clearly helpful.

Patients with hyperkalemic periodic paralysis or potassium-aggravated myotonia should be given dietary advice to help them avoid potassium-rich foods. Awareness of concomitant conditions such as hypothyroidism is important as this worsens paramyotonia.

Symptoms of paramyotonia congenita should improve with mexilitene, which acts partly as a sodium channel stabilizer. All patients with myotonia permanens should be treated with either mexilitene or agents such as carbamazepine. Some cases of paramyotonia respond to acetazolamide. Acetazolamide or thiazide diuretics may also be helpful in hyperkalemic periodic paralysis patients, probably due to their tendency to lower serum potassium via a specific channel effect. Precautions for general anesthetics are advised, and agents such as suxamethonium and anticholinesterases should not be given. Even so, anesthetic recovery may be prolonged, especially in hyperkalemic periodic paralysis patients. Optimization of perioperative serum potassium concentration is important in improving outcome.

Calcium Channel Disorders (CACNL1A3)

Epidemiology

Hypokalemic periodic paralysis is an autosomal dominant condition with a prevalence of approximately 1 : 100,000, which makes it twice as common as hyperkalemic periodic paralysis.

Clinical Features

Hypokalemic periodic paralysis is a periodic paralysis without myotonia that varies in severity from mild, infrequent episodes beginning in adult life to prolonged, frequent attacks starting in childhood. Intrafamilial variability may be marked. Patients at the more severe end of the spectrum may have weakness that is present constantly but varies in degree. In all patients, many factors may affect strength, including serum potassium levels (influenced by diet and drugs and preceding vigorous exercise), glucose levels (dependent on carbohydrate intake and concomitant illnesses), and emotional stress and lifestyle (affecting the degree of activity).

Episodes of paralysis in hypokalemic periodic paralysis may be heralded by vague nonspecific symptoms followed by attacks of localized or generalized weakness that tend to be more prolonged than in hyperkalemic periodic paralysis. As in hyperkalemic periodic paralysis, older patients may develop fixed weakness due to vacuolar myopathy.

Investigation

Creatine kinase levels are normal or slightly raised, in contrast to sodium channel disorders. Serum potassium concentration is usually normal between attacks, and it can be either lower than normal or within the low-normal range during attacks. After an episode of paralysis, serum potassium concentration may be misleadingly high.

The electromyography in hypokalemic periodic paralysis does not show myotonic discharges, in contrast to hyperkalemic periodic paralysis, where myotonia is part of the condition. Interictal electromyography in mildly affected patients is usually normal. Ictal recordings show small or absent compound muscle action potentials. In patients who develop fixed weakness, there are electromyographic changes consistent with myopathy and muscle biopsy shows a vacuolar myopathy similar to that in hyperkalemic periodic paralysis.

Provocative tests are used occasionally but great care should be exercised. The principle is to induce hypokalemia by administering glucose with or without insulin, thus provoking an episode of paralysis.

Molecular Pathophysiology

The voltage-gated skeletal muscle L-type calcium channel α1S subunit (dihydropyridine receptor) is encoded by the CACN1AS gene located on chromosome 1q31-32; three missense mutations in CACN1AS account for about 60% of hypokalemic periodic paralysis cases. Mutations in this gene are also responsible for some cases of malignant hyperthermia.

The calcium channel α1S subunit and its associated subunits form a transmembrane pore through which calcium ions pass. In hypokalemic periodic paralysis patients, calcium flux through the channel is reduced, which may reduce muscle membrane excitability. The channel may also be involved in the initial phase of excitation-contraction coupling, although its exact role in this process is unclear.

Surprisingly, four missense mutations in the sodium channel gene SCN4A have been associated with 20% of hypokalemic periodic paralysis cases. Inactivation of sodium channels is increased, thus making the muscle cell membrane less excitable.

Treatment

Awareness and modification of environmental and lifestyle are again important. High-carbohydrate and high-salt meals are potential precipitants of episodic paralysis. Extremes of exercise or inactivity should be avoided. Both patients and clinicians should be alert to the possibility that unavoidable factors, such as viral illnesses, can precipitate an episode.

Potassium supplements may be helpful on a daily basis and higher doses should be given if an episode of paralysis occurs. Intravenous potassium is rarely indicated and should be administered only with cardiac monitoring. Low-dose acetazolamide may help prevent attacks in patients with CACN1AS mutations. General anesthetics may precipitate a severe paralytic episode, so awareness of the patient’s condition is important.

Andersen’s Syndrome

Andersen’s syndrome is an autosomal dominant condition associated with mutations in the Kir2.1 potassium channel α subunit gene KCNJ2. Features comprise episodes of periodic paralysis associated with high- or low-serum potassium levels, potentially life-threatening cardiac dysrhythmias, and a mildly dysmorphic appearance. The Kir2.1 channels are expressed in both skeletal and cardiac muscles and are required to maintain the high negative resting membrane potential in resting skeletal muscle and in the depolarization phase of the action potential in cardiac muscle; dominant negative mutations in patients with Andersen’s syndrome reduce potassium ion flow. Treating the cardiac dysrhythmias and periodic paralysis is difficult.

Thyrotoxic Periodic Paralysis

Thyrotoxic periodic paralysis is a late-onset disorder, usually occurring in patients of east Asian descent, in whom thyrotoxicosis is associated with episodes of paralysis precipitated by hypokalemia. Acute treatment is based on administration of potassium and/or propranolol. Once the thyroid dysfunction is corrected, the attacks of periodic paralysis disappear.

Secondary Hypokalemic Periodic Paralysis

Paralytic episodes may occur in conditions where hypokalemia is due to a variety of chronic disorders such as renal tubular acidosis, gastrointestinal potassium loss, or Cushing’s syndrome. Investigation should reveal the underlying metabolic disturbance, and treatment directed at the cause often abolishes paralytic attacks.