Channelopathies: Episodic and Electrical Disorders of the Nervous System

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Chapter 64 Channelopathies

Episodic and Electrical Disorders of the Nervous System

Channelopathies are disorders caused by ion channel dysfunction. Because of the great diversity of ion channel proteins and their expression in different tissues, channelopathies comprise a wide variety of clinical diseases (Table 64.1), the discovery of which helps elucidate how ion channels function in both illness and health. The periodic paralyses—the first group of ion channel disorders characterized at a molecular level—defined the field of channelopathies, which now encompasses diseases not only in muscle but also in the kidney (Bartter syndrome), epithelium (cystic fibrosis), and heart (long QT syndrome) as well as neurons. Because muscles and neurons are electrical organs, it is not surprising that most channelopathies are associated with neurological disease. Despite significant heterogeneity, a pervasive feature of neurological channelopathies is a paroxysmal phenotype. After a brief introduction to ion channels, this chapter describes disorders caused by congenital and acquired dysfunction of ion channels expressed in skeletal muscle and neurons.

Ion Channels

One needs a basic understanding of channel structure and function before addressing channelopathies and their clinical manifestations. Ion channels are transmembrane glycoprotein pores that underlie cell excitability by regulating ion flow into and out of cells. A channel is a macromolecular protein complex, often composed of distinct protein subunits, each encoded by a separate gene. The categorization of most channels, depending on their means of activation, is as voltage-gated or ligand-gated. Changes in membrane potentials activate and inactivate voltage-gated ion channels. They are named according to the physiological ion preferentially conducted (e.g., Na+, K+, Ca2+, Cl). Ligand-gated ion channels respond instead to specific chemical neurotransmitters (e.g., acetylcholine, glutamate, γ-aminobutyric acid [GABA], glycine). Other channels not discussed in this chapter are cyclic nucleotide-gated, mechanically gated, or second messenger–gated.

Distributed ubiquitously in excitable tissues, voltage-gated ion channels are critical for establishing a resting membrane potential and generating action potentials. These channels consist of one or more pore-forming subunits (generally referred to as α-subunits) and a variable number of accessory subunits (often denoted β, γ, etc.). Whereas α-subunits typically determine ion selectivity and mediate the voltage-sensing functions of the channel, accessory subunits act as modulators. Channels exist in one of three states: open, closed, or inactivated. Voltage-gated channels open (or activate) with threshold changes in membrane potential, then transition after a characteristic interval to either a closed or an inactivated state. From the closed state, a channel can reopen with an appropriate change in membrane potential. In the inactivated state, a change in membrane potential normally sufficient to open the channel is ineffective, and the channels will not conduct current. Inactivation is both time and voltage dependent, and many channels display both fast and slow inactivation.

Depending on the location within the channel, mutations could alter voltage-dependent activation, ion selectivity, or time and voltage dependence of inactivation. Thus, two different mutations within the same gene can result in dramatically different physiological defects. For example, a mutation that prevents or slows inactivation could lead to a persistent ionic current. Conversely, a mutation elsewhere in the same gene that prevents activation will decrease ionic current. Phenotypic heterogeneity describes how different mutations in a single gene cause distinct phenotypes. For instance, mutations in the skeletal muscle voltage-dependent sodium channel can result in hyperkalemic periodic paralysis, hypokalemic periodic paralysis, potassium-aggravated myotonia, or paramyotonia congenita (see Table 64.1 and Fig. 64.1). In contrast, genetic heterogeneity occurs when a consistent clinical syndrome results from a variety of underlying mutations.

Voltage-gated potassium channels (VGKC) consist of four homologous α-subunits that combine to create a complete channel. Like the other channels described later, humans possess many distinct VGKC genes, and the resulting channels exhibit specialized properties and display rich tissue-type and cellular-compartment specificity. Each α-subunit contains six transmembrane segments (S1 to S6) linked by extracellular and intracellular loops (Fig. 64.2). The S5-S6 loop penetrates deep into the central part of the channel and lines the pore. The S4 segment contains positively charged amino acids and acts as the voltage sensor. These channels serve many functions, most notably to establish the resting membrane potential and to repolarize cells following an action potential. A unique class of potassium channel, the inwardly rectifying potassium channel, is homologous to the S5 to S6 segment of the VGKC. Because the voltage-sensing S4 domain is absent, voltage dependence results from a voltage-dependent blockade by magnesium and polyamines.

