Skeletal Muscle Sodium Channel Research Articles

Familial Normokalemic Periodic Paralysis Associated With Mutation in the SCN4A p.M1592V

Periodic paralysis (PP) is an uncommon inherited disorder causing recurrent episodes of muscle weakness, with an incidence of 0.001%. Normokalemic periodic paralysis (NormoKPP) as the rarest subtype of PP contains both familial and sporadic. Familial NormoKPP caused by the p.M1592V mutation of the skeletal muscle sodium channel alpha subunit (SCN4A) gene is rarely reported. Only three pedigrees of NormoKPP related to mutations in the SCN4A p.M1592V have been previously reported. We herein presented a family case of NormoKPP associated with the SCN4A p.M1592V mutation, in which respiratory muscle paralysis occurred in the proband while not in his children. Moreover, we conducted a thorough literature review. To our knowledge, this is the first report of respiratory muscle paralysis as a symptom of NormoKPP associated with mutation in the SCN4A p.M1592V.

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential.

Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.

PH Modulation of Voltage-Gated Sodium Channels.

Changes in blood and tissue pH accompany physiological and pathophysiological conditions including exercise, cardiac ischemia, ischemic stroke, and cocaine ingestion. These conditions are known to trigger the symptoms of electrical diseases in patients carrying sodium channel mutations. Protons cause a diverse set of changes to sodium channel gating, which generally lead to decreases in the amplitude of the transient sodium current and increases in the fraction of non-inactivating channels that pass persistent currents. These effects are shared with disease-causing mutants in neuronal, skeletal muscle, and cardiac tissue and may be compounded in mutants that impart greater proton sensitivity to sodium channels, suggesting a role of protons in triggering acute symptoms of electrical disease.In this chapter, we review the mechanisms of proton block of the sodium channel pore and a suggested mode of action by which protons alter channel gating. We discuss the available data on isoform specificity of proton effects and tissue level effects. Finally, we review the role that protons play in disease and our own recent studies on proton-sensitizing mutants in cardiac and skeletal muscle sodium channels.

Review of the Diagnosis and Treatment of Periodic Paralysis.

ABSTRACTPeriodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen‐Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522–530, 2018

Current state of the art for cardiac arrhythmia gene therapy.

Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential. Atrial fibrillation has been prevented by gene transfer of either a dominant negative mutant of a repolarizing potassium channel, a gap junction, or an siRNA directed against caspase 3. Inherited arrhythmia syndromes have been corrected by replacement of the causative genes. Post-infarct ventricular tachycardia has been reduced by gene therapy with the skeletal muscle sodium channel and connexins and eliminated with the dominant negative mutant of the potassium channel responsible for resting membrane potential. These ideas show considerable promise. Long-term efficacy and safety studies are required to see if they can become viable therapies.

Classification of Involuntary Movements in Dogs: Myoclonus and Myotonia

Myoclonus is a sudden brief, involuntary muscle jerk. Of all the movement disorders, myoclonus is the most difficult to encapsulate into any simple framework. On the one hand, a classification system is required that is clinically useful to aid in guiding diagnosis and treatment. On the other hand, there is need for a system that organizes current knowledge regarding biological mechanisms to guide scientific research. These 2 needs are distinct, making it challenging to develop a robust classification system suitable for all purposes. We attempt to classify myoclonus as “epileptic” and “nonepileptic” based on its association with epileptic seizures. Myotonia in people may be divided into 2 clinically and molecularly defined forms: (1) nondystrophic myotonias and (2) myotonic dystrophies. The former are a group of skeletal muscle channelopathies characterized by delayed skeletal muscle relaxation. Many distinct clinical phenotypes are recognized in people, the majority relating to mutations in skeletal muscle voltage‐gated chloride (CLCN1) and sodium channel (SCN4A) genes. In dogs, myotonia is associated with mutations in CLCN1. The myotonic dystrophies are considered a multisystem clinical syndrome in people encompassing 2 clinically and molecularly defined forms designated myotonic dystrophy types 1 and 2. No mutation has been linked to veterinary muscular dystrophies. We detail veterinary examples of myotonia and attempt classification according to guidelines used in humans. This more precise categorization of myoclonus and myotonia aims to promote the search for molecular markers contributing to the phenotypic spectrum of disease. Our work aimed to assist recognition for these 2 enigmatic conditions.

