Review of recent literature: Myotonia congenita.
Sources: Pub med: Central Library of the Faculty of Medicine in Zagreb
NKS proxy National University Library in Zagreb
August 2024
In the period from 2020-2024, relatively few works were published on non-dystrophic myotonia, i.e. congenital myotonia. Since DNA analysis is possible today in most countries, the largest number of earlier and new works represent population studies of the frequency of occurrence of myotonia congenita in certain countries and regions (regions in China, Egypt, Korea, Portugal, Bulgaria…). The frequency is lower than expected, probably due to the incomplete coverage of affected persons. Such tests enabled the discovery of new mutations of pathological gene changes, and now more than 280 mutations are known (in 2023).
Therapeutic procedures for non-dystrophic myotonia (myotonia congenita), symptomatic treatment of myotonia
Treatment of skeletal muscle channelopathies is a combination of lifestyle recommendations along with pharmacological interventions. The rarity of these conditions is an obstacle to clinical studies, but the example of a randomized clinical trial with mexiletine shows that innovative trial design can overcome these obstacles. Further research is needed to test the effectiveness of drugs that have been shown in preclinical trials to have promising effects in the treatment of myotonia, such as safinamide, riluzule and magnesium.
A review of the available literature did not find a single reference that would report potential substances before clinical studies (in vitro) that would enable etiological treatment that would change the natural course of the disease. This is expected considering that it is a rare disorder, with a large number of pathological gene mutations and a relatively benign course of the disease.
All tests are aimed at the symptomatic treatment of the myotonic phenomenon.
Physiologically, myotonia can be interpreted as an increase in the excitability of the muscle membrane. At the level of ion channels, it is caused by the loss of the function of chlorine channels (myotonia congenita) or the disruption of sodium channels (paramyotonia congenita). Pharmacological treatment could therefore theoretically target increasing chloride conductance and/or decreasing sodium channel opening. In practice, there have been no successful chlorine channel openers, and most of the pharmacological agents used to treat myotonia are focused on sodium channel blockers, regardless of which channels are primarily damaged.
Mexiletine is considered today as the drug of first choice in the symptomatic treatment of non-dystrophic myotonic disorders. In 2018, it was approved in Europe (EMA) for this indication with the designation of drug for rare diseases. It is primarily an antiarrhythmic, and is used in cardiology to treat heart rhythm disorders.
Mexiletine blocks sodium channels more intensively in situations of excessive increase in action potentials and/or prolonged depolarization, which occurs in diseased muscles, than in physiological excitability. Mexiletine is therefore most active on muscle fibers that are frequently activated (such as skeletal muscles). It relieves the symptoms of myotonia by reducing muscle stiffness by shortening the delay in muscle relaxation.
Given that it is a rare disease, randomized controlled clinical trials are difficult to perform due to the small number of patients. “Myomex study” 2021 is the first randomized, double-blind, placebo-controlled, cross-over, multicenter trial. A study with 59 patients with NDM showed that mexiletine 200 mg three times a day significantly reduces stiffness and myotonia of the hand and other muscles. This had an impact on the quality of life. The most common side effects
that affected 38% of respondents were gastrointestinal complaints (nausea, abdominal pain) and insomnia. Some participants experienced transient bradycardia, but this did not require discontinuation of treatment. However, it should be noted that the dose of Mexiletine 600mg per day is very high, and many clinicians do not recommend it.
Antiepileptics – (lamotrigine, carbamazepine) are sodium channel blockers and also reduce hyperexcitability of the muscle membrane. Lamotrigine was tested in a double-blind, randomized, placebo-controlled trial in 26 patients with genetically confirmed dg. myotonia congenita and paramyotonia congenita. Oral lamotrigine was administered once daily in escalating doses of 25 to 300 mg for 8 weeks. Only the estimated severity of myotonia according to the Myotonia Behavior Scale (MBS) was reduced by 29%. Lamotrigine also improved clinical myotonia and quality of life. The most common side effects were headache, skin rash, muscle pain, and fatigue, which were considered acceptable and resolved after stopping the drug. Lamotrigine is a suitable alternative if mexiletine is not effective (because it works in a different way) or if its use is not possible due to contraindications and side effects.
Flecainide is a class Ic antiarrhythmic. In experiments in vitro, it showed that the specific block of sodium channels of human skeletal muscle is greater compared to mexiletine. However, although quite effective, it is rarely used due to the possible triggering of dangerous arrhythmias in patients with structural heart problems. As the incidence of heart disease increases with age, and myotonia treatment is often lifelong, this risk increases over time.