Voltage-gated sodium and calcium channels are highly homologous and share homology with VGKCs, from which they evolved. The α-subunits contain four highly homologous domains in tandem within a single transcript (DI–DIV) (Fig. 64.3). Each domain resembles a VGKC α-subunit, with six transmembrane segments as described earlier. Sodium and calcium channels differ in several regards, despite their many similarities. The amino acid sequence forming the selectivity filter and the modulatory auxiliary subunits are different. The sodium channel is composed of an α- and a β-subunit, and the calcium channel is composed of a pore-forming α1-subunit, an intracellular β-subunit, a membrane-spanning γ-subunit, and a membrane-anchoring α2δ-subunit. Sodium channels mediate fast depolarization and underlie the action potential, whereas voltage-gated calcium channels (VGCCs) mediate neurotransmitter release and allow the calcium influx that leads to second messenger effects.

Ligand-gated ion channels activate on binding with their respective agonists. Among the diverse array of ligand-gated channels, GABAA, glycine, and nicotinic acetylcholine receptors (nAChRs) possess the only known disease-causing mutations. Although distinguished by their ligand binding and ion permeability, channels gated by GABA, glycine, and acetylcholine share several structural similarities. Five intrinsic membrane subunits assemble to form hetero- or homopentamers. Each subunit contains four transmembrane domains (M1 to M4), the second of which lines the pore and determines ionic selectivity (Fig. 64.4). Subunits contributing to nAChRs at the neuromuscular junction differ from those expressed in the central nervous system, explaining why mutation of one gene may cause seizures without affecting neuromuscular transmission, or vice versa. Binding of acetylcholine opens the channel, which conducts monovalent cations (Na+ and K+) with little or no selectivity, and some are additionally permeable to calcium. Channel activation results in membrane depolarization and excitation of the postsynaptic neuron or muscle fiber.

The GABAA and glycine receptors belong to the nAChR superfamily and similarly consist of five subunits. GABAA receptors include α-, β-, and either γ- or δ-subunits. The predominant glycine receptor is a heteropentamer of three α-subunits to two β-subunits. Agonist binding in either case opens the channel and allows the flux of chloride (Cl) into the cell, generally causing hyperpolarization and decreased excitability. Therefore, both GABA and glycine mediate inhibitory synaptic transmission.

Genetic Disorders of Muscular Ion Channels

The periodic paralyses and nondystrophic myotonias encompass several skeletal muscle disorders inherited as autosomal dominant traits. These disorders include hypokalemic periodic paralysis (hypoKPP), hyperkalemic periodic paralysis (hyperKPP), paramyotonia congenita, myotonia congenita, potassium-aggravated myotonia, and Andersen-Tawil syndrome. General features include episodic weakness or stiffness, interictal return to an asymptomatic state, and responsiveness to carbonic anhydrase inhibition (see Table 64.3).

Hypokalemic Periodic Paralysis

Pathophysiology

In up to 70% of cases, the responsible mutation has been linked to a gene encoding a VGCC on chromosome 1q (Venance et al., 2006). The gene, CACNA1S, encodes the α1-subunit of the dihydropyridine-sensitive L-type VGCC found in skeletal muscle. This channel functions as the voltage sensor of the ryanodine receptor and plays an important role in excitation-contraction coupling in skeletal muscle. Four mutations in the S4 segments are responsible for voltage sensitivity. Two mutations, one involving arginine-to-histidine substitutions within the highly conserved S4 segments of DII and DIV (Arg-528-His and Arg-1239-His) account for most cases. The others involve arginine-to-glycine substitutions at the same locations.

Some 10% to 20% of families with hypoKPP have mutations in the gene encoding the α-subunit of the skeletal muscle voltage-gated sodium channel (SCN4A) on chromosome 17q. This is the same channel implicated in hyperKPP and other disorders described later (see Fig. 64.1). Evidence suggests that this sodium channel–associated syndrome is phenotypically different from the more common CACNA1S form. A proposed separate clinical entity, hypoKPP2, may be distinguishable from hypoKPP associated with CACNA1S by the presence of myalgias following paralytic attacks, and the presence of tubular aggregates instead of vacuoles in the muscle biopsy. In some patients, acetazolamide worsens symptoms (Bendahhou et al., 2001; Sternberg et al., 2001). In a large retrospective series, hypoKPP2 was associated with an older age of onset and shorter duration of attacks than classical hypoKPP (Miller et al., 2004).

