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Pflugers Archiv : European Journal of... Oct 2020In myotonia, reduced Cl conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane...
In myotonia, reduced Cl conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. Repetitive contraction temporarily decreases myotonia, a phenomena called "warm up." The underlying mechanism for the reduction of hyperexcitability in warm-up is currently unknown. Since potassium displacement is known to reduce excitability in, for example, muscle fatigue, we characterized the role of potassium in native myotonia congenita (MC) muscle. Muscle specimens of ADR mice (an animal model for low gCl conductance myotonia) were exposed to increasing K concentrations. To characterize functional effects of potassium ion current, the muscle of ADR mice was exposed to agonists and antagonists of the big conductance Ca-activated K channel (BK) and the voltage-gated Kv7 channel. Effects were monitored by functional force and membrane potential measurements. By increasing [K] to 5 mM, the warm-up phenomena started earlier and at [K] 7 mM only weak myotonia was detected. The increase of [K] caused a sustained membrane depolarization accompanied with a reduction of myotonic bursts in ADR mice. Retigabine, a Kv7.2-Kv7.5 activator, dose-dependently reduced relaxation deficit of ADR myotonic muscle contraction and promoted the warm-up phenomena. In vitro results of this study suggest that increasing potassium conductivity via activation of voltage-gated potassium channels enhanced the warm-up phenomena, thereby offering a potential therapeutic treatment option for myotonia congenita.
Topics: Animals; Chloride Channels; Chlorides; KCNQ Potassium Channels; Large-Conductance Calcium-Activated Potassium Channels; Male; Membrane Potentials; Mice; Muscle Contraction; Mutation; Myotonia Congenita; Potassium; Potassium Channel Blockers
PubMed: 32748018
DOI: 10.1007/s00424-020-02410-4 -
Zhonghua Nei Ke Za Zhi Jul 2020To investigate the clinical, myopathological and genetic mutation characteristics in two Chinese families with paramyotonia congenita (PMC). Clinical manifestations,...
To investigate the clinical, myopathological and genetic mutation characteristics in two Chinese families with paramyotonia congenita (PMC). Clinical manifestations, electrophysiology, muscle pathology and gene sequencing of two Chinese families with PMC were analyzed retrospectively. Family 1 involved 12 patients in 4 consecutive generations and family 2 involved only 1 patient in 3 generations. The onset of symptoms in all patients started at early childhood. Both probands presented with myotonia triggered by cold and paroxysmal weakness. However, the other 11 patients in family 1 only manifested cold-induced myotonia. Serum creatine kinase (CK) was slightly elevated between attacks of weakness in the 2 probands, and was even greater than 10 000 U/L during the episodes of weakness in the second proband, whose lower limb MRI revealed edema in bilateral medial gastrocnemius. Electromyography showed diffuse myotonia discharge and myogenic impairment in both probands, and myotonia discharge in the first proband's mother. Muscle pathology of both probands showed mild myopathic changes, and tube aggregation was occasionally observed in the second one. Genetic testing revealed a maternally inherited heterozygous R1448H mutation of SCN4A gene in the first proband and part of his family. A novel heterozygous R1448G mutation of SCN4A gene was reported in the second proband. Cold-triggered myotonia with or without paroxysmal weakness are the common characteristics of PMC. Myotonic potential and myogenic impairment can be tested in electromyography. The p.R1448G mutation is a new missense mutation.
Topics: Child; Child, Preschool; Humans; Mutation; Mutation, Missense; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Retrospective Studies
PubMed: 32594687
DOI: 10.3760/cma.j.cn112138-20191014-00690 -
Neurological Sciences : Official... Dec 2021Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis,...
INTRODUCTION
Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are distinguished from dystrophic myotonias by the absence of progressive weakness and extramuscular systemic involvement.
METHODS
We present an Italian family with 2 subjects carrying a p.Asn1180Ile mutation in SCN4A gene showing a peculiar clinical picture characterized by the association of myopathic features and myotonia.
RESULTS
The clinical, electromyographic and histological findings of these patients are reported. The possible pathogenicity of the mutation was tested by three different software, all giving positive results.
DISCUSSION
This is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of non-congenital myopathy and myotonic syndrome. We suggest that, in patients with myotonia and myopathy not related to dystrophic myotonias, the sequence analysis of SCN4A gene should be performed.
Topics: Humans; Muscular Diseases; Mutation; Myotonia; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Pedigree
PubMed: 34378097
DOI: 10.1007/s10072-021-05537-z -
Experimental and Clinical... Jun 2023Czechoslovakia was created after the First World War in 1918 as a common state of Czechs, Moravians, and Slovaks. After several transformations, 2 separate republics...
Czechoslovakia was created after the First World War in 1918 as a common state of Czechs, Moravians, and Slovaks. After several transformations, 2 separate republics were established from Czechoslovakia in 1993: the Czech Republic and the Slovak Republic. The objective of this article was to analyze the Prague Spring (1968), the period after the invasion into Czechoslovakia by Warsaw Pact Troops (1968), the period of cruel normalization (1968-1989), and the influence of Soviet domination in the Czechoslovak Republic on people with higher education. The invasion of the Warsaw Pact Troops into Czechoslovakia and the period of normalization had a highly negative impact on the life and work of the Czechoslovak people. Many eminent scientists left the Republic. The reason for this was persecution for their attitude to the situation behind the Iron Curtain. Professor Jan Brod, a world-renowned nephrologist and cardiologist, one of the signatories of the Two Thousand Words Manifesto, emigrated to the Federal Republic of Germany in 1968. Professor William Ganz, a world-renowned cardiologist of Slovak origin, emigrated to the United States in 1966. With Jeremy Swan, he was a coinventor of the Swan-Ganz balloon flotation catheter. Primary reasons for the emigration of scientists from Czechoslovakia was the suppression of the nascent democracy (the Prague Spring in 1968 by the invasion of Warsaw Pact Troops and the continuation of Soviet rule).