There are reports of trials of several substances that have been hypothesized to have antimyotonic effects such as the antiarrhythmics tocainamide and procainamide, the antiepileptic (phenytoin) antidepressants imipramine, and amitriptyline and other substances including taurine, quinine, dantrolene and dehydroepiandrosterone sulfate, botulinum toxin. However, it was about small studies. Today, these preparations are considered outdated, since there is an alternative with a better effect and less side effects, some of them have been completely discarded.
Possible new antimyotonic drugs
Although there are several treatment options for myotonia, many patients do not achieve satisfactory symptom control due to insufficient efficacy, side effects and contraindications that prevent the use of some drugs. Therefore, research into new antimyotonic substances is needed.
Although it is known that myotonia congenita is caused by a mutation in the CLCN gene that encodes the voltage-gated chloride channels of skeletal muscle, this discovery has led to little progress in the development of therapy. Current treatment is primarily aimed at reducing hyperexcitability by blocking Na+ channels. Other approaches such as increasing the potassium ion current may also be effective. A study of the K+ channel activator antiepileptic drug retigabine was conducted, which showed a significant reduction in the duration of myotonia in vitro. However, retigabine did not improve the motility of the tested mice with myotonia congenita.
Safinamide is a well-known neuronal sodium channel blocker used as an adjunctive therapy for Parkinson’s disease. A recent report based on in vitro cell models and a rat model suggests that it has an effect on reducing myotonia.
Rilulzole and lubeluzole, (benzothiazolamines) with known sodium ion channel blocking effects have also shown promising antimyotonic properties in a rat myotonia model. However, lubeluzole has possible cardiac side effects (prolongation of the QT interval). Riluzole has a good safety profile as a licensed drug used in patients with motor neuron diseases. It is neuroprotective and activity is thought to be mediated by inhibition of sodium influx, a mechanism that can also reduce muscle hyperexcitability.
Lifestyle and diet
Exercise or rest after exercise can be the main trigger of myotonia, but activity is essential for a healthy lifestyle. Therefore, it is important to find a balance between activities that can be performed without causing symptoms and inactivity that can not only worsen myotonia, but also lead to an increase in the risk of developing other accompanying diseases.
Patients with myotonia should avoid sudden forceful contraction, i.e. sudden movement and instead gradually increase activity, with occasional rests during certain activities. Exposure to cold is a risk for the development of myotonic spasm in congenital paramyotonia, but people with congenital myotonia should also wear appropriate clothing and avoid major physical activities in open spaces during colder weather. A particular risk is swimming in cold water, where increased stiffness can be life-threatening. Dietary changes do not affect most patients with myotonia, but some people with sodium channel mutations (paramyotonia congenita) may be sensitive to a potassium-rich diet.
Literature:
- Stunnenberg BC, LoRusso S, Arnold WD, Barohn, Cannon SC, Fontaine B, Griggs RC, Hanna MG, Matthews E, Meola G, Sansone. Trivedi JR, van Engelen B Vicart, Statland JM: Guidelines on clinical presentation and management of nondystrophic myotonias; Muscle Nerve. 2020;62:430–444
- Arnold DV, Kline D, Sanderson A, Hawash AA, Bartlett A, Novak KR, Rich MM, Kissel, JT: Open-label trial of ranolazine for the treatment of myotonia congenita; Neurology89 August 15, 2017
- Dupont CX, Denman CS, Hawash AA, Voss AA, Rich MM: Treatment of Myotonia Congenita with Retigabine in Mice; Exp Neurol. 2019 May ; 315: 52–59.
- Jitpimolmard N. Matthews E, Fialho D: Treatment Updates for Neuromuscular Channelopathies; Curr Treat Options Neurol (2020) 22: 34
- Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA. Salajegheh MK, Venance SL, Ciafaloni E, Matthews E, Meola G, Herbelin L, Griggs RC, Barohn RJ, Hanna MG: Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia A Randomized Controlled Trial JAMA, October 3, 2012—Vol 308 , No. 13
- Trip J, Drost G, Engelen B.G.M, van; Faber C.G: Drug treatment for myotonia The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2011
- Desaphya JF, Altamuraa C, Vicartb S. Fontaine B: Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine; Journal of Neuromuscular Diseases 8 (2021) 357–381
- Hoppe K, Sartorius T, Chaiklieng S, Wietzorrek G, Ruth P, Jurkat-Rott K, Wearing S, Lehmann-Horn F, Klingler W: Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia A Preclinical investigation Frontiers in Physiology 2020 | Volume 11 | Article 533946