Whether involving SCN4A or CACNA1S, virtually all mutations causing hypoKPP involve an S4 voltage-sensor domain. In the case of the sodium channel, these mutations allow a leak current to pass through the “gating pore” at resting membrane potentials, bypassing the central channel pore and leading to inappropriate muscle fiber depolarization and consequent channel inactivation and action potential failure (Sokolov et al., 2007). Speculation exists that this phenomenon may also occur in mutated VGCCs.

Diagnosis

An accurate medical history is essential for the diagnosis because observation of attacks is unusual, and patients are often normal between attacks. Characteristic features of hypoKPP that distinguish it from hyperKPP are that paralytic attacks are less frequent, longer lasting, precipitated by a carbohydrate load, and often begin during sleep (Table 64.2). Potassium concentrations are usually low during an attack, although concentrations less than 2 mM should suggest a secondary form of periodic paralysis. Electrocardiogram (ECG) changes such as increased PR and QT intervals, T-wave flattening, and prominent U waves suggest an underlying hypokalemia. Provocative testing can be dangerous and is not routine. Test performance requires a hospitalized setting with continuous cardiac monitoring and should be performed only in patients without cardiac or renal disease. After giving an oral glucose load (2-5 mg/kg up to a maximum of 100 g) without or, less commonly, with subcutaneous insulin (0.1 U/kg), perform serial examinations of strength while monitoring serum glucose and potassium concentrations. Other diagnostic tests include electromyography (EMG), which may show decreased compound muscle action potential amplitudes during attacks compared with interictal values. Muscle histology reveals nonspecific myopathic changes of tubular aggregates or vacuoles within fibers. Genetic testing should render muscle biopsy and provocative testing obsolete for diagnosis.

Thyrotoxic periodic paralysis may be clinically indistinguishable from hypoKPP, except that it is not familial and serum potassium levels are often lower than in familial hypoKPP (<2.5). Some cases may be associated with a mutation in KCNJ18, the gene encoding a novel inwardly rectifying potassium channel (Ryan et al., 2010). All patients with hypoKPP require screening for hyperthyroidism, as the treatment—correction of the thyroid disorder—differs from that outlined later for idiopathic hypoKPP. Exclude other secondary forms of hypokalemic paralysis when serum potassium concentrations remain low between attacks. Renal, adrenal, and gastrointestinal causes of persistent hypokalemia are common, and thiazide diuretic use or licorice (glycyrrhizic acid) intoxication are considerations.

Treatment

An effective holistic approach to treatment includes lifestyle modifications and acute and chronic pharmacological intervention. Dietary modification to avoid high carbohydrate loads and refraining from excessive exertion helps prevent attacks. Oral potassium (5-10 g load) reverses paralysis during an acute attack. Prophylactic use of acetazolamide (Table 64.3) decreases the frequency and severity of attacks. Dichlorphenamide is another carbonic anhydrase inhibitor that effectively prevents attacks, as demonstrated in a randomized clinical trial (Tawil et al., 2000) where the average dose was 100 mg daily. More potent than acetazolamide, dichlorphenamide may be useful when efficacy of the former begins to fail. Many believe, without supporting evidence, that reducing the frequency of paralytic attacks provides protection against the development of myopathy. As insight into molecular pathophysiology expands, new treatment possibilities—and a new understanding of old treatments—seem likely (Matthews and Hanna, 2010).

Table 64.3 Acetazolamide

Use Prophylactic agent for some channelopathies (see text)
Mechanism Inhibits carbonic anhydrase
Dosing Adults: start 125 mg daily, titrating as needed up to a maximum daily dose of 1000-1500 mg, divided bid–qid. An extended release formulation is available.
Children: consult a pharmacist.
Side effects Taste changes (especially for carbonated drinks), fatigue, paresthesias, metabolic acidosis, blurred vision, myelosuppression, nephrolithiasis, etc. (Increased dietary citrate might be recommended to compensate for decreased urinary citrate observed during acetazolamide therapy.)
Monitoring Check electrolytes, BUN, creatinine, and CBC at baseline and periodically throughout therapy.
Metabolism None; excreted unchanged by kidneys

Please note that this table is for brief informational purposes only. Prescribing physicians should consult a pharmacist or an appropriate reference for complete and updated information.

bid, Twice daily; BUN, blood urea nitrogen; CBC, complete blood cell count; qid, 4 times daily.

