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Perturbations to body temperature affect almost all cellular processes and, within certain limits, results in minimal effects on overall physiology. Genetic mutations to ion channels, or channelopathies, can shift the fine homeostatic balance resulting in a decreased threshold to temperature induced disturbances. This review summarizes the functional consequences of currently identified voltage-gated sodium (NaV) channelopathies that lead to disorders with a temperature sensitive phenotype. A comprehensive knowledge of the relationships between genotype and environment is not only important for understanding the etiology of disease, but also for developing safe and effective treatment paradigms.

Paralysis periodica paramyotonia (PPP) is caused by mutation of the adult skeletal muscle sodium channel gene's alpha (α)-subunit (SCN4A). Here, we report four generations of a Chinese family affected by a remarkably severe form of PPP with progressive myopathy. Routine electromyograms (EMG) showed myotonic discharge and after a long exercise test, compound motor action potential amplitudes were markedly decreased by 40-55%. Muscle biopsy revealed obvious vacuolar changes. Moreover, genetic analysis revealed the Met1592Val mutation in the α-subunit, SCN4A. The patients showed a striking clinical and electrophysiological improvement during treatment with acetazolamide. Thus, our findings showed that mutation of Met1592Val in the SCN4A gene is associated with aggressive development of PPP characterized by severe vacuolar myopathy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Five hereditary sodium channelopathies of skeletal muscle have been identified. Prominent symptoms are either myotonia or weakness caused by an increase or decrease of muscle fiber excitability. The voltage-gated sodium channel NaV1.4, initiator of the muscle action potential, is mutated in all five disorders. Pathogenetically, both loss and gain of function mutations have been described, the latter being the more frequent mechanism and involving not just the ion-conducting pore, but aberrant pores as well. The type of channel malfunction is decisive for therapy which consists either of exerting a direct effect on the sodium channel, i.e., by blocking the pore, or of restoring skeletal muscle membrane potential to reduce the fraction of inactivated channels.

Paramyotonia congenita (PC), first described in 1886 by Eulenberg, is characterized by cold and exercise-induced muscle stiffness and intermittent flaccid paresis not necessarily related to cold or myotonia. Several authors segregated a pure form of PC, which has no periodic paralysis, even after cold exposure. The existence of this phenotype has been debated in the literature. We describe electrophysiological and molecular genetic features of a patient with PC who had no history of periodic paralysis. Immersion in cold water or potassium load could not induce clinical paralysis. However, repetitive nerve stimulation and exercise test demonstrated a drop in compound muscle action potential amplitude. Genetic analysis revealed the substitution of valine for glycine on the human skeletal muscle sodium channel (SCN4A) gene. The G1306V mutation is rare in the classic form of PC, and moreover might be the first in pure paramyotonia.

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF-hand calcium-binding motif in the intracellular C-terminus. A functional analysis of the mutant channel using the voltage-clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C-terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666-673, 2009.

A 32-year-old woman with a 4-year history of multiple sclerosis presented with persistent clawing of the right hand. History revealed that she and five family members had lifelong symptoms of paradoxical myotonia (impaired relaxation of muscles following muscle contraction), exacerbated by cold. The family was diagnosed with paramyotonia congenita, based on neurophysiological and genetic studies. To our knowledge, this is the first report of an Australian family with paramyotonia congenita.

Background: Missense mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. The mechanistic basis for the phenotypic variability of these allelic disorders of muscle excitability remains unknown. An atypical phenotype with cold-induced hypokalemic paralysis and myotonia at warm temperatures was reported to segregate with the P1158S mutation., Objective: This study extends the functional characterization of the P1158S mutation and tests the specific hypothesis that impairment of Na channel slow inactivation is a common feature of periodic paralysis., Methods: Mutant NaV1.4 channels (P1158S) were transiently expressed in human embryonic kidney cells and characterized by voltage-clamp studies of Na currents., Results: Wild-type and P1158S channels displayed comparable behavior at 37 degrees C, but upon cooling to 25 degrees C, mutant channels activated at more negative potentials and slow inactivation was destabilized., Conclusions: Consistent with other NaV1.4 mutations associated with a paralytic phenotype, the P1158S mutation disrupts slow inactivation. The unique temperature sensitivity of the channel defect may contribute to the unusual clinical phenotype.

In this study we investigated a family with paramyotonia (PC) congenita caused by a Gly1306Val mutation in the voltage-gated sodium-channel gene SCN4A. A previous study showed that exposure to cold aggravates the muscle stiffness in patients with this mutation. However, the mechanism behind cold sensitivity and the sodium-channel defect remained unclear. In order to gain a better understanding of sarcolemmal propagation in these patients, we measured muscle-fiber conduction velocity (MFCV) invasively. We studied four PC patients and four healthy subjects at room temperature. After the muscle was cooled, MFCV was measured again in the two PC patients and four control subjects. MFCV was significantly lower in the PC patients at room temperature, compatible with dysfunctional sodium channels. After cooling, MFCV was significantly lower in both groups as compared with room temperature. The relative slowing was 1.4% per degrees C for PC patients and 1.5% per degrees C for healthy subjects. These results indicate that, in these PC patients, mutant and wild-type sodium channels respond equally to cold exposure. Thus, MFCV is abnormal in these patients, but the aggravation of muscle stiffness cannot be explained by an abnormal sarcolemmal response to cold.

