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Key points Patients with myotonia congenita suffer from slowed muscle relaxation caused by hyperexcitability. The diaphragm is only mildly affected in myotonia congenita; discovery of the mechanism underlying its resistance to myotonia could identify novel therapeutic targets. Intracellular recordings from two mouse models of myotonia congenita revealed the diaphragm had less myotonia than either the extensor digitorum longus (EDL) or the soleus muscles. A mechanism contributing to resistance of the diaphragm to myotonia was reduced depolarization of the interspike membrane potential during repetitive firing of action potentials, a process driven by build‐up of K+ in small invaginations of muscle membrane known as t‐tubules. We explored differences between diaphragm and EDL that might underlie reduction of K+ build‐up in diaphragm t‐tubules. Smaller size of diaphragm fibres, which promotes diffusion of K+ out of t‐tubules, was identified as a contributor. Intracellular recording revealed slower repolarization of action potentials in diaphragm suggesting reduced Kv conductance. Higher resting membrane conductance was identified suggesting increased Kir conductance. Computer simulation found that a reduction of Kv conductance had little effect on K+ build‐up whereas increased Kir conductance lessened build‐up, although the effect was modest. Our data and computer simulation suggest opening of K+ channels during action potentials has little effect on K+ build‐up whereas opening of K+ channels during the interspike interval slightly lessens K+ build‐up. We conclude that activation of K+ channels may lessen myotonia by opposing depolarization to action potential threshold without worsening K+ build‐up in t‐tubules. In mouse models of the muscle disease myotonia congenita, the diaphragm has much less myotonia (muscle stiffness) than the extensor digitorum longus or soleus muscles. Identifying why the diaphragm is resistant to myotonia may help in developing novel therapy. We found the reason the diaphragm has less myotonia is that it is less prone to depolarization caused by K+ build‐up in t‐tubules during repetitive firing of action potentials. Smaller fibre size contributes to resistance to K+ build‐up with differences in K+ currents playing little role. Our data suggest drugs that open K+ channels may be effective in treating myotonia as they may lessen excitability without worsening K+ build‐up in t‐tubules. [ABSTRACT FROM AUTHOR]

Abstract Objectives 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. Methods 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. Results 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. Significance 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. Plain Language Summary 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.

The function of the chloride channel ClC‐1 is crucial for the control of muscle excitability. Thus, reduction of ClC‐1 functions by CLCN1 mutations leads to myotonia congenita. Many different animal models have contributed to understanding the myotonia pathophysiology. However, these models do not allow in vivo screening of potentially therapeutic drugs, as the zebrafish model does. In this work, we identified and characterized the two zebrafish orthologues (clc‐1a and clc‐1b) of the ClC‐1 channel. Both channels are mostly expressed in the skeletal muscle as revealed by RT‐PCR, western blot, and electrophysiological recordings of myotubes, and clc‐1a is predominantly expressed in adult stages. Characterization in Xenopus oocytes shows that the zebrafish channels display similar anion selectivity and voltage dependence to their human counterparts. However, they show reduced sensitivity to the inhibitor 9‐anthracenecarboxylic acid (9‐AC), and acidic pH inverts the voltage dependence of activation. Reduction of clc‐1a/b expression hampers spontaneous and mechanically stimulated movement, which could be reverted by expression of human ClC‐1 but not by some ClC‐1 containing myotonia mutations. Treatment of clc‐1‐depleted zebrafish with mexiletine, a typical drug used in human myotonia, improves the motor behaviour. Our work extends the repertoire of ClC channels to evolutionary structure–function studies and proposes the zebrafish clcn1 crispant model as a simple tool to find novel therapies for myotonia. Key points: We have identified two orthologues of ClC‐1 in zebrafish (clc‐1a and clc‐1b) which are mostly expressed in skeletal muscle at different developmental stages.Functional characterization of the activity of these channels reveals many similitudes with their mammalian counterparts, although they are less sensitive to 9‐AC and acidic pH inverts their voltage dependence of gating.Reduction of clc‐1a/b expression hampers spontaneous and mechanically stimulated movement which could be reverted by expression of human ClC‐1.Myotonia‐like symptoms caused by clc‐1a/b depletion can be reverted by mexiletine, suggesting that this model could be used to find novel therapies for myotonia. [ABSTRACT FROM AUTHOR]