Convergent adaptation to dangerous prey proceeds through the same first-step mutation in the garter snake Thamnophis sirtalis.

Convergent phenotypes often result from similar underlying genetics, but recent work suggests convergence may also occur in the historical order of substitutions en route to an adaptive outcome. We characterized convergence in the mutational steps to two independent outcomes of tetrodotoxin (TTX) resistance in separate geographic lineages of the common garter snake (Thamnophis sirtalis) that coevolved with toxic newts. Resistance is largely conferred by amino acid changes in the skeletal muscle sodium channel (NaV 1.4) that interfere with TTX-binding. We sampled variation in NaV 1.4 throughout western North America and found clear evidence that TTX-resistant changes in both lineages began with the same isoleucine-valine mutation (I1561V) within the outer pore of NaV 1.4. Other point mutations in the pore, shown to confer much greater resistance, accumulate later in the evolutionary progression and always occur together with the initial I1561V change. A gene tree of NaV 1.4 suggests the I1561V mutations in each lineage are not identical-by-decent, but rather they arose independently. Convergence in the evolution of channel resistance is likely the result of shared biases in the two lineages of T. sirtalis-only a few mutational routes can confer TTX resistance while maintaining the conserved function of voltage-gated sodium channels.

The anti-convulsants lacosamide, lamotrigine, and rufinamide reduce myotonia in isolated human and rat skeletal muscle.

In myotonia congenita, loss of ClC-1 Cl- channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage-gated sodium channel in skeletal muscle (Nav1.4). In this study we explored whether 3 sodium channel-modulating anti-epileptics can reduce myotonia in isolated rat and human muscle. Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from subclinical to maximal clinical concentrations. Drug synergy was determined using isobole plots. All drugs were capable of abolishing myotonia in both rat and human muscles. Lamotrigine and rufinamide completely suppressed myotonia at submaximal clinical concentrations, whereas lacosamide had to be raised above the maximal clinical concentration to suppress myotonia completely. A synergistic effect of lamotrigine and rufinamide was observed. These findings suggest that lamotrigine and rufinamide could be considered for anti-myotonic treatment in myotonia congenita. Muscle Nerve 56: 136-142, 2017.

Investigating Ca2+-Dependent Regulation of Sodium Channels via Thermodynamic and Structural Analysis of Nav1.4 and Nav1.5 Carboxy Tail Interactions with Calmodulin

Voltage-gated sodium channels (Nav) are essential for cardiac and skeletal muscle function. Channelopathic mutations in cardiac sodium channel (Nav1.5) and skeletal muscle sodium channel (Nav1.4), particularly in their cytoplasmic carboxy tails (CTNav), give rise to numerous arrhythmias and myotonias. In Nav regulation, CTNav partners with the Ca2+-sensing protein calmodulin (CaM). We aim to understand how CaM regulates channel function. Ca2+-free CaM (apoCaM) is a regulatory modulator of Nav, and apoCaM bound to the CTNav increases the channel's open probability. CaM also participates in the Ca2+-dependent inactivation (CDI) of Nav1.4. In contrast, Nav1.5 does not show CDI and no role of Ca2+-CaM is known in Nav1.5. To understand the Ca2+-control of CaM regulation of these sodium channels we have collected binding data of CTNavs with CaM, in the presence and absence of Ca2+. Binding data of CTNavs with CaM mutants with Ca2+-binding knocked out in either of CaM's functional domains (lobes) have also been collected to understand the distinct roles of CaM's lobes. Collectively, these binding data have allowed us to predict CTNav and CaM populations as a function of Ca2+ concentration. To gain information on the structural changes induced by Ca2+ on the CTNav-CaM complexes, we conducted small angle scattering (SAXS) experiments on CTNav1.4-CaM and CTNav1.5-CaM in the presence and absence of Ca2+. The distance distribution function, P(r), shows changes in both complexes upon addition of Ca2+. Computational modeling of flexible forms of the complexes reveals conformations of CTNav-CaM, in the presence and absence of Ca2+, that are compatible with our SAXS data. The molecular envelope of the CTNav1.5-apoCaM matches well with the apoCaM-CTNav1.5 crystal structure previously determined by our lab.

