The author: Professor Yasser Metwally
INTRODUCTION
February 9, 2010 — The past decade has witnessed exciting developments in the understanding of the pathogenesis of neurologic disease. The recognition that diverse neurologic disorders are caused by dysfunction of ion channels in excitable tissue has epitomized this molecular biologic advance in clinical neurology. The role of ion channels in neurologic disease began with the discovery that skeletal muscle diseases are linked to missense mutations of calcium, sodium, and chloride channels. This entire group of periodic paroxysmal neurologic diseases is termed “channelopathies” [1]. Availability of new molecular genetic tools has led to a rapidly increasing number of recognized channelopathies that reflect abnormalities in the structure and function of the various ion channels. Disorders as diverse as cardiac arrhythmias, epilepsy, myotonia, malignant hyperthermia, and cystic fibrosis have been linked to mutations in genes encoding for ion channels.
Channelopathies have surprisingly similar clinical features. Typically, neurologic channelopathies manifest as paroxysmal attacks of paralysis, myotonia, headache, or ataxia and are precipitated by physiologic stresses. Symptoms attributed to channelopathies may represent an abnormal gain of function (such as myokymia, myotonia, or epilepsy) or an abnormal loss of function (such as weakness) depending on whether or not the defect leads to increased membrane excitability or inexcitability.
Mutations in a specific ion channel gene can be associated with heterogeneous phenotypes. Conversely, mutations in different channel genes can produce similar clinical phenotypes. Given such clinical and genetic heterogeneity, any attempt at classification of channelopathies based solely on clinical signs and symptoms has limitations. Accordingly, this review is based on the particular ion channel involved rather than clinical manifestations.
Two types of sodium channelopathy exist as follows
| Skeletal muscle Sodium channelopathy | 1- Hyperkalemic periodic paralysis 2- Paramyotonia congenita 3- Potassium-aggravated myotonia |
| Neuronal Sodium channelopathy | 1- Generalized epilepsy with febrile seizures plus |
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Ion channel structure
Cell membranes are impermeable to charged ions. Resultant ion concentration differentials are the source of an electrical potential difference across cell membranes. Membranes have protein pores or “channels” that allow ions to pass through. These channels display ion selectivity and have “gates” that open or close in response to specific stimuli, such as a change in the transmembrane voltage or the binding of a specific ligand.
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Video 1. The Ion channel
Structurally, ion channels are composed of individual subunits or groups of subunits, each subunit containing six hydrophobic transmembrane regions, S1 through S6. The sodium and calcium channels are composed of a single a subunit containing four repeats of the six transmembrane-spanning segments. Voltage-gated potassium channels are composed of four distinct subunits, each subunit containing different six transmembrane-spanning segments. The subunits are assembled to form the central pore in a process that also determines the basic properties of gating and selective permeability characteristic of the channel type. The peptide chain (H5 or P loop) between the membrane-spanning segments S5 and S6 projects into and lines the water-filled channel pore. Mutations in this region alter the permeability properties of the channel. The S4 segment contains a cluster of positively charged amino acids (lysine and arginine) and is the major voltage sensor of the ion channel. Voltage-dependent “fast inactivation” of the channel is mediated by a tethered amino-terminal-blocking particle (the “ball and chain”) that swings in to occlude the permeation pathway. Most gain-of-function (myokymia, myotonia, or epilepsy) ion channel mutations affect the gating process by preventing channel closure.
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Video 2. The ion channels structure and function
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Structure of sodium channel (Click for more details)
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane.[1] They are classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change (voltage-gated sodium channels) or binding of a substance (a ligand) to the channel (ligand-gated sodium channels).
In excitable cells such as neurons, myocytes, and certain types of glia, sodium channels are responsible for the rising phase of action potentials.
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Voltage-gated sodium channel
Voltage-sensitive sodium channel a-subunit. G – glycosylation, P – phosphorylation, S – ion selectivity, I – inactivation, positive (+) charges in S4 are important for transmembrane voltage sensing, See fig.1 .[3] Sodium channels consist of a large a subunit that associates with other proteins, such as ß subunits. An a subunit forms the core of the channel and is functional on its own. When the a subunit protein is expressed by a cell, it is able to form channels that conduct Na+ in a voltage-gated way, even if ß subunits or other known modulating proteins are not expressed. When accessory proteins assemble with a subunits, the resulting complex can display altered voltage dependence and cellular localization.
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Figure 1. Voltage-sensitive sodium channel α-subunit. G – glycosylation, P – phosphorylation, S – ion selectivity, I – inactivation, positive (+) charges in S4 are important for transmembrane voltage sensing. (Click to enlarge figure)
The a-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6. The highly conserved S4 region acts as the channel’s voltage sensor. The voltage sensitivity of this channel is due to positive amino acids located at every third position. When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through a pore, which can be broken into two regions. The more external (i.e., more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. This region is the most narrow part of the pore and is responsible for its ion selectivity. The inner portion (i.e., more cytoplasmic) of the pore is formed by the combined S5 and S6 regions of the four domains. The region linking domains III and IV is also important for channel function. This region plugs the channel after prolonged activation, inactivating it.
