Peripheral Neuropathies

Fall 2002
Volume 13, Number 2

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Disorders of voltage-gated ion channels are responsible for a diverse group of neurological and muscular diseases. These diseases are now called "channelopathies." Ion channels are normally responsible for the generation of electrical currents across excitable membranes, and the "channelopathies" are characterized by increased or decreased excitability of nerve or muscle. One way of understanding this diverse group of disorders is to subdivide it into toxin-mediated, immune-mediated, and genetically-determined "channelopathies." The largest and most rapidly expanding subgroup is the genetically-determined subgroup secondary to mutations in genes coding for voltage-gated ion channels. The increasing availability of genetic DNA analysis is already allowing a precise diagnosis for many of the genetic "channelopathies." Additionally, understanding the ion channel basis of these diseases should provide the basis for the development of more effective pharmacological treatments.

Introduction. Voltage-gated ion channels are responsible for the generation and propagation of action potentials along electrically excitable membranes. Ion channels are fundamentally important for the conduction of impulses along the membranes of neurons, skeletal muscle, and cardiac muscle. All ion channels are transmembrane proteins that form selective ion-conducting pores in the cell membrane. Voltage-gated ion channels, specifically sodium, potassium, and calcium channels, are sensitive to changes in transmembrane voltage. Thus, voltage-gated ion channels activate (ie, open) or inactivate (ie, close) in response to changes in transmembrane voltage.

Targeted disorders of ion channels are increasingly recognized as causes of specific neurological and muscular diseases.1 These so-called "channelopathies" are characterized primarily by increased or decreased excitability of nervous or muscle tissues. Disorders of ion channels can be toxin-mediated, immune-mediated, or genetically determined. Several biological toxins and venoms act upon specific ion channels. Specific examples of toxin-mediated diseases include tetrodotoxin, saxitoxin, and ciguatoxin, all of which have direct effects on sodium channels. The best characterized antibody-mediated channelopathy is the Lambert-Eaton syndrome, which is due to antibody-induced blockade of calcium channels in presynaptic motor nerve terminals. Neuromyotonia (Isaacs' syndrome) appears to be due to antibody-induced blockade of potassium channels along peripheral axons. The newest category of channelopathies are those due to mutations in the coding regions of ion channel genes. The list of genetically-determined channelopathies is steadily increasing, but at this time over 30 different human diseases are a consequence of mutations in ion channels.

What follows is a review of some of the most well characterized channelopathies with specific attention to those disorders affecting nerves and muscles.

Toxin-Mediated Channelopathies. Tetrodotoxin (TTX) is a potent nonprotein toxin that is present in a number of animals, the most famous of which is the puffer fish, Fugu. TTX is a selective and powerful blocker of sodium channels. Poisoning of humans results usually from ingestion of improperly prepared puffer fish, which is considered a delicacy in some parts of the world, especially Japan. TTX poisoning is characterized by the rapid onset of paresthesias and numbness involving the lips, tongue, and extremities. This is followed by generalized weakness. If weakness of respiratory muscles is severe, death can result from respiratory insufficiency. However, with appropriate medical care, recovery over several days can be expected.2

Nerve conduction studies in TTX poisoning show diffusely slow conduction velocities and decreased amplitudes in both motor and sensory nerves. These abnormalities of conduction recover rapidly over 4 to 5 days with no long lasting abnormalities.2 All of these findings are a direct result of TTX blockade of axonal voltage-gated sodium channels. Demyelination of nerve does not occur with TTX poisoning.

Saxitoxin Poisoning. Saxitoxin blocks voltage-gated sodium channels in the same manner as tetrodotoxin. Saxitoxin is a diguanidinium compound produced by marine dinoflagellates of the genus, Gonyaulax. Human paralytic illness occurs after consumption of shellfish (mainly clams and mussels) that have been contaminated with saxitoxin.3 The human illness that results from saxitoxin ingestion is nearly identical to TTX poisoning. With adequate supportive care, recovery generally occurs over several days.

Ciguatera Poisoning. Ciguatoxin is a very potent and heat stable sodium channel toxin. In contrast to tetrodotoxin and saxitoxin which blocks sodium channels, most ciguatera toxins cause prolonged activation of sodium channels.4 However, a novel ciguatoxin from farm-raised salmon has been shown to have sodium channel blocking activity.5 Ciguatera intoxication mainly results from eating predatory reef fish found in semitropical and tropical seas of the Caribbean and Indo-Pacific regions.4-6 Ciguatoxin is produced by the dinoflagellate, Gambierdiscus toxicus, which lives in dead coral and algae. The toxin is passed up the fish food chain and becomes concentrated in the larger reef fish.