Role for Fast Inactivation in Domain I of Voltage Gated Sodium Channels

In sodium channels, the voltage sensing S4 segments move outward in response to membrane depolarization to promote activation and fast inactivation of the channel. Domain-specific roles for S4 segments include activation and fast inactivation. In the present work we investigated the role of domain I in activation, deactivation and fast inactivation of the skeletal muscle sodium channel hNaV1.4. Charge reversal at R1 (R219D) produced a significant hyperpolarizing shift of the activation curve, an effect confirmed in an inactivation deficient background (R219D/QQQ) and with gating currents. Charge reversal at residues lower in the S4 segment (R225D, K228D) produced a depolarizing shift of the activation curve. R219D selectively enhanced fast inactivation from closed states (hyperpolarizing shift of the steady-state fast inactivation curve, and accelerated kinetics of closed-state fast inactivation. Fast inactivation from the open state was not affected by R219D. Lesser effects on closed-state fast inactivation were observed for charge reversal at DIS4 residues lower in that voltage sensor. Charge reversal at inner negative countercharges (E171R, S2; D197R, S3) also produced a hyperpolarizing shift of the steady-state fast inactivation curve and accelerated kinetics of closed-state fast inactivation. These results suggest that in the wild type NaV1.4 channel, interactions of inner negative charges with the outer charge in DIS4 restrict outward movement of that voltage sensor in response to weak depolarization, and limit fast inactivation elicited from closed states. This work was supported by NIH 1R15NS093579-01A1 to JRG and NIH P20GM103408 to ISU.

The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of NaV1.4.

μ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of NaV1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against NaV1.4 was assayed by whole cell patch-clamp on rNaV1.4, heterologously expressed in HEK293 cells. The corresponding IC50 values were 0.069 ± 0.005 μM for GIIIA, 2.1 ± 0.3 μM for GIIIA-1, 3.3 ± 0.2 μM for GIIIA-2, and 15.8 ± 0.8 μM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3–Cys15, Cys4–Cys20 and Cys10–Cys21, respectively). Other analogues were not active enough for IC50 measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of NaV1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10–Cys21 is the most important for the NaV1.4 potency.

A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype

In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T-tubular swelling and mitochondrial stress. A possible contribution of the loss-of-function features towards myotonia and myopathy is discussed.

A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes

Non-dystrophic myotonias are caused by mutations of either the skeletal muscle chloride (CLCN1) or sodium channel (SCN4A) gene. They exhibit several distinct phenotypes, including myotonia congenita, paramyotonia congenita and sodium channel myotonia, and a genotype-phenotype correlation has been established. However, there are atypical cases that do not fit with the standard classification. We report a case of 27-year-old male who had non-dystrophic myotonia with periodic paralysis and two heterozygous mutations, E950K in CLCN1 and F1290L in SCN4A. His mother, who exhibited myotonia without paralytic attack, only harbored E950K, and no mutations were identified in his asymptomatic father. Therefore, the E950K mutation was presumed to be pathogenic, although it was reported as an extremely rare genetic variant. The proband experienced paralytic attacks that lasted for weeks and were less likely to be caused by CLCN1 mutation alone. Functional analysis of the F1290L mutant channel heterologously expressed in cultured cells revealed enhanced activation inducing membrane hyperexcitability. We therefore propose that the two mutations had additive effects on membrane excitability that resulted in more prominent myotonia in the proband. Our case stresses the value of performing genetic analysis of both CLCN1 and SCN4A genes for myotonic patients with an atypical phenotype.