The relaxation of trapezius muscles is widely believed to alleviate fatigue or injury of the trapezius muscles and reduce the risk of shoulder and neck pain. This study aims to examine the effects of different muscle relaxation techniques on the physical properties of the trapezius muscle and to explore how changes in the physical properties of the upper trapezius muscle affect those of the middle trapezius muscle. Twenty-four healthy males (mean age: 23.08 ± 0.97 years; height: 172.42 ± 4.61 cm; weight: 66.38 ± 6.68 kg; and body mass index: 22.30 ± 1.81 kg/m2), randomly divided into four groups: stretching relaxation group (ST, n = 6), mechanical vibration massage (MV, n = 6), pulse massage (PU, n = 6), and control (CO, n = 6). Measurements using the Myoton digital muscle assessment system were conducted daily over 2 weeks. The experimental groups demonstrated a notable decrease in tension and stiffness, accompanied by heightened elasticity in the upper trapezius muscles. Conversely, the control group exhibited contrasting trends. Although no significant variances were detected among the relaxation techniques, all proved efficacious compared to the control group (P < 0.05). Moreover, relaxation of the upper trapezius muscles significantly influenced the middle trapezius muscles (P < 0.05). Various relaxation methods positively influenced trapezius muscle attributes over 2 weeks, with inter-regional effects noted. [ABSTRACT FROM AUTHOR]

Objectives: 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. Methods: 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. Results: 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. Significance: 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. Plain Language Summary: 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. [ABSTRACT FROM AUTHOR]

BackgroundSevere muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon.ObjectivesTo evaluate signalment, presentation, treatments, and long-term outcomes of dogs with concurrent HC and SMS.AnimalsThirty-seven dogs.MethodsMedical records of dogs with HC and concurrent SMS were recruited from 10 institutions. Clinical information, test results, therapeutic responses, and survival times were reviewed.ResultsAll 37 dogs with HC and SMS had pituitary-dependent hypercortisolism (PDH); 36/37 weighed

Objective To analyze the relationship between biceps, triceps surface integrated electromyography (iEMG) recorded by surface electromyography (sEMG) and the degree of myotonia in patients with Parkinson's disease (PD), and to explore the feasibility of iEMG value as an objective quantitative index of the degree of myotonia in patients with PD. Methods A total of 51 patients with PD who were admitted to The First Affiliated Hospital of Anhui Medical University from September 2022 to November 2023 were included, as well as 19 healthy controls matched by sex and age. The motor symptoms and myotonic degree of the subjects were evaluated by Unified Parkinson's Disease Rating Scale Ⅲ (UPDRS Ⅲ). sEMG was used to collect the sEMG signals of the biceps and triceps of the subjects during passive upper limb movement, and the iEMG value was calculated. A total of 32 patients with PD were randomly selected for Levodopa Shock Test. iEMG values and UPDRSⅢ myotonic scores of upper limbs were collected before and after the test. Spearman rank correlation analysis was used to analyze the correlation between iEMG values and UPDRSⅢ myotonic scores of upper limbs. Results In PD group, the iEMG values of biceps muscle (Z = ‑ 4.874, P = 0.000) and triceps muscle (Z = ‑ 4.880, P = 0.000) of more severe symptoms side were higher than those of less severe symptoms side. Spearman rank correlation analysis showed that myotonic scores of upper limbs (0-3 points) in PD group was positively correlated with biceps (rs = 0.735, P = 0.000) and triceps (rs = 0.545, P = 0.000) iEMG values. The iEMG values of muscles with myotonia score of 1 (biceps Z = 5.344, P = 0.000; triceps Z = 5.146, P = 0.000), 2 (biceps Z = 7.421, P = 0.000; triceps Z = 6.891, P = 0.000), 3 (biceps Z = 5.340, P = 0.000; triceps Z = 5.145, P = 0.000) in PD group were higher than those in control group. In addition, before levodopa impact (biceps rs = 0.664, P = 0.000; triceps rs = 0.386, P = 0.029) and after impact (biceps rs = 0.620, P = 0.000; triceps rs = 0.588, P = 0.000) in PD group, there was a positive correlation between myotonic scores of upper limbs and iEMG values. Conclusions The iEMG values of biceps and triceps can reflect the severity of myotonia in PD patients, and can be used as a quantitative evaluation index of myotonia in PD patients.

