Muscle Channelopathies Research Articles

LB6. Electrodiagnosis of muscle channelopathies

LB6. Electrodiagnosis of muscle channelopathies

Canalopatías del músculo esquelético de base genética: parálisis periódicas y miotonías no distróficas

Skeletal muscle channelopathies cover a group of rare hereditary diseases, clinically characterized by myotonia, muscle paralysis or a combination of both diseases. Its prevalence is low and clinical manifestations are unspecific. History clinical features and typical clinical signs (neurological examination and neurophysiological tests) are the objective of current update. Clinical presentation, the genetic basis, diagnostic approach and therapeutic options currently available will be reviewed in the present paper.

Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate

Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297K, p.F1298C, p.G1306E, p.I1310N, and p.T1313M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life.

Chapter 17 - Normal and abnormal spontaneous activity

Assessment of spontaneous waveforms recorded in a resting muscle during needle electromyography is important to determine the type of underlying neuromuscular disorder, temporal course of a disease, and severity and prognosis. A variety of different spontaneous waveforms may be recorded. Some waveforms may be recording in patients without neuromuscular disorders, such as end-plate activity or fasciculation potentials, while others occur only in abnormal muscles. Fibrillation potentials are the most common abnormal spontaneous waveform and are encountered in a wide variety of neuromuscular disorders causing denervation or damage to muscle fibers. Myotonic discharges, when diffuse, are seen in a small number of myopathies or muscle channelopathies. Complex repetitive discharges are nonspecific spontaneous waveforms that may be encountered in chronic or longstanding neurogenic or myopathic disorders. Myokymic and neuromyotonic discharges are rare spontaneous waveforms that suggest either focal or diffuse peripheral nerve hyperexcitability. When interpreted in conjunction with voluntary motor unit potentials as well as nerve conduction study findings, spontaneous waveforms are useful to fully assess the types of disorders of patients with neuromuscular complaints.

WED 236 Skeletal muscle channelopathies and sudden infant death syndrome

BackgroundSkeletal muscle channelopathies are rare genetic disorders causing periodic paralysis and myotonia. They are generally considered debilitating but not life-threatening. However cases of life-threatening respiratory muscle crises have recently been reported in infants requiring ITU support. We hypothesised muscle channelopathy gene variants may contribute to the risk of sudden infant death.MethodsWe analysed the SCN4A gene for rare variants in 278 cases of sudden infant death (SIDS) and 729 ethnically matched controls. Biophysical characterisation was performed using a heterologous expression system.ResultsFour of the 278 SIDS cases (1.4%) had an ultra-rare, functionally disruptive SCN4A variant compared to 0/729 ethnically matched controls (p=0.0057). The degree of channel perturbation associated with these four variants was qualitatively similar to the SCN4A variants previously implicated in infants with life-threatening apnoeic events.ConclusionsRare SCN4A variants that directly alter channel function occur in sudden infant death cases. These variants are predicted to significantly alter muscle membrane excitability compromising respiratory and laryngeal function. Data on pregnancy/post-natal complications is now being collected from parents with genetically confirmed sodium channelopathies via clinic and on-line registry. Laryngospasm has recently been implicated in SUDEP - analysis of SCN4A variants in SUDEP cases is also underway.

Lower-extremity magnetic resonance imaging in patients with hyperkalemic periodic paralysis carrying the SCN4A mutation T704M: 30-month follow-up of seven patients

Hyperkalemic periodic paralysis (hyperKPP) is a muscle channelopathy characterized by recurrent paralytic attacks. Our previous study, in which we conducted whole-body muscle magnetic resonance imaging (MRI) in patients with hyperKPP, revealed muscle atrophy and fatty change in the lower extremity, especially in older persons. The aim of current study was to identify the progression of myopathy in hyperKPP patients had been assessed in the previous study. We performed lower-extremity muscle MRI in seven hyperKPP patients carrying the T704M mutation in the SCN4A gene at an interval of 30 months. Muscle atrophy, edematous change, fatty change, and fat fraction quantified using the Dixon technique were compared with the previous MRI findings. The lower-extremity MRI scan showed progressive muscle pathologic findings when compared with the previous study. Muscle atrophy, edematous change, and fatty change were prominent in the superficial posterior compartment of the lower leg. The follow-up lower-extremity muscle MRI findings provide evidence for chronic progressive myopathy and suggest the usefulness of MRI for assessing disease progression in patients with hyperKPP. This study is meaningful in terms of providing data showing the longitudinal changes of muscles in patients with periodic paralysis.

Flecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature

Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the SCN4A gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the SCN4A gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the SCN4A gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome.

S14. PURA (Purine-Rich Element Binding Protein A) syndrome

Introduction Burst suppression is an electroencephalographic (EEG) pattern characterized by a brief interval of relatively high voltage activity with intervening periods of generalized suppression. It is commonly seen consequent to anoxic brain injury, deep coma states, encephalopathies or hypothermia. This pattern is differentiated from trace discontinua because of longer interburst interval and higher amplitude during bursts. Myotonic discharges (M.D.) seen in an electromyographic (EMG) study are the abnormal wave of excitation due to the firing of repetitive action potentials. It is characterized by waveforms with alternating frequency and amplitude. This unique pattern is seen in muscular dystrophies, muscle channelopathies, toxic or inflammatory myopathies. We report a case of PURA syndrome with significant EEG findings of burst suppression and EMG pattern of myotonic discharges which has not been described in literature before. Methods A male infant was born at 37-week gestation via spontaneous vaginal delivery to a 35-year-old G1P0 after an uneventful pregnancy. At birth, the infant was observed to have generalized central hypotonia and seizure-like spells of posturing, lip-smacking and blinking lasting for 10–15 s. Family history was unremarkable. A video EEG and EMG were ordered for futher evaluation, in addition to other routine testing. Results Video EEG demonstrated excessive multifocal sharps and periods of burst suppression. EMG study reported myotonic discharges in the first dorsal interosseous and tibialis anterior. Work up for metabolic etiologies were negative. CSF studies, chromosomal studies, infantile epilepsy panel, myotonic dystrophy panel were unremarkable. Whole exome sequencing was significant for a de novo mono-allelic mutation of the PURA gene (variant PR245X, coding DNA c.733 C > T). Conclusion PURA (purine-rich element binding protein A) syndrome is a genetic disorder caused by a gene deletion in 5q31.3, characterized by neonatal hypotonia, seizures and intellectual disability. It leads to an alteration in the PURA protein, affecting the protein’s DNA regulatory function. All reported deletions have been de novo. Therefore the risk of future inheritance of this genetic mutation is low. PURA Syndrome is known to cause epilepsy in 54% of previously reported patients. In our case, the patient’s EEG pattern was consistent with burst suppression, which supports the fact that PURA Syndrome is a state of generalized brain dysfunction. EMG reports were consistent with myotonic discharges. The significance of this finding in our patient is unclear and requires further research to characterize EMG findings in affected patients with PURA syndrome. This case however underscores the importance of considering PURA syndrome in the differential diagnosis of neonatal EEG findings of burst suppression pattern and EMG findings of myotonic discharge.

A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the “skeletal muscle”, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results suggest that, unlike in WT-Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger the noted phenotypes in P1158S patients.

NMJ&C07 - Pilot study to explore the frequency and severity of pain in skeletal muscle channelopathies

NMJ&C07 - Pilot study to explore the frequency and severity of pain in skeletal muscle channelopathies

Skeletal muscle channelopathy: a new risk for sudden infant death syndrome

Skeletal muscle channelopathy: a new risk for sudden infant death syndrome

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990–2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16–2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively.Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen–Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Substitutions of the S4DIV R2 residue (R1451) in NaV1.4 lead to complex forms of paramyotonia congenita and periodic paralyses

Mutations in NaV1.4, the skeletal muscle voltage-gated Na+ channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L.

What the internist should know about hereditary muscle channelopathies

Objectives: Non-dystrophic myotonia, periodic paralysis and, to a certain extent, myotonic dystrophies are rare hereditary skeletal muscle channelopathies, charactarized by myotonia or episodic muscle weakness. This review highlights the diagnostic challenges and treatment options.Results: Some of these rare skeletal muscle disorders are associated with a broad range of systemic and nonspecific muscle symptoms. Consequently, patients are often referred to the internist before seeing a neurologist. This article provides clinical clues to better diagnose an tackle these unique disorders.Conclusion: A increased knowledge will reduce the diagnostic delay, improve monitoring and treatment, and might even prevent potentially life-threatening conditions as seen in DM.