Recent advances in congenital myasthenic syndromes

AbstractCongenital myasthenic syndromes (CMS) are heterogeneous disorders caused by germline mutations in genes expressed at the neuromuscular junction. Mutations have been identified in 24 genes encoding acetylcholine receptor subunits (CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG), skeletal muscle sodium channel (SCN4A), signaling molecules driving acetylcholine receptor subunits clustering (AGRN, LRP4, MUSK and DOK7), synaptic structural proteins (COLQ, LAMB2 and COL13A1), postsynaptic structural proteins (RAPSN and PLEC), presynaptic molecules (CHAT, SYT2), glycosylation enzymes (GFPT1, DPAGT1, ALG2, ALG14 and GMPPB), and other less characterized molecules (PREPL and SCL25A1). CMS are recessive disorders, except for slow channel CMS and synaptotagmin 2 (SYT2)‐CMS. Onsets are largely less than 2 years, but adult‐onset is not rare, especially in slow‐channel CMS and limb‐girdle type CMS caused by glycosylation defects and by DOK7 mutations. Clinical features include fatigable muscle weakness, amyotrophy and minor facial anomalies. Eye, facial and bulbar muscles are frequently affected, but sparing of these muscles is observed, especially in limb‐girdle type CMS. Serum creatine kinase levels are frequently elevated in slow‐channel CMS, glutamine‐fructose‐6‐phosphate aminotransferase 1 (GFPT1)‐CMS, and guanosine diphosphate mannose pyrophosphorylase B (GMPPB)‐CMS. Electrophysiological findings supporting compromised neuromuscular signal transmission are a prerequisite for diagnosing CMS. Most CMS patients are likely to be underdiagnosed, and recognition of CMS in undiagnosed muscle weakness and/or amyotrophy is critical for diagnosing CMS.

Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis.

Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na(+) current density to support sustained high-frequency action potentials in muscle.

Point-Mutations in Skeletal Muscle Voltage-Gated Sodium Channels Confer Resistance to Tetrodotoxin: But at a Cost?

The interaction between toxic newts (Taricha) and several resistant garter snakes (Thamnophis) provides a model system for the study of predator-prey coevolution (Brodie & Brodie 1999). Pacific newts secrete through their skin the potent neurotoxin, tetrodotoxin (TTX, Fuhrman et al., 1964), a compound that specifically binds to the outer pore of voltage-gated sodium channels (NaV proteins, Fozzard et al., 1994). TTX-ligation prevents sodium ion movement across the membrane and therefore abolishes excitability in skeletal muscle and peripheral nerves (Hille, 2001). Three species of garter snake that prey on sympatric newts have adapted to these toxic newts by circumventing the block through several independently evolved mutations within the pore loop of the skeletal muscle channel variant, NaV1.4 (Feldman et al., 2012). These mutations reduce the affinity of TTX to the pore and provide physiological resistance (Feldman et al., 2009). However, these same mutations are also expected to alter the biophysical properties of the channel, in particular the permeation and selectivity (Hille, 2001). We show that animals with greater TTX resistance displayed diminished skeletal muscle performance (phasic and tetanic contractions). We are currently testing the hypothesis that changes in skeletal muscle sodium channel current density, activation, inactivation, and recovery could potentially explain the tissue-level findings.

Probing Voltage-Dependent Structural Changes of the VSD in Mammalian Nav with LRET