Abstract Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by typical facial dysmorphism, generalized muscle stiffness, joint contracture, and skeletal abnormalities. This condition is caused by mutations in the heparan sulfate proteoglycan 2 (HSPG2) gene, which encodes perlecan, a component of the basement membrane. The management of patients with SJS primarily aims to alleviate symptoms related to muscle stiffness. In this report, we describe a male patient with SJS type 1A. Trio whole-exome sequencing identified a pathogenic mutation (NM_001291860.1: c.10897C>T; p.Arg3633Ter) and variants of unknown significance (NM_001291860.2: c.413+10G>T). The patient experienced difficulty in opening his eyes and mouth, which significantly limited his daily activities. Botulinum toxin A injection was administered and demonstrated significant clinical improvement after the treatment.

Abstract Background Muscle 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. Methods We 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. Conclusion Muscle 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.

A distinct myotonia is a muscle disorder that may occur secondary to excess corticosteroids (hyperadrenocorticism, HAC, or Cushing’s disease) and is associated with electrodiagnostic abnormalities on electromyography (EMG). Clinically these disorders cause muscle stiffness, weakness, atrophy, and/or contractures, which can severely limit the quality of life of those affected. To date, there are very few published data regarding the onset, development, and treatment of hyperadrenocorticism-associated myotonia/pseudomyotonia. This is a multi-institutional retrospective study describing the clinical signs, diagnosis, and treatment of HAC-associated myotonia/pseudomyotonia. We found that this disorder was and continues to be rare. It most commonly occurs in adult dogs with chronic steroid exposure secondary to pituitary-dependent HAC. No cases of adrenal dependent HAC were identified in this population. In addition to muscle stiffness, dermatologic disease and liver enzyme abnormalities were common. A wide variety of therapeutic strategies, including polypharmacy and physical rehabilitation, were implemented, with little success. Analgesics were the most frequently administered type of medication.

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by typical facial dysmorphism, generalized muscle stiffness, joint contracture, and skeletal abnormalities. This condition is caused by mutations in the heparan sulfate proteoglycan 2 (HSPG2) gene, which encodes perlecan, a component of the basement membrane. The management of patients with SJS primarily aims to alleviate symptoms related to muscle stiffness. In this report, we describe a male patient with SJS type 1A. Trio whole-exome sequencing identified a pathogenic mutation (NM_001291860.1: c.10897C>T; p.Arg3633Ter) and variants of unknown significance (NM_001291860.2: c.413+10G>T). The patient experienced difficulty in opening his eyes and mouth, which significantly limited his daily activities. Botulinum toxin A injection was administered and demonstrated significant clinical improvement after the treatment. [ABSTRACT FROM AUTHOR]

Myotonia congenita is a hereditary muscle disease mainly characterized by muscle hyperexcitability, which leads to a sustained burst of discharges that correlates with the magnitude and duration of involuntary aftercontractions, muscle stiffness, and hypertrophy. Mutations in the chloride voltage-gated channel 1 (CLCN1) gene that encodes the skeletal muscle chloride channel (ClC-1) are responsible for this disease, which is commonly known as myotonic chloride channelopathy. The biophysical properties of the mutated channel have been explored and analyzed through in vitro approaches, providing important clues to the general function/dysfunction of the wild-type and mutated channels. After an exhaustive search for CLCN1 mutations, we report in this review more than 350 different mutations identified in the literature. We start discussing the physiological role of the ClC-1 channel in skeletal muscle functioning. Then, using the reported functional effects of the naturally occurring mutations, we describe the biophysical and structural characteristics of the ClC-1 channel to update the knowledge of the function of each of the ClC-1 helices, and finally, we attempt to point out some patterns regarding the effects of mutations in the different helices and loops of the protein. [ABSTRACT FROM AUTHOR]

