The Non-dystrophic Myotonias: Molecular Pathogenesis, Diagnosis and Treatment

E. Matthews; D. Fialho; S. V. Tan; S. L. Venance; S. C. Cannon; D. Sternberg; B. Fontaine; A. A. Amato; R. J. Barohn; R. C. Griggs; M. G. Hanna


Brain. 2010;133(1):922 

In This Article


For those patients with mild symptoms no specific drug treatment may be needed, although it is important to provide advice regarding the avoidance of precipitating factors such as cold exposure or strenuous exercise. In those patients with significant symptoms and disability from myotonia, a variety of agents have been suggested which we outline in chronological order.

In early studies, procainamide, quinine and glucocorticosteroids were employed. A small randomized double blind trial compared the efficacy of each of these treatments in relation to placebo in 20 individuals with myotonic disorder (16 myotonic dystrophy, 4 myotonia congenita). The diagnosis was made on a clinical basis without genetic confirmation. The trial lasted 12 weeks and all participants received each of the four treatments for a 3 week period with no washout period. An end-point of at least a 50% reduction in the duration of hand grip myotonia, measured by EMG and timed clinically, was employed. Using this endpoint, 6/20 participants taking quinine, 15/20 taking procainamide, 15/19 taking prednisone (one patient did not receive prednisone) and 0/20 taking placebo showed improvement (Leyburn and Walton, 1959). This study, although imperfect, illustrated a low efficacy of quinine. Despite the suggested benefits of procainamide and prednisone the side effect profile of both these drugs restricts their use and they are no longer recommended as therapeutic agents in the non-dystrophic myotonias.

The carbonic anhydrase inhibitor acetazolamide is commonly used in the periodic paralyses and has been reported to be beneficial in the non-dystrophic myotonias (Trudell et al., 1987; Ferriby et al., 2006). In a small series of nine patients with myotonia, seven diagnosed clinically with myotonia congenita and two with paramyotonia congenita, all cases reported a subjective and objective (timed measurements of myotonia) improvement in myotonia with acetazolamide. However, one individual with paramyotonia congenita developed quadrapareses 12 h after the ingestion of acetazolamide (Griggs et al., 1978). Larger studies of acetazolamide use in the non-dystrophic myotonias have not been performed, and while there is evidence of some benefit, it is not generally considered as a first line agent for the treatment of myotonia.

Anti-convulsants, local anaesthetics and anti-arrhythmic drugs which block sodium channels are the most frequently used agents in the treatment of myotonia. There are currently no safe drugs which specifically act on the chloride channel CLCN-1 (Verkman et al., 2009). Phenytoin has been shown to improve the righting time of myotonic mice turned onto their backs (Aichele et al., 1985). Ricker et al. (1978) reported subjective improvement in muscle stiffness and an improved timed walk in one patient with myotonia congenita and a dose dependant improvement in isometric force in another. The lignocaine derivative tocainide gave encouraging results initially (Rudel et al., 1980; Streib, 1987) but was eventually withdrawn from the market due to the risk of potentially fatal agranulocytosis (Volosin et al., 1985). Synthesis of tocainide analogues has been attempted in vitro and it may be of value for future study as anti-myotonic agents if the efficacy and side effect profiles are favourable (Catalano et al., 2008).

More recently class I anti-arryhthmics have offered potential for treatment. Flecainide, a class Ic anti-arrhythmic, has been shown to be effective in vitro (Aoike et al., 2006) although its use in clinical practice as an anti-myotonic agent is rarely reported (Rosenfeld et al., 1997). An improvement in clinical symptoms and cold induced EMG findings with propafenone, another class Ic anti-arrhythmic has been reported in a single case of paramyotonia congenita (Alfonsi et al., 2007).

