Muscle Channelopathies Research Articles

Potassium Therapy in Patients with Hypokalemic Periodic Paralysis in RSUD Kabupaten Empat Lawang: A Case Report

Introduction: Hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle channelopathy characterized by episodic attacks of moderate to severe flaccid muscle tetraparesis accompanied by hypokalemia. This case report aims to discuss the case and management of hypokalemic periodic paralysis with potassium therapy at RSUD Kabupaten Empat Lawang. Case Presentation: A 29-year-old female presented with sudden bilateral limb weakness, vomiting, and nausea. She had no breathing, swallowing issues, or pain. Physical examination showed reduced muscle strength and epigastric tenderness. Laboratory tests indicated elevated leukocytes and decreased kalium. Diagnosed with hypokalemic periodic paralysis and a UTI, she received IV fluids, potassium chloride, and other supportive treatments, leading to immediate condition resolution. Conclusion: Hypokalemic Periodic Paralysis (HypoPP) is a rare neuromuscular disorder characterized by periodic muscle weakness ranging from mild to complete paralysis.. The etiology in this case was secondary to hyperemesis. Failure to diagnose and manage periodic paralysis can be fatalIt can lead to respiratory failure and death. Treatment involves potassium supplementation and monitoring for cardiac complications.

Quality of life in hypokalemic periodic paralysis - a survey

Primary hypokalemic periodic paralysis (HypoPP) is a skeletal muscle channelopathy most commonly caused by pathogenic variants in the calcium channel gene, CACNA1S. HypoPP can present with attacks of paralysis and/or permanent muscle weakness. Previous studies have shown that patients with HypoPP can have impaired quality of life (QoL). In this cross-sectional study, we aimed to describe the QoL in patients with HypoPP caused by pathogenic variants in CACNA1S using The Individualized Neuromuscular Quality of Life (INQoL) questionnaire, a validated tool to measure the QoL of patients with neuromuscular diseases (higher score, worse QoL). We showed that muscle weakness and fatigue were the symptoms with the greatest impact on participants' lives and that “activities”, in the life domain of the INQoL, was most affected by HypoPP. Furthermore, we showed that the total INQoL score increased with age. Low QoL was primarily driven by progressive permanent muscle weakness and not attacks of paralysis, although half of the participants reported that attacks of paralysis challenged their daily life. The results suggest that special attention should be given to muscle weakness and fatigue in patients with HypoPP.

Idiopathic generalized epilepsy in a family with SCN4A-related myotonia.

Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed. All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

Brody Disease, an Early-Onset Myopathy With Delayed Relaxation and Abnormal Gait: A Case Series of 9 Children.

Brody disease is a rare autosomal recessive myopathy, caused by pathogenic variants in the ATP2A1 gene. It is characterized by an exercise-induced delay in muscle relaxation, often reported as muscle stiffness. Children may manifest with an abnormal gait and difficulty running. Delayed relaxation is commonly undetected, resulting in a long diagnostic delay. Almost all published cases so far were adults with childhood onset and adult diagnosis. With diagnostic next-generation sequencing, an increasing number of patients are diagnosed in childhood. We describe the clinical and genetic features of 9 children from 6 families with Brody disease. All presented with exercise-induced delayed relaxation, reported as difficulty running and performing sports. Muscle strength and mass was normal, and several children even had an athletic appearance. However, the walking and running patterns were abnormal. The diagnostic delay ranged between 2 and 7 years. Uniformly, a wide range of other disorders were considered before genetic testing was performed, revealing pathogenic genetic variants in ATP2A1. To conclude, this case series is expected to improve clinical recognition and timely diagnosis of Brody disease in children. We propose that ATP2A1 should be added to gene panels for congenital myopathies, developmental and movement disorders, and muscle channelopathies.

Contractile properties and magnetic resonance imaging-assessed fat replacement of muscles in myotonia congenita.

Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients. Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole-body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross-sectional area (PT/CCSA). Muscle contractility was compared with clinical data. Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0-14.3% vs. 5.3-9.6%, PT/CCSA = 1.1-4.9 Nm/cm2 vs. 1.9-5.8 Nm/cm2 [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms. Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.

Pediatric neuromuscular channelopathies.

Pediatric skeletal muscle channelopathies include a spectrum of conditions including nondystrophic myotonias and periodic paralyses. They are rare inherited conditions that can cause significant morbidity. They are characterized by episodic stiffness and weakness. While there is significant phenotypic variability, there are distinct diagnostic features. The nondystrophic myotonias encompass myotonia congenita, paramyotonia congenita, and sodium channel myotonia caused by mutations in chloride and sodium channels. The clinical manifestations vary across age groups and a small subset with sodium channel mutations may have severe presentation with fetal akinesia, laryngospasm, or congenital myopathy. The periodic paralyses include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. The phenotypic differences between the groups can be helpful in diagnosis. It is important to review the cardiac phenotype in Andersen-Tawil syndrome due to a risk of life-threatening cardiac arrhythmias. Early and accurate diagnosis utilizing clinical features aided by investigations is important across all the pediatric channelopathies, as effective symptomatic treatment is available and can substantially improve quality of life.