Abstract Background Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen’s congenital myotonia. Case presentation We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan’s anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. Conclusions Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Abstract Background Severe muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon. Objectives To evaluate signalment, presentation, treatments, and long‐term outcomes of dogs with concurrent HC and SMS. Animals Thirty‐seven dogs. Methods Medical records of dogs with HC and concurrent SMS were recruited from 10 institutions. Clinical information, test results, therapeutic responses, and survival times were reviewed. Results All 37 dogs with HC and SMS had pituitary‐dependent hypercortisolism (PDH); 36/37 weighed

The article focuses on a 9-year and 9-month-old Jack Russell Terrier with stiffness in all four limbs, detailing a chronic history of polyphagia, polyuria, and polydipsia. It mentions the dog, previously diagnosed with hyperadrenocorticism (Cushing's disease) and treated with trilostane, was referred to the neurology service due to the progression of clinical signs over a year.

The field of pediatric skeletal muscle channelopathies has seen major new advances in terms of a wider understanding of clinical presentations and new phenotypes. Skeletal muscle channelopathies cause significant disability and even death in some of the newly described phenotypes. Despite this, there are virtually no data on the epidemiology and longitudinal natural history of these conditions or randomized controlled trial evidence of efficacy or tolerability of any treatment in children, and thus best practice care recommendations do not exist. Clinical history, and to a lesser extent examination, is key to eliciting symptoms and signs that indicate a differential diagnosis of muscle channelopathy. Normal routine investigations should not deter one from the diagnosis. Specialist neurophysiologic investigations have an additional role, but their availability should not delay genetic testing. New phenotypes are increasingly likely to be identified by next-generation sequencing panels. Many treatments or interventions for symptomatic patients are available, with anecdotal data to support their benefit, but we lack trial data on efficacy, safety, or superiority. This lack of trial data in turn can lead to hesitancy in prescribing among doctors or in accepting medication by parents. Holistic management addressing work, education, activity, and additional symptoms of pain and fatigue provides significant benefit. Preventable morbidity and sometimes mortality occurs if the diagnosis and therefore treatment is delayed. Advances in genetic sequencing technology and greater access to testing may help to refine recently identified phenotypes, including histology, as more cases are described. Randomized controlled treatment trials are required to inform best practice care recommendations. A holistic approach to management is essential and should not be overlooked. Good quality data on prevalence, health burden, and optimal treatment are urgently needed. [ABSTRACT FROM AUTHOR]

We present the report of trismus due to hyperadrenocorticism-associated myotonia diagnosed by electromyography in a dog. An intact female Miniature Dachshund, 13 years and 9 months old, presented with stiff gait and trismus as well as polyuria and polydipsia. Abdominal ultrasonography showed enlarged adrenal glands. An adrenocorticotropic hormone stimulation test revealed an exaggerated response. Based on these findings, this case was diagnosed with hyperadrenocorticism. Electromyography revealed myotonic discharge in the temporalis muscle and limbs. Therefore, trismus was considered to be caused by hyperadrenocorticism-associated myotonia, and the case was treated with oral trilostane (1.3 mg/kg, once daily). During the 4-month follow-up period, despite the partial improvement in stiff gait, trismus did not recover. Long-term data on more cases are warranted to assess the prognosis and clinical characteristics of trismus due to hyperadrenocorticism-associated myotonia. [ABSTRACT FROM AUTHOR]

Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction of the GSK3β-CUGBP1 pathway in DM1 mice (HSALR model) expressing 250 CUG repeats using the GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected the expression of ~17% of genes misregulated in DM1 mice, including genes involved in cell transport, development and differentiation. The expression of chloride channel 1 (Clcn1), the key trigger of myotonia in DM1, was also corrected by TG. We found that correction of the GSK3β-CUGBP1 pathway in mice expressing long CUG repeats (DMSXL model) is beneficial not only at the prenatal and postnatal stages, but also during adulthood. Using a mouse model with dysregulated CUGBP1, which mimics alterations in DM1, we showed that the dysregulated CUGBP1 contributes to the toxicity of expanded CUG repeats by changing gene expression and causing CNS abnormalities. These data show the critical role of the GSK3β-CUGBP1 pathway in DM1 muscle and in CNS pathologies, suggesting the benefits of GSK3 inhibitors in patients with different forms of DM1. [ABSTRACT FROM AUTHOR]

[This corrects the article DOI: 10.3389/fneur.2020.00077.].

Background: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. Case presentation: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. Conclusions: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases. [ABSTRACT FROM AUTHOR]

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 since they have usually not been validated against robust functional assays. We compare 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 with Mutation Taster (84.58%) and REVEL (82.54%). However, both scores have poor specificity. EVE has better specificity. Combined methods based on concordance, improved performance overall but still lacked specificity. Our calculated statistics for the predictive tools are different to reported values for other genes in the literature suggesting that 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. [ABSTRACT FROM AUTHOR]

Introduction: Myotonic dystrophy type 2 (DM2) is a rare, multisystemic, autosomal dominant disease with highly variable clinical presentation. DM2 is considered to be highly underdiagnosed. Objective: The aim of this study was to determine which symptoms, signs, and diagnostic findings in patients referred to neurological outpatient units are the most indicative to arouse suspicion of DM2. We tried to make a useful and easy-to-administer clinical scoring system for early diagnosis of DM2-DM2 early diagnosis score (DM2-EDS). Patients and methods: Two hundred ninety-one patients with a clinical suspicion of DM2 were included: 69 were genetically confirmed to have DM2, and 222 patients were DM2 negative. Relevant history, neurological, and paraclinical data were obtained from the electronic medical records. Results: The following parameters appeared as significant predictors of DM2 diagnosis: cataracts (beta = 0.410, p < 0.001), myotonia on needle EMG (beta = 0.298, p < 0.001), hand tremor (beta = 0.211, p = 0.001), positive family history (beta = 0.171, p = 0.012), and calf hypertrophy (beta = 0.120, p = 0.043). In the final DM2-EDS, based on the beta values, symptoms were associated with the following values: cataracts (present 3.4, absent 0), myotonia (present 2.5, absent 0), tremor (present 1.7, absent 0), family history (positive 1.4, negative 0), and calf hypertrophy (present 1.0, absent 0). A cut-off value on DM2-EDS of 3.25 of maximum 10 points had a sensitivity of 84% and specificity of 81% to diagnose DM2. Conclusion: Significant predictors of DM2 diagnosis in the neurology outpatient unit were identified. We made an easy-to-administer DM2-EDS score for early diagnosis of DM2. [ABSTRACT FROM AUTHOR]

Schwartz–Jampel syndrome (SJS) is an autosomal recessive disorder caused by loss-of-function mutations in heparan sulfate proteoglycan 2 (HSPG2), which encodes the core basement membrane protein perlecan. Myotonia is a major criterion for the diagnosis of SJS; however, its evaluation is based solely on physical examination and can be challenging in neonates and young children. Furthermore, the pathomechanism underlying SJS-related myotonia is not fully understood, and effective treatments for SJS are limited. Here, we established a cellular model of SJS using patient-derived human-induced pluripotent stem cells. This model exhibited hyper-responsiveness to acetylcholine as a result of abnormalities in the perlecan molecule, which were confirmed via comparison of their calcium imaging with calcium imaging of satellite cells derived from Hspg2−/−-Tg mice, which exhibit myotonic symptoms similar to SJS symptoms. Therefore, our results confirm the utility of creating cellular models for investigating SJS and their application in evaluating myotonia in clinical cases, while also providing a useful tool for the future screening of SJS therapies. [ABSTRACT FROM AUTHOR]

ObjectiveTo identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, SCN4A.MethodsA combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and Xenopus oocytes.ResultsMissense mutations of the same residue in the skeletal muscle sodium channel, R1460 of NaV1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes.ConclusionsNovel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia.