Hyperkalemic Periodic Paralysis

Pathophysiology

HyperKPP is as an autosomal dominant disorder, with some sporadic cases. The disorder links to SCN4A, the same gene responsible for a minority of hypoKPP cases. Among several identified missense mutations, four account for about two-thirds of cases (see Fig. 64.1). Functional expression of naturally occurring mutations demonstrated a decrease in the voltage threshold of channel activation or abnormally prolonged channel opening or both (Bendahhou et al., 2002; Hayward et al., 1999), effectively increasing the depolarizing inward current. If sustained long enough, this would lead to inactivation of the sodium channels, transitory cellular inexcitability, and weakness.

Diagnosis

Despite advances in defining the underlying genetic mutations, a thorough medical and family history and physical examination remain the best diagnostic tools. Furthermore, genetic testing is not generally available, and the high number of causative sodium channel mutations makes widespread use of genetic testing unlikely in the near future. Serum potassium is normal between attacks and even during many attacks. Unlike hypoKPP, potassium administration may precipitate an attack. In the absence of provocative testing, the basis for diagnosis is the clinical presentation. Myotonia is present in many patients between attacks, either spontaneously or after muscle percussion, and failure to produce myotonia discriminates hypoKPP from hyperKPP (see Table 64.2). Take care not to confuse subjective muscle stiffness with objective changes. Peaked T waves on ECG suggest hyperkalemia and are an aid to diagnosis. As in hypoKPP, serum creatine kinase concentrations may be normal or elevated. Electrodiagnostic studies are useful for demonstrating subclinical myotonic discharges, not seen in hypoKPP. Nonspecific findings such as fibrillation potentials and small polyphasic motor unit potentials occur during late stages of disease.

A potassium-loading test provokes an attack but is not usually necessary and can be dangerous. Patients are placed on cardiac monitors following exercise and are given an oral potassium load of 1 mEq/kg (4-10 g KCl) in a fasting state. Weakness generally ensues 20 to 60 minutes later, and the accompanying rise in potassium occurs as a second peak 90 to 180 minutes after administration. Concomitant EMG shows decreasing amplitude of the compound muscle action potential.

Paramyotonia Congenita

Myotonia Congenita

Potassium-Aggravated Myotonia

Pathophysiology

PAM links to chromosome 17q, where mutations in the SCN4A gene cause the disease. This sodium channel is the same one implicated in hyperKPP, PMC, and the sodium channel subtype of hypoKPP (see earlier discussion and Fig. 64.1). Functional expression studies reveal that the disease-causing mutations lead to a large persistent sodium current secondary to an increased rate of recovery from inactivation and an increased frequency of late channel openings (Wu et al., 2001). The cause of myotonia is this enhanced inward current, which leads to prolonged depolarization and subsequent membrane hyperexcitability.

Andersen-Tawil Syndrome

Clinical

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant disorder characterized by the triad of periodic paralysis, cardiac arrhythmias, and dysmorphic features (including hypertelorism, micrognathia, low-set ears, high-arched or cleft palate, short stature, and clinodactyly) (Yoon et al., 2006a). The periodic paralysis, often triggered by rest after exercise, prolonged rest, and stress, is often the presenting symptom and can be hypo-, normo-, or hyperkalemic. The cardiac phenotype, often discovered later, includes prolonged QT intervals, but bidirectional ventricular tachycardia is common. Despite the known association of cardiac arrhythmias in rare periodic paralysis patients, ATS was only recognized as a separate entity in 1971. In families segregating an ATS allele, the phenotypic expressivity can vary greatly. Patients can manifest one, two, or three features of the triad, and the severity of any one feature can be extremely variable. Rare individuals are asymptomatic disease-gene carriers. Finally, ATS patients may exhibit neurocognitive deficits in executive function and abstract reasoning (Yoon et al., 2006b).

Pathophysiology

Mutations in the KCNJ2 gene on chromosome 17q account for approximately two-thirds of ATS probands. KCNJ2 encodes a widely expressed inwardly rectifying potassium channel (Plaster et al., 2001). Interestingly, among all identified probands, about 50% have an autosomal dominant disorder, and identification of sporadic cases with de novo mutations is common. The mechanisms of channel dysfunction are heterogeneous, including impaired phospholipid binding, pore function, or protein trafficking. Because VGKCs are tetrameric complexes, many (if not all) of the mutations are dominant negative.