Voltage-gated sodium channels (Nav) play an essential role in the generation and propagation of action potentials. Mammalian Nav alpha subunits are large single polypeptide chains organized in four different domains (DI-DIV). Each domain is composed of 6 transmembrane segments (S1-S6) in which S1-S4 constitute the voltage sensing domain (VSD) and S5 and S6 form the pore. Although Nav function has been studied comprehensively, the precise structural basis for the gating mechanisms has not been fully elucidated. Recently, the crystal structures of several prokaryotic sodium channels have been solved, but they are homo-tetrameric proteins in contrast to the mammalian Navs and these studies only provide a single snapshot of the channels in one of many possible conformational states. Therefore, techniques that provide dynamic structural information are needed. In this work we have used Lanthanide-based resonance energy transfer (LRET) to obtain structural information and conformational dynamics of the VSD from each domain of the rat skeletal muscle sodium channel (Nav1.4). We prepared Nav1.4 constructs with a genetically encoded lanthanide binding tag (LBT), which binds a lanthanide (Tb3+) ion with high affinity, inserted in several strategic places at the top of the S4 segment in each domain. Two new conotoxin analogs were synthesized to function as LRET acceptors: KIIIA-Bodipy and GIIIA-Bodipy. We calculated multiple distances from each one of the domains to the pore region where the labeled toxin binds in both resting and slow inactivated states in voltage-clamped Xenopus laevis oocytes expressing our Nav1.4 constructs, which remained functionally active. The results give a geometrical map of the S4 positions of each domain in the mammalian Nav channels and provide evidence for voltage-dependent structural changes. Support: 13POST14800031 (AHA), MOP-10053 (CIHR), GM68044-07, U54GM087519 and GM030376.

Is there more than one way to skin a newt? Convergent toxin resistance in snakes is not due to a common genetic mechanism.

Convergent evolution of tetrodotoxin (TTX) resistance, at both the phenotypic and genetic levels, characterizes coevolutionary arms races between amphibians and their snake predators around the world, and reveals remarkable predictability in the process of adaptation. Here we examine the repeatability of the evolution of TTX resistance in an undescribed predator-prey relationship between TTX-bearing Eastern Newts (Notophthalmus viridescens) and Eastern Hog-nosed Snakes (Heterodon platirhinos). We found that that local newts contain levels of TTX dangerous enough to dissuade most predators, and that Eastern Hog-nosed Snakes within newt range are highly resistant to TTX. In fact, these populations of Eastern Hog-nosed Snakes are so resistant to TTX that the potential for current reciprocal selection might be limited. Unlike all other cases of TTX resistance in vertebrates, H. platirhinos lacks the adaptive amino acid substitutions in the skeletal muscle sodium channel that reduce TTX binding, suggesting that physiological resistance in Eastern Hog-nosed Snakes is conferred by an alternate genetic mechanism. Thus, phenotypic convergence in this case is not due to parallel molecular evolution, indicating that there may be more than one way for this adaptation to arise, even among closely related species.

Episodic weakness and vacuolar myopathy in hypokalemic periodic paralysis

We report a 50-year-old woman who presented with a 20year history of gradually progressive lower extremity weakness, characterized by knee buckling with occasional falls and foot dragging. She also experienced difficulty in lifting her arms above her shoulders. The primary periodic paralyses are rare disorders caused by dysfunctional ion channels in skeletal muscle. The hypokalemic type is generally an autosomal dominant condition, due to missense mutations in the alpha subunits of the skeletal muscle L-type calcium channel genes, CACN1AS, or the skeletal muscle sodium channel gene, SCN4A. The affected patients typically present with episodic weakness. For our patient, the consumption of foods high in carbohydrates seemed to precipitate the episodes of weakness. Her family history was significant for six blood relatives, including three sons and three relatives on the paternal side, who had experienced similar symptoms. A biopsy of the left rectus femoralis muscle showed vacuolar myopathic changes in the scattered muscle fibers, accompanied by occasional degenerating and regenerating muscle fibers. There was no evidence of inflammation on the biopsy. The vacuoles were often associated with increased acid phosphatase staining. An electron microscopic examination showed that the vacuolar changes were due to T-tubule dilation, a characteristic of hypokalemic periodic paralysis. Other metabolic etiologies of vacuolar myopathy, such as acid phosphatase (lysosomal) associated acid maltase deficiency (a glycogen storage disease), need to be considered in the differential diagnosis.

Painful cramps and giant myotonic discharges in a family with the Nav1.4‐G1306A mutation

Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. A G1306A mutation in the Nav1.4 voltage-gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium-aggravated myotonia than myotonia fluctuans.