Background. Dystrophic myotonia type 1 (DM1) is the most common muscular dystrophy in patients of any age. Myotonia “delayed relaxation of muscle” is the leading symptom in DM1 and can occur at any time after onset disease. Myotonia symptoms and electrical myotonia registration are delayed after onset in patients with congenital and infantile forms of DM1. This makes it difficult to diagnose and prevent fatal complications in these patients in a timely manner. Objective: presentation of the clinical data and results of needle electromyography in patients with DM1 onset in the first decade of the life; determination of the first symptoms of the disease, to estimate the age of myotonia and electrical myotonia manifestation for the optimization of the timely diagnostics of the disease.Materials and methods. 13 patients with DM1 aged from 2 months to 34 years were described. 10 patients underwent needle electromyography with analysis of spontaneous activity and needle EMG pattern. The diagnosis was made on the basis of clinical and paraclinical manifestations of the disease and identification of an increase in CTG repeats (>50) in the DMPK gene.Results. The onset with extramuscular signs of respiratory and/or feeding disturbances, dysarthria, school learning disorders, autism spectrum disturbance and “floppy infant syndrome” was noted as the first symptoms of the disease. Clinical myotonia symptoms and electrical manifestations of myotonia were absent in all patients for a long time after the disease onset. DM1 was confirmed in all mothers, however in 5 cases the onset of the disease was later than the first symptoms in patients with congenital and childhood onset forms of DM1.Conclusion. The first symptoms of the congenital and infantile forms of DM1 are not specific and occur in a wide range of diseases. Such discriminating signs of DM1 as clinical myotonia, distal muscle atrophy and electrical myotonia appear much later than the onset disease. In the group of patients before and after the formation of phrasal speech, the presented combinations of symptoms allow diagnostics of the congenital and infantile forms of DM1 at the onset of the disease. In its turn, it allows genetic counseling in burdened families and timely prevention of fatal complications.

A 21-year-old woman developed an acute myotonic reaction while undergoing anaesthesia using succinylcholine. Examination later showed she had shoulder, neck and calf hypertrophy, bilateral symmetrical ptosis and eyelid, handgrip and percussion myotonia. Peripheral neurophysiology studies identified significant, continuous myotonic discharges in both upper and lower limbs. Genetic analysis identified a c.3917G>A (p.Gly1306Glu) mutation in the SCN4A gene, confirming a diagnosis of sodium channel myotonia. Succinylcholine and other depolarising agents can precipitate lifethreatening acute myotonic reactions when given to patients with myotonia. Patients with neuromuscular disorders are at an increased risk of perioperative anaesthetic complications. We report a woman who developed an acute myotonic reaction whilst undergoing anaesthesia, in the context of an unrecognised myotonic disorder. We then discuss an approach to the diagnosis of myotonic disorders. [ABSTRACT FROM AUTHOR]

The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In several excitability disorders, including epilepsy, cardiac arrhythmias, chronic pain, and non-dystrophic myotonia, blockers of voltage-gated sodium channels are clinically used. Myotonia is a skeletal muscle condition characterized by the over-excitability of the sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. The therapeutic management of this disorder relies on mexiletine and other sodium channel blockers, which are not selective for the Nav1.4 skeletal muscle sodium channel isoform. Hence, the importance of deepening the knowledge of molecular requirements for developing more potent and use-dependent drugs acting on Nav1.4. Here, we review the available treatment options for non-dystrophic myotonia and the structure–activity relationship studies performed in our laboratory with a focus on new compounds with potential antimyotonic activity. [ABSTRACT FROM AUTHOR]

