Edited by: Mohamed Chahine, Laval University, Canada
Reviewed by: Stephen Cannon, University of Texas Southwestern Medical Center, USA; Theodore R Cummins, Indiana University School of Medicine, USA
*Correspondence: Saïd Bendahhou, UMR 6097, CNRS, TIANP, University of Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France. e-mail:
This article was submitted to Frontiers in Pharmacology of Ion Channels and Channelopathies, a specialty of Frontiers in Pharmacology.
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Five inherited human disorders affecting skeletal muscle contraction have been traced to mutations in the gene encoding the voltage-gated sodium channel Nav1.4. The main symptoms of these disorders are myotonia or periodic paralysis caused by changes in skeletal muscle fiber excitability. Symptoms of these disorders vary from mild or latent disease to incapacitating or even death in severe cases. As new human sodium channel mutations corresponding to disease states become discovered, the importance of understanding the role of the sodium channel in skeletal muscle function and disease state grows.
Voltage-gated sodium channels are essential in the generation and propagation of action potentials (APs) in excitable tissues such as muscle, heart, and nerve. Proper activity of these channels is crucial to the initiation of APs which ultimately lead to muscle contraction or neuronal firing. The necessity of Na+ channels is better emphasized by the existence of human inherited skeletal muscle disorders caused by mutations in the Na+ channel Nav1.4 which is specifically expressed in skeletal muscle. Mutations in the
Skeletal muscles have complex structures working in concert to provide the appropriate response to nerve impulse and metabolic processes. Specialized compartments within skeletal muscle fibers such as neuromuscular junctions, sarcolemma membrane, traverse tubules, and the sarcoplasmic reticulum (SR) provide the mechanical architecture required for the excitation–contraction coupling mechanism to take place.
At the neuromuscular junction, motoneuron activity is transferred to skeletal muscle generating an acetylcholine (ACh) dependent endplate potential. ACh is released from the nerve terminal and binds to nicotinic acetylcholine receptors (AChR). A large enough endplate potential can induce a sarcolemmal AP that propagates from the endplate to the tendon and through the transverse tubular (T-tubules) system which is mediated by the opening of the voltage-gated Nav1.4 Na+ channels. Na+ channels quickly inactivate and the depolarized potential enables the opening of delayed rectifier K+ channels which mediate outward K+ current during the repolarization stage of the muscle AP (Jurkat-Rott and Lehmann-Horn,
The contraction of the muscle occurs as a result of Ca2+ release from the SR which binds to troponin (a calcium binding protein which is part of the thin filaments necessary to produce muscle contraction) enabling filament sliding and contraction. The process, which allows Ca2+ release, is initiated by voltage changes of the AP. These changes will target in part the voltage sensor of the voltage-gated Cav1.1 Ca2+ channel (Dihydropyridine receptor or DHPR) leading to channel conformation rearrangements. The DHPR is believed to physically interact with a calcium release channel of the SR the ryanodine receptor (RYR) which releases calcium stores from the SR allowing calcium to bind to troponin (Rios et al.,
Voltage-gated sodium channels are large integral membrane proteins expressed densely at the neuromuscular junctions where they selectively conduct sodium ions into the muscle fibers in physiological conditions. The Nav1.4 channel is composed of a 260-kDa α-subunit which consists of four homologous domains (I–IV), and each domain has six transmembrane segments (S1–S6; Figure
Over 40 Nav1.4 channel mutations leading to disease states have been found throughout each domain and segment of this channel (Figure
Mutation | Location | Phenotype | References |
---|---|---|---|
I141V | IS1 | SCM | Petitprez et al. ( |
R222W | ISIV | HypoPP | Park and Kim ( |