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Gating of sodium channel
Voltage-gated sodium channels have three types of states: deactivated (closed), activated (open), and inactivated (closed). Channels in the deactivated state are thought to be blocked on their intracellular side by an "activation gate", which is removed in response to stimulation that opens the channel. The ability to inactivate is thought to be due to a tethered plug (formed by domains III and IV of the alpha subunit), called an inactivation gate, that blocks the inside of the channel shortly after it has been activated. During an action potential the channel remains inactivated for a few milliseconds after depolarization. The inactivation is removed when the membrane potential of the cell repolarizes following the falling phase of the action potential. This allows the channels to be activated again during the next action potential. Genetic diseases that alter sodium channel inactivation can cause muscle stiffness or epileptic seizures because of the introduction of a so-called window current, during which sodium channels are tonically active, causing muscle and/or nerve cells to become over-excited.
The temporal behaviour of sodium channels can be modeled by a Markovian scheme or by the Hodgkin-Huxley-type formalism. In the former scheme, each channel occupies a distinct state with differential equations describing transitions between states; in the latter, the channels are treated as a population that are affected by three independent gating variables. Each of these variables can attain a value between 1 (fully permeant to ions) and 0 (fully non-permeant), the product of these variables yielding the percentage of conducting channels.
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Skeletal muscle Sodium channelopathy
The muscle disorders caused by defective sodium channels include hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia. These disorders are caused by mutations in the voltage-gated skeletal muscle sodium ion channel gene (SCN4A) located on chromosome 17q [8–14]. Reported SCN4A mutations have been in domains 2, 3, and 4 of the sodium channel a subunit. These disorders display autosomal dominant inheritance and result from a common underlying defect of muscle membrane excitability. Linkage of malignant hyperthermia to the SCN4A gene in some families suggests that patients with sodium channel disease have a risk of malignant hyperthermia when exposed to certain anesthetic and muscle relaxing agents.
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Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis was recognized as a distinct entity in 1955 [15]. The onset of attacks of weakness typically is in late childhood or early adolescence. Complete limb paralysis during attacks is rare. The episodes of weakness are brief, lasting 30 minutes to a few hours. Focal weakness is common. Attacks are precipitated by skipping meals and can be prevented by frequent high carbohydrate snacks. Common precipitants include rest after a period of exercise, stress, or cold. With increasing age, the frequency of attacks declines and interictal weakness may develop. Muscle biopsy may show vacuoles or tubular aggregates. Serum potassium during an attack may be elevated to approximately 6.0 mEq/L or can be normal (particularly if measured late in an attack). EMG can show interictal myotonic discharges or electrical silence during an attack. Genetic analysis yields diagnosis and obviates the need for potassium loading tests, which can be dangerous. Because attacks are brief, treatment may not be required. Prompt ingestion of carbohydrates at the onset of weakness often aborts attacks. Acetazolamide is an effective prophylaxis and may act through hypokalemia or acidosis. Thiazide diuretics often are preferable and appear to be equally effective.
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Paramyotonia congenita
Described by Eulenburg in 1886, paramyotonia congenita is an autosomal dominant disorder characterized by myotonia that worsens with activity (paradoxical myotonia) [15]. This type of myotonia distinguishes paramyotonia congenita from the classical myotonia seen in myotonia congenita. Classical myotonia improves with repetitive movements, a feature known as the “warm-up” phenomenon. The myotonia and weakness in paramyotonia congenita are dramatically worsened by cold exposure. The onset of myotonia occurs in infancy. Attacks of periodic paralysis may develop in adolescence and may be associated with either hypokalemia or hyperkalemia. Stiffness after cooling in paramyotonia is not the result of myotonia, but rather contractures. Paradoxical myotonia is secondary to increasing membrane failure. The underlying membrane defect leads to increased sodium permeability, which is further increased with cooling. A similar effect seen in hyperthyroidism may explain marked worsening of exercise-induced weakness in paramyotonia congenita associated with hyperthyroidism. EMG reveals myotonic discharges. Muscle biopsy usually does not demonstrate any specific abnormalities, although some biopsy specimens show increased variation in myofiber size and reduced numbers of type 2B myofibers. Tocainide is an effective treatment, although mexiletine is preferred because of less toxicity. Acetazolamide may precipitate weakness but improve myotonia. Chorthiazide may improve weakness and myotonia.
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Potassium-aggravated myotonia
Potassium-aggravated myotonia previously was known as myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia [15]. The myotonia in this disorder is induced by potassium ingestion and rest after exercise [16]. Phenotypic variation exists. The mild cases show extremely variable muscle stiffness with symptom-free periods lasting days or weeks (myotonia fluctuans) [17]. The severe phenotype includes permanent and profound muscle stiffness with hypertrophy of neck and shoulder muscles. Painful myotonia is a clue to this diagnosis, but also is seen in patients with myotonia that results from chloride channel abnormalities. Acetazolamide may be helpful.
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Neuronal Sodium channelopathy
Sodium channels are prevalent throughout the nervous system [22]. Many anticonvulsants are believed to exert their therapeutic response by modulation of neuronal sodium channels [18].
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Generalized epilepsy with febrile seizures plus
Generalized epilepsy with febrile seizures plus is a recently described benign childhood-onset epileptic syndrome with autosomal dominant inheritance. This disorder is associated with mutations in a gene encoding a voltage-gated subunit of a neuronal sodium channel [19].The most common phenotype is febrile seizures and generalized tonic-clonic seizures that are not associated with fever. In approximately one third of patients, additional seizure types occur, including absence, myoclonic, or atonic seizures [20,21].
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