The clinical presentation of ciguatera intoxication consists of vomiting and diarrhea followed by paresthesias in the extremities and perioral region, pruritus, myalgias, and weakness. Two unique sensory features are the reversal of hot and cold sensation and a sensation of loose teeth. Severe bradycardia and hypotension may occur. Sensory symptoms commonly persist for several months and rarely persist for a year or two.5, 7

Immune-Mediated Channelopathies. There are several autoimmune disorders of ion channels. The known immune-mediated channelopathies have antibodies directed at epitopes on the ion channel proteins. The best characterized of these diseases are myasthenia gravis in which antibodies are directed against the nicotinic acetylcholine receptor and the Lambert-Eaton syndrome in which antibodies are directed against voltage-gated calcium channels within presynaptic motor nerve terminals. These disorders are well described in standard textbooks and will not be covered here. More recently, generalized myokymia and neuromyotonia have been associated with antibodies directed against potassium channels in peripheral nerve. This disorder is discussed briefly below.

Anti-Potassium Channel Antibodies and Myokymia/Neuromyotonia. Myokymia is characterized by tetanic bursts of single motor unit potentials recurring at semiregular or regular intervals. These ectopic discharges arise along a region of unstable membrane of motor axons. Myokymia is most often associated with injury and demyelination of motor axons as occurs in radiation-injury to nerves or other neuropathies. Generalized myokymia and neuromyotonia may be seen in the absence of traditional disease of peripheral nerves or motor neurons as in Isaacs' syndrome. Such generalized acquired neuromyotonia has been shown to be associated with autoantibodies directed against potassium channels in peripheral motor axons.8, 9 These anti-potassium channel antibodies appear to block voltage-gated potassium channels in peripheral nerve resulting in motor axon hyperexcitability and myokymia/neuromyotonia. Indirect confirmation of this presumed antibody-mediated abnormality has been provided by the improvement in neuromyotonia after plasmapheresis.8

Genetically-Determined Channelopathies. The explosion of molecular genetics within the past decade has resulted in the identification of an entirely new class of ion channel diseases Ñ the genetically determined channelopathies.1 Mutations of ion channel genes have now been identified as the cause of over 30 different disorders, and more will most certainly be characterized. The genetic channelopathies represent a diverse group of disorders affecting heart, skeletal muscle, and brain. This review will concentrate on the most well described genetic channelopathies affecting skeletal muscle.

Skeletal Muscle Channelopathies. The skeletal muscle channelopathies are divided into sodium channel defects, chloride channel defects, and calcium channel defects (Table 1).

Sodium Channel Defects. The so-called muscle "sodium channelopathies" share an abnormality of muscle membrane excitability that can be variably expressed as myotonia or weakness. This group of muscle diseases are due to missense mutations in the gene that codes for the skeletal muscle sodium channel a-subunit (SCN4A).1,10 The SCN4A gene maps to chromosome 1q 23-25. Three of these allelic disorders characteristically exhibit myotonia of variable severity and have been termed the "sodium channel myotonias." The known sodium channel myotonias are paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia.10-12 The mutations of the skeletal muscle sodium channel that cause these disorders result in gain-of-function defects, whereby the mutant channels pass more Na+ current than normal. In most cases, this is due to an impairment of fast inactivation of the mutant sodium channels.

Paramyotonia congenita is an autosomal dominant muscle disease that is characterized by cold-induced and exercise-induced myotonia.10,12 The myotonia is called paradoxical since it increases with exercise in contrast to other myotonic diseases in which myotonia decreases with exercise. Muscles of the face, neck, and distal extremities are the most severely affected. Myotonia can be followed by weakness after prolonged exposure to cold or prolonged exercise. Fixed or progressive weakness or atrophy usually do not occur in this disease, but the serum creatine kinase (CK) is often elevated. EMG shows myotonic potentials. The majority of patients with paramyotonia congenita do not require specific drug treatment for myotonia. In severe cases, the sodium channel blocking agents mexiletine and tocainide may be helpful for treating the myotonia. Mexilitene should be tried first since it has less toxic side effects than tocainide.

Hyperkalemic periodic paralysis is an autosomal dominantly inherited periodic paralysis that may or may not have concomitant myotonia.11,12 The attacks of weakness usually start during the first decade of life. The attacks are more frequent and shorter in duration than those associated with hypokalemic periodic paralysis. Weakness is often precipitated by rest after exercise, cold, and oral potassium loading. Although the designation "hyperkalemic" suggests that the serum level of potassium is elevated during an attack of paralysis, this is not invariable. In fact, the absolute level of potassium can be normal or even low depending upon the time when the patient is evaluated. Myotonia on needle EMG is present in many patients, and paradoxical myotonia of the eyelids can be seen clinically. Acetazolamide or thiazide diuretics are effective in preventing attacks in many patients.