R225W | ISIV | SCM | Lee et al. ( |
L266V | IS5 | PMC/CAM | Wu et al. ( |
Q270K | IS5 | PAM | Carle et al. ( |
V445M | IS6 | PAM | Wang et al. ( |
R669H | IIS4-1 | HypoPP | Struyk et al. ( |
R672H | IIS4-2 | HypoPP | Kuzmenkin et al. ( |
R672G | IIS4-2 | HypoPP | Kuzmenkin et al. ( |
R672S | IIS4-2 | HypoPP | Bendahhou et al. ( |
R672C | IIS4-2 | HypoPP | Kim et al. ( |
R675G | IIS4-3 | NormoPP | Vicart et al. ( |
R675Q | IIS4-3 | NormoPP | Vicart et al. ( |
R675W | IIS4-3 | NormoPP | Vicart et al. ( |
L689I | IIS4S5 | HyperPP | Bendahhou et al. ( |
I693T | IIS4S5 | HyperPP | Plassart-Schiess et al. ( |
T704M | IIS4S5 | HyperPP | Cannon and Strittmatter ( |
V781I | IIS6 | HyperPP? | Baquero et al. ( |
A799S | IIS6 | SCM/SNEL | Lion-Francois et al. ( |
S804F | IIS6 | PAM | McClatchey et al. ( |
R1132Q | IIIS4 | HypoPP | Carle et al. ( |
R1135H | IIIS4 | HypoPP | Matthews et al. ( |
A1152D | IIIS4S5 | PMC | Bouhours et al. ( |
A1156T | IIIS4S5 | PMC/HyperPP | McClatchey et al. ( |
P1158S | IIIS4S5 | HypoPP/SCM | Sugiura et al. ( |
I1160V | IIIS4S5 | PAM | Richmond et al. ( |
V1293I | IIIS6 | PMC | Green et al. ( |
N1297K | III–IV | CAM | Gay et al. ( |
G1306A | III–IV | PAM | Mitrovic et al. ( |
G1306V | III–IV | PAM | Mitrovic et al. ( |
G1306E | III–IV | PAM/PMC | Mitrovic et al. ( |
T1313M | III–IV | PMC | Yang et al. ( |
T1313A | III–IV | PMC | Bouhours et al. ( |
M1360V | IVS1 | PMC/HyperPP | Wagner et al. ( |
I1363T | IVS1 | PMC | Miller et al. ( |
M1370V | IVS1 | PMC | Okuda et al. ( |
L1433R | IVS3 | PMC | Yang et al. ( |
L1436P | IVS3 | PMC/CAM | Matthews et al. ( |
V1442E | IVS4 | CMS | Tsujino et al. ( |
R1448C | IVS4-1 | PMC | Chahine et al. ( |
R1448H | IVS4-1 | PMC | Chahine et al. ( |
R1448P | IVS4-1 | PMC | Lerche et al. ( |
R1448S | IVS4-1 | PMC | Bendahhou et al. ( |
G1456E | IVS4 | PMC | Sasaki et al. ( |
V1458F | IVS4 | PAM | Lehmann-Horn et al. ( |
F1473S | IVS4S5 | PAM | Fleischhauer et al. ( |
M1476I | IVS4S5 | SCM | Rossignol et al. ( |
A1481D | IVS4S5 | CAM | Schoser et al. ( |
I1490L/M1493I | IVS5 | HyperPP/SCM | Bendahhou et al. ( |
I1495F | IVS5 | HyperPP | Bendahhou et al. ( |
V1589M | IVS6 | PAM | Mitrovic et al. ( |
M1592V | IVS6 | HyperPP | Cannon and Strittmatter ( |
Q1633E | C-term | PAM | Kubota et al. ( |
E1702K | C-term | PMC | Miller et al. ( |
F1705I | C-term | PMC | Wu et al. ( |
A common feature of myotonia is delayed relaxation of the muscle after voluntary contraction or mechanical stimulation, electrophysiologically characterized by highly organized repetitive electrical activity of the muscle fibers. Non-dystrophic myotonias can be caused by mutations in the Nav1.4 sodium channel which increases its function or the ClC-1 chloride channel decreasing channel function (Trip et al.,
Potassium-aggravated myotonia includes atypical myotonia congenita, moderate myotonia, myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia, and painful myotonia which have overlapping clinical features. The prevalence of PAM is estimated at ∼1:400,000 (Lehmann-Horn et al.,
Potassium-aggravated myotonia is exacerbated by potassium ingestion (but not cold temperatures) because increased K+ ingestion causes cellular depolarization (George,
Eight Nav1.4 mutations causing PAM have been found in humans: V445M, S804F, I1160V, G1306A/V/E, V1458F, F1473S, and V1589M (McClatchey et al.,
Nav1.4 channel kinetics are altered by these mutations in such a way that the channel open probability is increased thus channel activity is up-regulated. With some of these PAM mutations, the rate of fast inactivation is slowed which allows the channels to stay open for a prolonged amount of time. However, the rate of recovery from inactivation is not found to be increased but deactivation is found to be slow for most of these PAM mutations. Most of these mutations have been reported to increase the size of the persistent Na+ current two to fourfold. The increase in this inward Na+ current generates after-depolarizations across the T-tubules and decreases the threshold required for AP generation consequently triggering repetitive AP and muscle contraction (Adrian and Marshall,
