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Revue Neurologique May 2024Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as...
Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as lifestyle adaptation and avoiding key triggers. To understand how myotonia affects patients' lives, the IMPACT survey, an online questionnaire on patient-reported outcomes, was developed based on international IMPACT questionnaire. The French IMPACT 2022 survey was completed by 47 NDM French patients. Besides muscle stiffness (98%), patients reported muscle pain (83%), falls (70%) and anxiety (77%). These issues negatively impacted abilities to work/study (49%), daily life at home (49%) and overall mobility outside (49%). Most patients (96%) reported ongoing pharmacological treatment (mexiletine, 91%) associated with improvement in muscle stiffness (100%) and reduction in falls (94%), muscle pain (87%) and anxiety (80%). Patients were moderately satisfied (19.1%), satisfied (42.6%) and very satisfied (29.8%) with the current management; 32% rated their quality of life positively (≥ 8 on 10-point scale). In conclusion, this French survey confirms the impact of myotonia on daily life and quality of life. The improvement in patient-reported outcomes in treated participants highlights the importance of managing myotonia with effective treatments. More work should be initiated to assess the importance of NDM symptom management and patients' adherence and compliance to treatment.
PubMed: 38811249
DOI: 10.1016/j.neurol.2024.04.007 -
Frontiers in Pharmacology 2024Na1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating... (Review)
Review
Na1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in Na1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of Na1.4 in complex with β1 has opened new possibilities for designing drugs and toxins that target Na1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with Na1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting Na1.4. Therefore, studying Na1.4 pharmacology is both theoretically and practically meaningful.
PubMed: 38725668
DOI: 10.3389/fphar.2024.1378315 -
Archives of Cardiovascular Diseases 2024In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with... (Review)
Review
In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.
Topics: Adult; Humans; Algorithms; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Decision-Making; Compassionate Use Trials; Consensus; France; Mexiletine; Myotonic Dystrophy; Risk Assessment; Risk Factors; Treatment Outcome; Voltage-Gated Sodium Channel Blockers
PubMed: 38677940
DOI: 10.1016/j.acvd.2024.03.001 -
Cureus Feb 2024Congenital myotonia represents a rare group of genetically inherited conditions. It can be either autosomal dominant (Thomsen) or autosomal recessive (Becker). It is...
Congenital myotonia represents a rare group of genetically inherited conditions. It can be either autosomal dominant (Thomsen) or autosomal recessive (Becker). It is characterized by muscular hypertrophy, proximal weakness, and myotonia, or impaired relaxation after contraction. These are due to mutations in the CLC1 gene. A 14-year-old male child presented with complaints of gradually progressive weakness for five years. Weakness was more pronounced in the proximal muscle groups. The weakness worsened after rest and improved with activity. This led to absenteeism and affected his school performance. Clinical examination showed generalized muscular hypertrophy with pronounced hypertrophy of the calf muscles. A neurological examination showed significant myotonia and impaired relaxation after making a fist. The diagnosis of myotonia was confirmed by electromyography, which produced a dive-bomber sound on insertion. Next-generation sequencing revealed a homozygous eight-base pair insertion in exon 19 of the CLCN1 gene. This mutation has not been reported in the existing literature for myotonia congenita. The child was started on mexiletine and improved significantly. Presently, the patient is on regular medications and doing well on follow-up. Though rare, congenital myotonia is an important cause of neuromuscular weakness. It can be easily diagnosed with a thorough clinical examination and routine testing for myotonia in all children with weakness. The treatment is relatively simple and can give the patient significant relief. Myotonia can be easily diagnosed clinically, and pharmacotherapy and proper monitoring can remarkably improve patients' quality of life.
PubMed: 38469025
DOI: 10.7759/cureus.53981 -
Journal of Neuromuscular Diseases 2024The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1...
BACKGROUND
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation.
METHODS
Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected.
RESULTS
A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude.
CONCLUSIONS
The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.
Topics: Adult; Female; Humans; Middle Aged; Electromyography; Italy; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Point Mutation
PubMed: 38427496
DOI: 10.3233/JND-230134 -
Clinical Research in Cardiology :... Jun 2024Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require... (Review)
Review
Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require antiarrhythmic drug therapy and may, e.g., in otherwise drug and/or ablation refractory situations, benefit from agents known for decades, such as mexiletine. Through its capability of blocking fast sodium channels in cardiomyocytes, it has played a minor to moderate antiarrhythmic role throughout the recent decades. Nevertheless, certain patients with structural heart disease suffering from drug-refractory, i.e., mainly amiodarone refractory ventricular arrhythmias, as well as those with selected forms of congenital long QT syndrome (LQTS) may nowadays still benefit from mexiletine. Here, we outline mexiletine's cellular and clinical electrophysiological properties. In addition, the application of mexiletine may be accompanied by various potential side effects, e.g., nausea and tremor, and is limited by several drug-drug interactions. Thus, we shed light on the current therapeutic role of mexiletine for therapy of ventricular arrhythmias and discuss clinically relevant aspects of its indications based on current evidence.
Topics: Mexiletine; Humans; Anti-Arrhythmia Agents; Tachycardia, Ventricular; Treatment Outcome
PubMed: 38353682
DOI: 10.1007/s00392-024-02383-9 -
World Journal of Clinical Cases Jan 2024Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on...
BACKGROUND
Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies.
CASE SUMMARY
We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated.
CONCLUSION
In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.
PubMed: 38322461
DOI: 10.12998/wjcc.v12.i3.587 -
Journal of Neuromuscular Diseases 2024Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction...
BACKGROUND
Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented.
OBJECTIVE
Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic.
METHODS
A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice.
RESULTS
The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic.
CONCLUSIONS
Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.
Topics: Adult; Humans; Mexiletine; Myotonia; Neurologists; Myotonic Dystrophy; Italy
PubMed: 38306059
DOI: 10.3233/JND-230115 -
Emergency Medicine International 2024[This retracts the article DOI: 10.1155/2022/4078895.].
Retracted: Curative Effect of Yangxin Dingji Capsule Combined With Mexiletine Hydrochloride on Postoperative Arrhythmia and Its Influences on the Vascular Endothelial Function in Coronary Bifurcation Lesions.
[This retracts the article DOI: 10.1155/2022/4078895.].
PubMed: 38299003
DOI: 10.1155/2024/9756981