Potassium-aggravated myotonia was recognized as a distinct disease only after molecular genetic analysis became available.1,11,13 These patients have autosomal dominantly inherited myotonia, but no attacks of weakness. Clinically, these patients resemble patients with autosomal dominant myotonia congenita (Thomsen's disease), and many have been erroneously diagnosed. However, patients with potassium-aggravated myotonia (as the name suggests) have myotonia that is aggravated by potassium loading. The myotonia of this disease also fluctuates more significantly than in myotonia congenita. In contrast to myotonia congenita, which is due to mutations in the skeletal muscle chloride channel, potassium-aggravated myotonia is due to mutations in the skeletal muscle sodium channel (SCN4A).

Chloride Channel Defects. Mutations in the skeletal muscle chloride channel (CLCN-1) on chromosome 7q35 cause both autosomal dominant and autosomal recessive myotonia congenita.1,11-13 The C1-current is normally responsible for ~70% of the skeletal muscle resting membrane conductance. Defective C1- conductance due to mutations in the CLCN-1 channel decreases the rate of action potential repolarization. This allows sufficient time for sodium channels to recover from inactivation even though the membrane remains depolarized, and repetitive myotonic potentials occur.

Myotonia is the major symptom of both autosomal dominant (Thomsen's) and autosomal recessive (Becker's) myotonia congenita. For the most part, weakness is not a prominent feature of myotonia congenita; however, muscle wasting and weakness can occur late, especially in the autosomal recessive phenotype. Myotonia manifesting as generalized stiffness, especially after rest, are prominent features in both types of myotonia congenita. Patients with myotonia congenita frequently appear "muscular" because of their prominent muscle hypertrophy. Many of these patients complain about their muscle stiffness. Mild exercise can decrease the myotonia, but many patients require drugs such as mexiletine or tocainide for symptomatic relief.

Calcium Channel Defects. Hypokalemic periodic paralysis is most commonly due to missense mutations in the a-subunit of the dihydropyridine- sensitive (L-type) calcium channel of skeletal muscle.1,13 The gene encoding this calcium channel (CACNL1A3) maps to chromosome 1q 21-31.14 This is by far the most common variety of periodic paralysis and is inherited in an autosomal dominant manner. Recently, one family with hypokalemic periodic paralysis was found to have a misense mutation in the skeletal muscle sodium channel, providing the first evidence that hypokalemic periodic paralysis may be genetically heterogeneous.15 The exact pathophysiological basis of the episodic attacks in hypokalemic periodic paralysis remains unknown.

In hypokalemic periodic paralysis, attacks of weakness usually begin in the second decade of life, and the attacks may be quite severe. Most attacks last for several hours and may persist for a day or more. The limb muscles are predominantly involved, and the weakness can be profound. However, difficulty swallowing or breathing rarely occurs. Low serum potassium during an attack is typically found and helps to distinguish this disorder from hyperkalemic periodic paralysis. Additionally, myotonia does not occur in hypokalemic periodic paralysis. Progressive and permanent proximal muscle wekaness with a "vacuolar myopathy" is common later is life. The attacks of weakness are often provoked by high carbohydrate meals, rest after exercise, cold, or emotional stress/excitement.

The most effective treatment for an acute attack of hypokalemic periodic paralysis is the administration of KC1. The KC1 can usually be given orally in a dose of 2 to 10 grams. However, potassium salts are usually not effective in preventing attacks when given chronically. Prophylactic therapy with acetazolamide, dichlorphenamide, or spironolactone may be useful.

In addition to excluding other causes of hypokalemia, the differential diagnosis of this disorder includes thyrotoxic periodic paralysis. Thyrotoxicosis may precipitate typical attacks of hypokalemic periodic paralysis in susceptible individuals. Most often this disorder occurs in young males of Asian descent, but thyroid function studies should be obtained in all individuals who present with periodic paralysis. Oral KC1, propranolol, and restoration of the euthyroid state are the recommended therapy for hypokalemic thyrotixic periodic paralysis.

Conclusion. Diseases secondary to dysfunction of ion channels are now recognized as an important class of disorders termed "channelopathies." They now comprise an important and expanding subset of neuromuscular disorders. The basic abnormality can be in neurons or muscle cells. Some of the toxin-mediated and immune- mediated disorders of ion channels have been known for some time, but the genetic revolution has resulted in the discovery of several genetically-determined channelopathies. Understanding the pathophysioloigcal basis of these diseases at the level of ion channels should provide the basis for the rational development of specific and effective treatments.

Address comments and questions to:

John D. England, MD, FAAN
Dept. of Neurology, Deaconess Billings Clinic
2825 Eight Avenue North
Billings, MT 59107

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