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

Disclosures

Brain. 2010;133(1):922 

In This Article

Abstract and Introduction

Abstract

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

Introduction

The non-dystrophic myotonias are skeletal muscle ion channel disorders traditionally considered to be distinct from myotonic dystrophy because of the absence of progressive weakness and systemic features. The non-dystrophic myotonias are now known to be caused by dysfunction of key skeletal muscle ion channels and include myotonia congenita, paramyotonia congenita and the sodium channel myotonias. The worldwide prevalence of non-dystrophic myotonia has been estimated to be ~1 in 100 000 (Emery, 1991). However, the prevalence seems to vary considerably between geographical regions. For example, myotonia congenita alone was estimated to have a prevalence of between 7 and 10 in 100 000 in Scandinavia (Baumann et al., 1998; Sun et al., 2001).

The major clinical manifestation of the non-dystrophic myotonias is muscle stiffness as a consequence of the myotonia. Additional common symptoms include pain, weakness and fatigue (Walsh et al., 2007; Trivedi et al., 2008; Wang et al., 2008c). Myotonia can be demonstrated on examination as delayed muscle relaxation following muscle contraction or following mechanical stimulation such as percussion. The underlying muscle membrane hyper-excitability manifests neurophysiologically as repetitive muscle fibre after-discharges on EMG. Recent studies have revealed a wide range of clinical phenotypes which may present diagnostic difficulty. Importantly, it has also been observed that patients with myotonic dystrophy type II may present with a clinical phenotype that is difficult to distinguish from myotonia congenita (Fialho et al., 2007). It is now clear that the clinical severity of these disorders can range from a neonatal life threatening presentation through to mild late-onset symptoms. The application of specialized electrophysiological protocols can reveal gene-specific patterns which can be used to direct DNA-based diagnosis (Fournier et al., 2004).

Myotonia congenita is caused by mutations in the skeletal muscle chloride channel gene (CLCN-1) and inherited in a dominant or in a recessive fashion. Paramyotonia congenita and the sodium channel myotonias are allelic, autosomal dominant disorders caused by point mutations in the skeletal muscle sodium channel gene (SCN4A). Hyperkalaemic periodic paralysis is also caused by mutations in SCN4A and may be accompanied by myotonia in some cases, although episodic paralysis is usually the dominant feature (Venance et al., 2006).

Here we review clinical presentations, genetics, electrodiagnosis and molecular pathogenesis of these disorders. We highlight important largely unresolved questions in relation to morbidity and natural history, mechanisms of muscle degeneration and treatment.

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