Objective: To study the clinical and genetic features in a large cohort of UK patients with sodium channel paramyotonia congenita., Methods: We conducted a UK-wide clinical and molecular genetic study of patients presenting with a phenotype suggestive of paramyotonia congenita., Results: We identified 42 affected individuals (28 kindreds). All cases met our core criteria for a clinical diagnosis of paramyotonia congenita. Seventy-five percent of patients (32 patients/20 kindreds) had SCN4A mutations. Twenty-nine subjects from 18 kindreds had exon 22 and 24 mutations, confirming these exons to be hot spots. Unexpectedly, 3 of these subjects harbored mutations previously described with potassium-aggravated myotonia (G1306A, G1306E). We identified two new mutations (R1448L and L1436P). Ten cases (8 kindreds) without mutations exhibited paramyotonia congenita with prominent pain and weakness., Conclusions: This study identifies two new mutations, confirms SCN4A as a common cause of paramyotonia congenita in the UK, and suggests further allelic and possibly genetic heterogeneity.

We performed anesthesia for a subtotal gastrectomy in a 70-year-old female patient with paramyotonia congenita (PC). She had been diagnosed with PC at the age of 47 years by electromyogram analysis. Several points to consider have been revealed regarding the management of anesthesia in patients with PC. In this patient, anesthesia was safely maintained using sevoflurane and nitrous oxide together with concomitant epidural anesthesia using mepivacaine. Efforts should be made to prevent perioperative attacks of muscle weakness when planning anesthesia for patients with this kind of disorder. Specifically, refraining from the use of muscle relaxants, care with regard to the composition of infusion fluids during operations, and the maintenance of body temperature are required for anesthesia. In addition, postoperative pain management using a continuous epidural block proved to be a useful method.

We report a phenotype associated with the Val1589Met substitution in SCN4A gene in a French family which would be better classified as paramyotonia congenita. The proband was a 48-year-old woman, who described muscle stiffness and occasional flaccid weakness, both symptoms being induced by exercise, cold and heat. Severe muscle stiffness affected facial, oropharyngeal and limb muscles leading to transient paralysis of these muscles. One sister, two nephews and the son of the proband had similar symptoms. Molecular analysis of the muscle sodium channel gene (SCN4A) by nucleotide sequencing revealed a G-to-A transition of cDNA nucleotide at position 4765 predicting a substitution of methionine for valine at position 1589. This shows that the Val1589Met mutation in the SCN4 gene may cause different phenotypes, either potassium-aggravated myotonia or paramyotonia congenita. Familial or individual factors other than the missense mutation per se influence the expression of the disease in sodium channel disorders.

The biophysical origins of paramyotonia congenita and its exacerbation in cold temperatures were examined. Human skeletal muscle voltage-gated sodium channels were expressed in Xenopus oocytes and macroscopic currents were recorded from cell-attached patches. Wild-type (hNaV1.4) channels were compared to two mutant channel isoforms, T1313M and R1448C. The voltage dependence and temperature sensitivity of activation, fast-inactivation onset and recovery, and deactivation were studied. Although activation and the onset of fast-inactivation were temperature sensitive in all three isoforms, and although these properties in mutant channels differed from those in wild-type channels, they did not account for cold-exacerbation. Deactivation, however, was disproportionately slower in R1448C, but not in T1313M, than in hNaV1.4. These defects may, at least in part, account for the clinical symptoms of paramyotonia congenita and its exacerbation by cold, and provide a basis for studies into the therapeutic alleviation of these symptoms., (Copyright 2004 Wiley Periodicals, Inc.)

Missense mutations of the human skeletal muscle voltage-gated Na+ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with subsequent paralysis. The mutation M1360V causes an overlapping syndrome with both K+-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na+ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at the R1448H mutation, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at the M1360V mutation or in the WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain the stronger cold-induced clinical symptoms resulting from the R1448H mutation in contrast to the M1360V mutation.

Paramyotonia congenita (PC) is linked to mutations of the skeletal muscle voltage-gated sodium channel alpha-subunit gene SCN4A. The authors report a family where the proband and three of her four children have PC (mutation R1448C) and present repolarization abnormalities at electrocardiogram. They demonstrate that the SCN4A alpha-subunit gene is expressed in normal human heart. Cardiac consequences of mutations of the SCN4A gene may be insignificant in standard conditions, but critical if patients with PC are treated with drugs inducing QT prolongation.