Paramyotonia congenita is different from PAM in that muscle stiffness is usually followed by flaccid weakness or paralysis (Lehmann-Horn et al.,
Sixteen mutations of the Nav1.4 channel have been found to cause PMC in humans: L266V, A1152D, A1156T, V1293I, G1306E, T1313M/A, M1360V, M1370V, L1433R, R1448C/H/P/S, G1456E, and F1705I (McClatchey et al.,
Functional expression revealed that in most cases, PMC mutations cause a decreased rate of channel inactivation and increased rate of recovery from inactivation and other mutations cause channel deactivation to be slowed (Chahine et al.,
Recently a novel Nav1.4 myotonia mutation was identified causing severe neonatal episodic laryngospasm (SNEL) found to be lethal in newborns (Lion-Francois et al.,
Na+ channel mutations have already been described in neonates (Tsujino et al.,
Periodic paralysis can be caused by mutations of the Nav1.4 sodium channel which decrease its function, the L-type calcium channel (DHPR), and the inwardly rectifying Kir2.1 channel by inhibiting its function in Andersen’s syndrome. In some cases of periodic paralysis, serum potassium levels are affected causing HyperPP, HypoPP, or normokalemic (where K+ levels remain normal) thus periodic paralysis is defined in terms of serum K+ levels.
Hyperkalemic periodic paralysis has been found in patients with sodium channel mutations that cause attacks of flaccid limb paralysis or weakness of the eye or throat muscles. HyperPP patients present with increased serum K+ levels during the episodes of weakness. The triggers of HyperPP include K+ ingestion, rest after exercise as well as cold temperatures, emotional stress, and fasting. HyperPP and PMC have overlapping symptoms because between episodes of periodic paralysis, HyperPP patients can experience a mild form of myotonia, which may be more pronounced before a paralytic attack. Also patients (which do not experience mild myotonia episodes between paralytic attacks) may be more prone to develop chronic progressive myopathy during midlife when paralytic attacks become more rare. Patients are usually diagnosed in the first decade of life and paralysis attacks increase in frequency and severity during puberty but begin to decrease after approximately 40 years of age. However, older individuals may develop permanent weakness related to the frequency and severity of prior attacks (Bradley et al.,
Several Nav1.4 mutations lead to HyperPP including L689I, I693T, T704M, A1156T, M1360V, I1490L, M1493I, I1495F, and M1592V (McClatchey et al.,
Hypokalemic periodic paralysis can be caused by mutations of the Nav1.4 channel or the skeletal muscle calcium channel Cav1.1, or the inward rectifier potassium channel Kir2.1. HypoPP caused by Ca2+ channel mutations is referred to as HypoPP1 while HypoPP caused by Na+ channel mutations is referred to as HypoPP2 (Jurkat-Rott et al.,
A number of Nav1.4 mutations resulting in HypoPP2 have been found including in humans: R222W, R669H, R672H/G/S, R1129Q, R1132Q, R1135H, and P1158S (Struyk et al.,
Recent studies propose that the depolarization seen with some HypoPP mutations can be due to a cationic leak through the voltage sensor created by the mutations called the gating pore current (channel up-regulation) which may cause a cellular pH imbalance due to proton movement into the fibers (Kuzmenkin et al.,
Myasthenic syndrome (CMS) is a disorder with defective transmission of neuromuscular excitation resulting in muscle fatigue from defects in presynaptic, synaptic, or postsynaptic proteins (Engel et al.,
In this case, a Nav1.4 channel mutation (V1442E) was found located at the extracellular linker between segments S3 and S4 of domain IV (Tsujino et al.,
Treatment for myotonia is focused on reducing the involuntary AP bursts without blocking the voluntary high-frequency muscle stimulation. Although, it is important that PAM and PMC patients modify their lifestyle to avoid the triggers of their diseases such as potassium ingestion or cold temperatures, drug therapies are commonly used to relieve and prevent muscle stiffness (Table
Disorders | Therapies |
---|---|