The class Ib anti-arrhythmic mexiletine is generally considered to be the first-line treatment of choice by myologists but a randomized controlled trial is required. It is usually well tolerated with only minor side effects reported. Importantly it has pro-arrhythmic potential and therefore pre- and post-treatment ECGs are essential to ensure satisfactory QT interval. More extensive cardiac evaluation prior to commencement is important if there is an abnormal baseline ECG or a history of cardiac disease. Single case reports have shown that mexiletine is effective in treating myotonia in both sodium and chloride channel disorders (Ceccarelli et al., 1992; Jackson et al., 1994). However, a recent Cochrane review highlighted the lack of adequate randomized double blind placebo controlled trials to prove efficacy (Trip et al., 2006). The ability to conduct such trials is partly hampered by the difficulty in quantitating myotonia (Torres et al., 1983; Hammaren et al., 2005; Logigian et al., 2005; Moxley et al., 2007; Hogrel, 2009) and in recruiting adequate numbers of patients to achieve statistical power. A recent study employed trunk sway analysis to measure the warm up phenomenon in recessive myotonia congenita and proposed that with further evaluation this may offer an alternative potential end-point for therapeutic trials (Horlings et al., 2009).

Sodium MRI has also recently been proposed as a possible outcome measure in patients with sodium channel diseases. An increase in intramuscular sodium content was demonstrated to accompany muscle weakness following exercise of cooled muscles in paramyotonia congenita. In a small group of patients this increase was significantly reduced following treatment with mexiletine (Weber et al., 2006). It is possible this technique could be used to monitor response to treatment in both a clinical and research setting. The Consortium for Clinical Investigation of Neurologic Channelopathies is currently performing a double-blind, placebo-controlled cross-over study of mexiletine for non-dystrophic myotonias (see and will study 60 subjects with paramyotonia congenita and myotonia congenita. The primary endpoint measurement is patient stiffness as reported in the interactive voice response system (Wang, 2008c). The interactive voice response was chosen as the primary endpoint for this study as quantification of myotonia using handgrip devices has not consistently demonstrated the delayed relaxation phenomenon in patients with non-dystrophic myotonia (Wang, 2008c). It is hypothesized that patients' self-reported responses of stiffness will be a more consistent and reliable endpoint measurement in order to determine efficacy of drug response.

In vitro studies continue to identify pharmacological agents that preferentially block sodium channels in the open state, thereby targeting persistent sodium currents (Wang et al., 2008a, b). These studies may identify future therapies.

No drugs are available which specifically act on the CLCN-1 channel. A number of experimental approaches may have future implications for the treatment of myotonia congenita (Cleland et al., 2008). It has been shown that alternative splicing of the CLCN-1 gene contributes to the myotonia in myotonic dystrophy type I and that directed anti-sense morpholino oligonucleotides to skip exon 7a restores chloride channel function and abolishes myotonia in a mouse model of myotonic dystrophy type I (Wheeler et al., 2007). It is possible that the development of this technique and its delivery could be a potential treatment for those cases of myotonia congenita due to splice site mutations.

Trans-splicing is a natural form of RNA processing where exons from two separate RNA transcripts are joined together. This can be manipulated to restore normal RNA processing of a mutant transcript. Such a technique has been employed using a trans-splicing ribozyme to restore a mutant chloride channel transcript in a cellular model. Although a good recovery of chloride channel function was observed in individual cells the efficiency of RNA repair in the cell culture as a whole was only 1.2% (Rogers et al., 2002).

Improving defective CLCN-1 channel protein transport from the endoplasmic reticulum to the Golgi apparatus is another potential therapeutic strategy. Defective transport has been demonstrated for the F413C and A531V CLCN-1 mutations associated with recessive myotonia congenita (Papponen et al., 2008). Furthermore, functional expression of the F413C mutation in vitro showed only a minimal shift in chloride conductance (Zhang et al., 2000). This suggests that if the protein could be restored to the muscle membrane, this may result in an at least partial restoration of chloride conductance. Pharmacological therapies need to be developed that promote correct trafficking and which also build on the partial success of trans-splicing techniques safely.

It remains to be established if more specific therapies will not only reduce myotonic symptoms but, if given prophylactically, will also reduce the probability of developing a fixed myopathy.


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