A retrospective study of accuracy and usefulness of electrophysiological exercise tests

ObjectivesThis study aimed to determine the usefulness of electrophysiological exercise tests. The significance of slightly abnormal exercise tests was also examined.MethodsWe identified all the patients who had undergone exercise testing between February 2007 to June 2022 in Tampere University Hospital, Finland. Their medical records after diagnostic workup and exercise test reports were reviewed. A binary logistic regression was performed to evaluate the association between positive test result in short exercise test, long exercise test, or short exercise test with cooling and genetically confirmed skeletal muscle channelopathy or myotonic disorder.ResultsWe identified 256 patients. 27 patients were diagnosed with nondystrophic myotonia, periodic paralysis, myotonic dystrophy type 1, myotonic dystrophy type 2, or other specified myopathy. 14 patients were suspected to have a skeletal muscle channelopathy, but pathogenic variants could not be identified. The remaining 215 patients were diagnosed with other conditions than skeletal muscle channelopathy or myotonic disorder. The combined sensitivity of exercise tests was 59.3% and specificity 99.1%. Abnormal exercise test result was associated with increased risk of skeletal muscle channelopathy or myotonic disorder (OR 164.3, 95% CI 28.3–954.6, p < 0.001).ConclusionsElectrophysiological exercise test is not optimal to exclude skeletal muscle channelopathy. It may be useful if a skeletal muscle channelopathy is suspected and genetic testing is negative or indeterminate and further evidence is required. Slightly abnormal exercise test results are possible in various conditions and result from different aetiologies. There is a demand for neurophysiological studies with higher sensitivity to detect skeletal muscle channelopathies.

Muscle channelopathies: A review

AbstractBackgroundMuscle channelopathies are a rare and heterogeneous group of disorders that can be clinically challenging and functionally disabling. These disorders can present in both adult and pediatric age groups. These disorders have been known since the turn of the 20th century, with a steady evolution in terms of understanding the pathophysiology, phenotype, diagnostic, and treatment modalities over the last three decades.MethodsWe present a comprehensive review of muscle channelopathies that includes nondystrophic myotonias and periodic paralyses. The disorders in this review have been classified based on the presence or absence of myotonia on either the clinical exam or on electrophysiological testing. The historical background, genetics, pathophysiology, phenotypic presentations, and treatment modalities of each disorder reveal similarities as well as specific nuances in the disease phenotypes. Neurophysiologic testing shows differences in responses on routine and exercise testing and can narrow the differential within subsets of nondystrophic myotonias and periodic paralyses. The advances in genetics further aid in specifying which of the putative channels are at fault. Management can then be guided by knowledge of the causative gene and involves either avoidance of triggers or channel‐based therapeutics.ConclusionMuscle channelopathies are rare, but a high index of suspicion along with a knowledge of the phenotype will help guide neurophysiological and genetic testing. A muscle channelopathy diagnosis, subsequently, can assist in avoiding triggers and directing treatments.

P186 Spectrum of skeletal muscle channelopathies in a cohort of Inherited neuromuscular disorders

P186 Spectrum of skeletal muscle channelopathies in a cohort of Inherited neuromuscular disorders

Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.

The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features. A total of 45 participants and eight healthy controls were enrolled and underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale. A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty-one (69%) had weakness, and 9 (20%) required a gait-aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri-tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness. We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.

Plateau potentials contribute to myotonia in mouse models of myotonia congenita.

It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action potentials). In a previous study, we identified a novel phenomenon in myotonic muscle: development of plateau potentials, transient depolarizations to near -35mV lasting for seconds to minutes. In the current study we examined whether plateau potentials contribute to myotonia. A recessive genetic model (ClCadr mice) with complete loss of muscle chloride channel (ClC-1) function was used to model severe myotonia congenita with complete loss of ClC-1 function and a pharmacologic model using anthracene-9-carboxylic acid (9AC) was used to model milder myotonia congenita with incomplete loss of ClC-1 function. Simultaneous measurements of action potentials and myoplasmic Ca2+ from individual muscle fibers were compared to recordings of whole muscle force generation. In ClCadr muscle both myotonia and plateau potentials lasted 10s of seconds to minutes. During plateau potentials lasting 1-2min, there was a gradual transition from high to low intracellular Ca2+, suggesting a transition in individual fibers from myotonia to flaccid paralysis in severe myotonia congenita. In 9AC-treated muscles, both myotonia and plateau potentials lasted only a few seconds and Ca2+ remained elevated during the plateau potentials, suggesting plateau potentials contribute to myotonia without causing weakness. We propose, that in myotonic muscle, there is a novel state in which there is contraction in the absence of action potentials. This discovery provides a mechanism to explain reports of patients with myotonia who suffer from electrically silent muscle contraction lasting minutes.

Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing

We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981–1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123–1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 – 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406–0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098–0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.

Functional analysis of the mutant channels associated with skeletal muscle channelopathies

Functional analysis of the mutant channels associated with skeletal muscle channelopathies

Update on Muscle Channelopathy

Skeletal muscle channelopathy are rare heterogeneous episodic disorders with marked genotypic and phenotypic variability resulting in periodic paralysis, falls in young people, which often misdiagnosed or undiagnosed due to its rarity often. The symptoms are miscommunicated to the treating physician due to its episodic nature and not uncommonly physical examination by the time patient attend the clinic or hospital will be unremarkable apart from periodic muscle paralysis where patient will presented to ED with flaccid weakness. In this review we will present two patients where the diagnosis was initially missed and it took some time to reach the correct diagnosis.

Muscle Channelopathies

This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.

In silico versus functional characterization of genetic variants: lessons from muscle channelopathies.

Accurate determination of the pathogenicity of missense genetic variants of uncertain significance is a huge challenge for implementing genetic data in clinical practice. In silico predictive tools are used to score variants' pathogenicity. However, their value in clinical settings is often unclear, as they have not usually been validated against robust functional assays. We compared nine widely used in silico predictive tools, including more recently developed tools (EVE and REVEL) with detailed cell-based electrophysiology, for 126 CLCN1 variants discovered in patients with the skeletal muscle channelopathy myotonia congenita. We found poor accuracy for most tools. The highest accuracy was obtained with MutationTaster (84.58%) and REVEL (82.54%). Both of these scores showed poor specificity, although specificity was better using EVE. Combining methods based on concordance improved performance overall but still lacked specificity. Our calculated statistics for the predictive tools were different to reported values for other genes in the literature, suggesting that the utility of the tools varies between genes. Overall, current predictive tools for this chloride channel are not reliable for clinical use, and tools with better specificity are urgently required. Improving the accuracy of predictive tools is a wider issue and a huge challenge for effective clinical implementation of genetic data.

European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders.

Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders. International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research &amp; Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process. A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies. This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.

COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.

Introduction/AimsAlthough we have gained insight into coronavirus disease‐2019 (COVID‐19) caused by severe acute respiratory syndrome–coronavirus 2 since the beginning of the pandemic, our understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID‐19 and COVID‐19 vaccination on skeletal muscle channelopathies.MethodsWe conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service.ResultsThirty‐eight patient responses were received. Six patients had COVID‐19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty‐six patients had received one or two COVID‐19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty‐two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported.DiscussionThe overall rates of COVID‐19 infection were low in our study and COVID‐19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post–COVID‐19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID‐19 infection and vaccination.

Abstract P1099: Evidence Of Sialylation Pathway Alterations In Peripheral Blood Of Brugada Syndrome Patients

Brugada syndrome (BrS) is a cardiac arrhythmia associated with a higher risk of SCD. BrS is considered a genetic disorder, and the most commonly mutated gene is SCN5A, encoding the alpha subunit of the voltage-gated cardiac sodium channel (NaV1.5). Mutations of SCN5A usually lead to impairment of NaV1.5 functionality, which is considered the main mechanism of the disease. However, SCN5A mutations are responsible for only 30% of BrS cases. Therefore, it is conceivable that other mechanisms such as post-translational modifications (PTMs) affect NaV1.5 activity. Among others, sialylation may alter ion channel activity by carrying a sugar with a negative charge. Alterations in sialylation have been described in several cardiovascular diseases, as myocardial infarction, Chagas disease, and congenital disorders of glycosylation. For these reasons, the aim was to investigate changes in sialylation in BrS patients to obtain new information on the pathogenesis of BrS. Peripheral blood mononuclear cells (PBMCs) were collected from BrS patients and healthy controls. SNA lectin, a sialic acid-binding protein, was used to characterize the protein sialylation status of PBMCs by Western blot and flow cytometry. Gene expression of enzymes involved in the sialic acid pathway was also examined. The results showed a significant decrease in intracellular and extracellular protein sialylation levels in BrS PBMCs compared with controls. In addition, changes in gene expression of enzymes involved in the sialic acid pathway were detected. Moreover, these changes correlated with clinical parameters associated with phenotypic expression of the disease, such as arrhythmogenic BrS substrate area and potential duration. These findings support that BrS should be considered a systemic disease and are consistent with the presence of overlapping non-cardiac pathologies, as epilepsy, cancer, diabetes, skeletal muscle channelopathies, and laminopathies in BrS patients. Moreover, the discovery that molecular alterations can be found in the peripheral blood of BrS patients supports the existence of a biomarker of the disease. It is a challenge to develop an effective diagnostic test to screen broadly for BrS. In this direction, a multiomic study is ongoing in our center.

Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study.

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70years vs. 9.23 ± 5.21years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.