N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita.

Paramyotonia congenita is a hereditary channelopathy caused by missense mutations in the SCN4A gene, which encodes the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. Affected individuals suffered from myotonia and paralysis of muscles, which were aggravated by exposure to cold. We report a three-generation Chinese family with patients presenting paramyotonia congenita and identify a novel N1366S mutation of NaV1.4. Whole-cell electrophysiological recordings of the N1366S channel reveal a gain-of-function change of gating in response to cold. Modelling and molecular dynamic simulation data suggest that an arginine-to-serine substitution at position 1366 increases the distance from N1366 to R1454 and disrupts the hydrogen bond formed between them at low temperature. We demonstrate that N1366S is a disease-causing mutation and that the temperature-sensitive alteration of N1366S channel activity may be responsible for the pronounced paramyotonia congenita symptoms of these patients. Paramyotonia congenita is an autosomal dominant skeletal muscle channelopathy caused by missense mutations in SCN4A, the gene encoding the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. We report a three-generation family in which six members present clinical symptoms of paramyotonia congenita characterized by a marked worsening of myotonia by cold and by the presence of clear episodes of paralysis. We identified a novel mutation in SCN4A (Asn1366Ser, N1366S) in all patients in the family but not in healthy relatives or in 500 normal control subjects. Functional analysis of the channel protein expressed in HEK293 cells by whole-cell patch clamp recording revealed that the N1366S mutation led to significant alterations in the gating process of the NaV1.4 channel. The N1366S mutant displayed a cold-induced hyperpolarizing shift in the voltage dependence of activation and a depolarizing shift in fast inactivation, as well as a reduced rate of fast inactivation and accelerated recovery from fast inactivation. In addition, homology modelling and molecular dynamic simulation of N1366S and wild-type NaV1.4 channels indicated that the arginine-to-serine substitution disrupted the hydrogen bond formed between N1366 and R1454. Together, our results suggest that N1366S is a gain-of-function mutation of NaV1.4 at low temperature and the mutation may be responsible for the clinical symptoms of paramyotonia congenita in the affected family and constitute a basis for studies into its pathogenesis.

P.229 - Skeletal muscle channelopathies: Rare treatable disorders with common presentation in childhood

P.229 - Skeletal muscle channelopathies: Rare treatable disorders with common presentation in childhood

P251 Contribution of electrophysiology in muscular channelopathies diagnosis

Muscle channelopathies are a rare group of neuromuscular disorders caused by mutations in ion channels. Periodic paralysis is defined by the occurrence of episodic acute and reversible attacks of muscle weakness, electrophysiological exploration was not enough codified, following the works of Fournier et al. (2004) the contribution of EDX was greatly improved. We report the results of 3 cases with periodic paralysis and discuss the interest of EDX. In 3 patients aged 14, 46 and 43 years, changes in the amplitude of motor potentials were studied during long and short-term stress tests. Results were compared with those observed in 10 controls. In both three patients, a reduction in amplitude of CMAP induced by stimulation of the ulnar nerve with recording at the adductor muscle of the 5th finger was noted after a long muscle contraction (5 min); This decrease is clear from 30 min after end of the exercise and persists for at least 50 min, this has never been observed in normal subjects. This results are similar to those reported by Fournier et al., 2004, Kuntzer et al., 2000, McManis et al., 1986, Meola et al., 2009, Tan Veronica et al., 2011. The diagnosis of periodic paralysis is difficult because of their rarity; from the poverty of objective clinical signs outside crises. Differential diagnosis may occur with other acute flaccid paralysis. electrophysiology can even guide the molecular analysis. electrophysiology, if executed according to recent protocols, is important to confirm the diagnosis (especially since EDX abnormalities can be found even a year after a crisis) and also to orient molecular diagnosis.

Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms

To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. Retrospective case review of 38 children with a skeletal muscle channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15-year period. Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential.

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.

S11 - Skeletal muscle channelopathies: new phenotypes and new genes

S11 - Skeletal muscle channelopathies: new phenotypes and new genes