PMC | Anticonvulsants (phenytoin and carbamazepine) |
Anti-arrhythmics of the class IB (mexiletine and tocainide) | |
Anti-arrhythmics class IC (flecainide and propafenone) | |
Local anesthetics (acetazolamide and hydrochlorothiazide) | |
PAM | Anticonvulsants (phenytoin and carbamazepine) |
Anti-arrhythmics of the class IB (mexiletine and tocainide) | |
Anti-arrhythmics class IC (flecainide and propafenone) | |
Local anesthetics | |
HyperPP | β-adrenergic agonists such as (salbutamol used as an inhalant) |
Glucose/insulin therapy | |
Diuretic carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide and thiazides) | |
HypoPP | Oral potassium |
Acetazolamide or dichlorphenamide, triamterene, aldosterone antagonists | |
Potassium-sparing diuretics |
For PMC and PAM patients, anticonvulsants (phenytoin and carbamazepine), anti-arrhythmics of the class IB (mexiletine and tocainide), class IC (flecainide and propafenone), and local anesthetics have been shown to have some efficacy relieving stiffness in PAM and preventing stiffness and weakness from occurring in PMC (Trip et al.,
Since PMC patients present with severe myotonia that overshadows their attacks of weakness most of these patients rarely require medications for weakness. However, sometimes diuretic carbonic anhydrase inhibitor medications such as acetazolamide and hydrochlorothiazide can be given to reduce serum K+ levels or lower the pH and decrease the frequency and severity of paralytic events (Rudel et al.,
Patients with HyperPP often find that reducing their carbohydrate intake and avoiding strenuous exercise and cold improves their condition. Other treatments include β-adrenergic agonists such as salbutamol used as an inhalant on patients without cardiac arrhythmia or glucose/insulin therapy (Hanna et al.,
Treatment of HypoPP is better achieved by administrating oral potassium and by avoidance of carbohydrates and sodium in the diet. Increasing K+ levels usually helps to reduce the paradoxical membrane depolarization and shifts the resting potential to more normal hyperpolarized voltages. Administration of acetazolamide or dichlorphenamide has also proven to be useful, however in some cases these agents can exacerbate symptoms and triamterene (kidney sodium channel blocker used as a potassium-sparing diuretic) is used instead (Torres et al.,
Skeletal muscle sodium channel disorders show significant intra and interfamilial phenotypical variability as well as variability in the functional electrophysiological properties of the Nav1.4 channel. It remains difficult to properly identify, classify, and treat myotonia and periodic paralysis patients due to an insufficient understanding of the mechanism by which these mutations bring about such variable phenotypes. Nav1.4 channel gating defects to produce gain-of-function which slows the rate of inactivation and or deactivation typically cause myotonia while Nav1.4 mutations that negatively shift the voltage dependence of activation typically cause HyperPP. Mutations that down-regulate Nav1.4 channel function by enhancing slow inactivation or the newly suggested mechanism of increased gating pore currents which depolarize muscle fibers in the presence of low extracellular K+ concentrations result in HypoPP. If gating pore currents do indeed underlie the abnormal depolarization associated with HypoPP, the “gating pore” may represent a novel therapeutic target for treating these patients. Nevertheless, functional studies may not lead to a full understanding of these diseases and careful analysis of clinical phenotypes, clinical trials, and genetic screening are clearly still lacking and needed. Understanding these different factors which underlie skeletal muscle sodium channel disorders may help to improve and develop new strategies of therapeutic treatment for these patients as well as treatments of related disorders of excitability.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the CentreNational de la RechercheScientifique (CNRS), Association Française contre les Myopathies (AFM) grant (Saïd Bendahhou), AFM and Châteaubriand fellowships to Dina Simkin.