Background: Myotonia and periodic paralysis caused by sodium channel mutations show variable responses to the anti-myotonic drug mexiletine., Objective: To investigate whether variability among sodium channel mutants results from differences in drug binding affinity or in channel gating., Methods: Whole-cell sodium currents (I(Na)) were recorded in tsA201 cells expressing human wild-type (WT) and mutant skeletal muscle sodium channels (A1156T, hyperkalemic periodic paralysis; R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia)., Results: At a holding potential (hp) of -120 mV, mexiletine produced a tonic (TB, 0.33 Hz) and a use-dependent (UDB, 10 Hz) block of peak I(Na) with a potency following the order rank R1448C > WT approximately equal A1156T > G1306E. Yet, when assayed from an hp of -180 mV, TB and UDB by mexiletine were similar for the four channels. The different midpoints of channel availability curves found for the four channels track the half-maximum inhibitory value (IC50) measured at -120 mV. Thus differences in the partitioning of channels between the closed and fast-inactivated states underlie the different IC50 measured at a given potential. The mexiletine-derivative, Me7 (alpha-[(2-methylphenoxy)methyl]-benzenemethanamine), behaved similarly but was approximately 5 times more potent than mexiletine. Interestingly, the higher drug concentrations ameliorated the abnormally slower decay rate of myotonic I(Na)., Conclusions: These results explain the basis of the apparent difference in block of mutant sodium channels by mexiletine and Me7, opening the way to a more rationale drug use and to design more potent drugs able to correct specifically the biophysical defect of the mutation in individual myotonic patients.

We examined the effects of propofol on a paramyotonia congenita mutant skeletal muscle sodium channel in vitro, because life-threatening complications resulting from severe muscle rigidity during induction of anesthesia have been observed using other anesthetics in patients with hereditary sodium channel myopathies. Our hypothesis was that propofol might interact directly with mutant channels, causing enhanced muscle excitability in affected patients. Whole-cell voltage-clamp experiments were performed on HEK 293 cells expressing R1448H mutant sodium channels. Propofol blocked sodium inward current at clinical concentrations (5 micromol/L) when depolarizing pulses were started from holding potentials close to the physiological resting potential (-70 mV). Higher propofol concentrations (>/=25 micromol/L) accelerated pathologically delayed inactivation kinetics and delayed pathologically enhanced recovery from inactivation. Our in vitro results show that inactivation-deficient sodium channels are specifically targeted and blocked by propofol. This might reduce enhanced muscle excitability experienced by affected patients in vivo., (Copyright 2001 John Wiley & Sons, Inc.)

Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degrees C. At 27 degrees C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of -40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22 degrees C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, tau(h), for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at -60, -40, and -20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior., (Copyright 2000 John Wiley & Sons, Inc.)

1. Using macropatch techniques, we tested the assumption that deactivation underlies the observed delay in the onset to recovery from fast inactivation by comparing open-state deactivation to recovery delay for rat skeletal muscle mutations R1441C and R1441P. 2. Deactivation kinetics from the open state were determined from the exponential decay of tail currents. R1441C and R1441P prolonged open-state deactivation, with the greatest effect produced by R1441P. 3. Delays in the onset to recovery from fast inactivation for R1441P and for R1441C were abbreviated compared to those for rSkM1. Recovery delay was longer in R1441P than R1441C at voltages more negative than -110 mV. Recovery from inactivation exhibited a voltage dependence which, unlike delay, saturated at depolarized voltages. Recovery rate constants were increased to a similar extent for R1441C and R1441P at -150 to -120 mV compared to rSkM1. 4. These results indicate that the delay in the onset to recovery from fast inactivation in skeletal muscle sodium channels is due to deactivation. Lessening of charge immobilization for R1441C and R1441P may contribute to observed biophysical defects underlying the hyperexcitability of muscle fibers containing paramyotonia congenita mutations. The second stage of recovery from fast inactivation may be affected differentially by these mutations.

Objective: To conduct the genotype-phenotype correlation in a family in which several individuals share clinical and electrophysiologic features of paramyotonia congenita (PC)., Background: PC, hyperkalemic periodic paralysis (HyperPP), and potassium-aggravated myotonias form the group of hereditary sodium channelopathies. Each of these disorders is associated with different point mutations in SCN4A, the gene encoding the alpha-subunit of the adult human skeletal muscle sodium channel. However, in HyperPP families, evidence of a causative gene different from SCN4A has been found., Methods: We conducted direct clinical examination, electrophysiologic (EMG/electroneurographic) and cardiologic studies, as well as laboratory screening in several affected and nonaffected members of the family. We performed the genotype-phenotype correlation by microsatellite linkage and cDNA-mutation analyses of the SCN4A gene., Results: Affected members in this family showed clinical and electrophysiologic features typical of PC. The disease phenotype segregated with the chromosomal region that includes the SCN4A gene. Analysis of the entire cDNA sequence of the SCN4A gene in the index case disclosed a G3826A transition, which results in the Val1276Ile substitution. However, PCR-single-stranded confirmation polymorphism and direct sequencing analysis of the segment coding for Val-1276 on genomic DNA confirmed the G3826A transition in the index case but was negative in 11 affected members of the family; however, neither mutations nor aberrant splicings causative of the PC phenotype in this family were found on SCN4A., Conclusion: The existence of a second gene different from SCN4A that can give rise to a clinical PC phenotype can be speculated upon.