Musculoskeletal disorders include a wide range of disorders which affect the locomotor system, i.e. muscles, bones, joints, and associated connective tissues like tendons and ligaments, which are listed in Chapter XIII of the International Classification of Diseases (ICD-10). While the primary pathology affects locomotor system, a number of these disorders are associated with systemic complications, resulting in increased morbidity and mortality in the perioperative period. Burns are an acute emergency and require anaesthetic or critical care input for assessment of injuries, early surgical intervention or organ support. Major burns are a multisystem disorder and although they account for less than 5% of all new burns cases, their management is complex and requires multidisciplinary approach in a specialized centre. This chapter highlights the important considerations for perioperative management of these conditions. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital myotonia is a congenital disorder that affects skeletal muscles with myotonia. Affected muscles show stiffness and pain sometimes. The two major types of myotonia congenita are known as Thomsen disease and Becker disease. These conditions are distinguished by the severity of their symptoms and their patterns of inheritance. The causative factor is mutations in CLCN1 gene. Myotonia congenita is rarely reported in black especially in black African. Case presentation This is a case report of Becker Congenital Myotonia in a 36-year-old male from Benin. The symptoms arose at the age of 7 years with regular and progressive course and muscles pains. Electromyogram, blood sampling, laboratory investigations and muscles biopsy confirm the diagnostic with molecular finding. Conclusion The authors report a case of Becker congenital myotonia in a black African with molecular confirmation. Mexiletine was used as symptomatic agent with good results.

Myotonia congenita is a hereditary muscle disease mainly characterized by muscle hyperexcitability, which leads to a sustained burst of discharges that correlates with the magnitude and duration of involuntary aftercontractions, muscle stiffness, and hypertrophy. Mutations in the chloride voltage-gated channel 1 (CLCN1) gene that encodes the skeletal muscle chloride channel (ClC-1) are responsible for this disease, which is commonly known as myotonic chloride channelopathy. The biophysical properties of the mutated channel have been explored and analyzed through in vitro approaches, providing important clues to the general function/dysfunction of the wild-type and mutated channels. After an exhaustive search for CLCN1 mutations, we report in this review more than 350 different mutations identified in the literature. We start discussing the physiological role of the ClC-1 channel in skeletal muscle functioning. Then, using the reported functional effects of the naturally occurring mutations, we describe the biophysical and structural characteristics of the ClC-1 channel to update the knowledge of the function of each of the ClC-1 helices, and finally, we attempt to point out some patterns regarding the effects of mutations in the different helices and loops of the protein.

Introduction/Aims: Although 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. Methods: We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service. Results: Thirty‐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. Discussion: The 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 FROM AUTHOR]

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Pieters, D, Wezenbeek, E, De Ridder, R, Witvrouw, E, and Willems, T. Acute effects of warming up on Achilles tendon blood flow and stiffness. J Strength Cond Res 36(10): 2717–2724, 2022—The aim of this study was to investigate the acute effect of frequently used warm-up exercises on the Achilles tendon blood flow and stiffness. In doing so, we want to explore which exercises are suitable to properly prepare the athlete's Achilles tendon in withstanding high amounts of loading during sport activities. This knowledge could help sport physicians and physiotherapists when recommending warm-up exercises that are able to improve sport performance while reducing the injury susceptibility. Achilles tendon blood flow and stiffness measurements of 40 healthy subjects (20 men and 20 women) aged between 18 and 25 years were obtained before and immediately after 4 different warm-up exercises: running, plyometrics, eccentric heel drops, and static stretching. The effect of these warm-up exercises and possible covariates (sex, age, body mass index, rate of perceived exertion, and sports participation) on the Achilles tendon blood flow and stiffness was investigated with linear mixed models. The level of significance was set at α = 0.05. The results of this study showed a significant increase in Achilles tendon blood flow and stiffness after 10 minutes of running (p < 0.001 and p < 0.001) and plyometrics (p < 0.001 and p = 0.039). Static stretching and eccentric exercises elicited no significant changes. From these results, it could be suggested that warm-up exercises should be intensive enough to properly prepare the Achilles tendon for subsequent sport activities. When looking at Achilles tendon blood flow and stiffness, we advise the incorporation of highly intensive exercises such as running and plyometrics within warm-up programs. [ABSTRACT FROM AUTHOR]