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.

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