Topics: Male; Humans; United States; Czechoslovakia; Emigration and Immigration; Slovakia; Interpersonal Relations; Myotonia Congenita
PubMed: 37496349
DOI: 10.6002/ect.IAHNCongress.17 -
Brain : a Journal of Neurology Feb 2020Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the...
Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
Topics: Adolescent; Adult; Calcium-Transporting ATPases; Child; Female; Humans; Male; Muscle, Skeletal; Muscular Diseases; Mutation; Myotonia Congenita; Phenotype; Sarcoplasmic Reticulum; Young Adult
PubMed: 32040565
DOI: 10.1093/brain/awz410 -
Neuromuscular Disorders : NMD Apr 2022Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst...
Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst in others (e.g. Hypokalaemic periodic paralysis) rodent physiology is protective. This suggests a species' difference in muscle excitability properties. In humans these can be measured indirectly by the post-impulse changes in conduction velocity, using Muscle Velocity Recovery Cycles (MVRCs). We performed MVRCs in mice and compared their muscle excitability properties with humans. Mouse Tibialis Anterior MVRCs (n = 70) have only one phase of supernormality (increased conduction velocity), which is smaller in magnitude (p = 9 × 10), and shorter in duration (p = 3 × 10) than human (n = 26). This abbreviated supernormality is followed by a period of late subnormality (reduced velocity) in mice, which overlaps in time with the late supernormality seen in human MVRCs. The period of late subnormality suggests increased t-tubule Na/K-pump activity. The subnormal phase in mice was converted to supernormality by blocking ClC-1 chloride channels, suggesting relatively higher chloride conductance in skeletal muscle. Our findings help explain discrepancies in phenotype between mice and humans with skeletal muscle channelopathies and potentially other neuromuscular disorders. MVRCs are a valuable new tool to compare in vivo muscle membrane properties between species and will allow further dissection of the molecular mechanisms regulating muscle excitability.
Topics: Channelopathies; Humans; Hypokalemic Periodic Paralysis; Muscle Fibers, Skeletal; Muscle, Skeletal; Myotonia Congenita
PubMed: 35339342
DOI: 10.1016/j.nmd.2022.02.011 -
Cureus Jun 2023Non-dystrophic myotonia (NDM) is a group of rare mono-genetic muscle disorders caused by skeletal muscle sodium or chloride channelopathies. These disorders are...
Non-dystrophic myotonia (NDM) is a group of rare mono-genetic muscle disorders caused by skeletal muscle sodium or chloride channelopathies. These disorders are characterized by high muscle tone and the inability of the muscles to relax spontaneously after voluntary contraction. Myotonia congenita refers to a form of NDM that typically manifests during the later stages of childhood. It occurs as a result of genetic mutations affecting the chloride channels found in the sarcolemma membrane of skeletal muscles. Here, we present a case series of two male siblings born out of third-degree consanguineous union ages 10 and eight years, respectively, who presented with proximal muscle weakness and the characteristic "Herculean body" appearance. They demonstrated characteristic clinical diagnostic signs of myotonia. The diagnosis of myotonia congenita was confirmed through distinctive electromyography (EMG) findings, which were further supported by genetic testing revealing a homozygous mutation c.1445G>A in exon 13 of the CLCN1 gene, indicating autosomal recessive inheritance. This uncommon condition exhibits characteristic clinical manifestations and classical EMG findings, which are difficult to disregard once encountered. Genetic tests serve as a valuable tool to validate the diagnosis.
PubMed: 37489215
DOI: 10.7759/cureus.40869 -
Muscle & Nerve Apr 2020Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis...
INTRODUCTION
Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM.
METHODS
We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM.
RESULTS
All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001).
DISCUSSION
Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.
Topics: Action Potentials; Electric Stimulation; Electrodiagnosis; Electromyography; Exercise Test; Female; Humans; Male; Muscle, Skeletal; Mutation; Myotonia Congenita; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ulnar Nerve
PubMed: 31944327
DOI: 10.1002/mus.26809 -
Journal of Biomedical Science Jan 2021Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently,...
BACKGROUND
Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown.
METHODS
Histopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated.
RESULTS
While TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, L-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by L-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by L-carnitine treatment.
CONCLUSIONS
These results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.
Topics: Animals; Animals, Genetically Modified; Carnitine; Muscle, Skeletal; Myotonia Congenita; Tropomyosin; Zebrafish
PubMed: 33435938
DOI: 10.1186/s12929-020-00707-1 -
Journal of Neuromuscular Diseases 2020Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to... (Review)
Review
BACKGROUND
Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon.
CASE REPORT
We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy.
CONCLUSIONS
PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.
Topics: Facial Muscles; Hand; Humans; Magnetic Resonance Imaging; Masticatory Muscles; Muscle Weakness; Muscle, Skeletal; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Pedigree
PubMed: 32083589
DOI: 10.3233/JND-190440