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


Skeletal Muscle Chloride Channel

Recessive and dominant myotonia congenita are caused by mutations in the voltage gated chloride channel gene on chromosome 7q35. (Koch et al., 1992; George et al., 1993). The functional chloride channel exists as a dimeric structure with two gating pores. To date, over 100 missense, non-sense, insertions, deletions and splice site mutations have been identified throughout CLCN-1. Many patients carry 'private' mutations. It is a particular feature of myotonia congenita that several mutations have been reported to be inherited in both an autosomal dominant and autosomal recessive manner in different families (George et al., 1994; Meyer-Kleine et al., 1995; Zhang et al., 1996; Papponen et al., 1999; Sun et al., 2001). The advent of molecular genetic testing has demonstrated that familial non-dystrophic myotonia with dominant inheritance is often caused by missense mutations in SCN4A. Those CLCN-1 mutations that do cause dominant myotonia congenita seem to cluster in exon 8 of the gene (Fialho et al., 2007)

A recent report indicates that there is a higher frequency of recessive CLCN-1 mutations in myotonic dystrophy type II patients from Finnish and German populations. In the cases described, co-segregation of the CCTG expansion in the first intron of zinc finger protein-9 and a CLCN-1 mutation produced more severe myotonia than is commonly encountered in myotonic dystrophy type II. However, the number of cases was too small for this finding to be statistically significant (Suominen et al., 2008). It is therefore not yet established if the presence of a CLCN-1 mutation is a genetic modifier of the myotonic dystrophy type II phenotype. This is an attractive hypothesis since both genetic changes would be predicted additively to impair chloride channel function. These findings also suggest that analysis of the myotonic dystrophy type II gene expansion should be considered in patients with myotonia only harboring a single recessive CLCN-1 mutation.

Skeletal Muscle Sodium Channel

Hyperkalaemic periodic paralysis was the first of the sodium channel disorders to be linked to the SCN4A gene on chromosome 17 which encodes the skeletal muscle voltage gated sodium channel Nav1.4 (Fontaine et al., 1990; Koch et al., 1991b; Ptacek et al., 1991c). Given some of the shared clinical features of hyperkalaemic periodic paralysis and paramyotonia congenita and the recognition of abnormal sodium conductance in both (Lehmann-Horn et al., 1981, 1987a, b) it was proposed and subsequently confirmed that paramyotonia congenita and hyperkalaemic periodic paralysis were allelic disorders (Koch et al., 1991a; Ptacek et al., 1991a, b; Rojas et al., 1991; McClatchey et al., 1992a, b). Later the phenotypes grouped together as the potassium aggravated myotonias were also shown to be sodium channel disorders (Lerche et al., 1993; Ptacek et al., 1994; Ricker et al., 1994)

All the skeletal muscle sodium channelopathies are autosomal dominant conditions and de novo mutations can occur. In a proportion of patients with a phenotype typical for paramyotonia congenita no mutation has been identified in SCN4A raising the possibility of further genetic heterogeneity (Miller et al., 2004). Virtually all described mutations are missense with the only exception being a three base pair deletion (Michel et al., 2007).

Over 40 different mutations including those responsible for periodic paralysis have been reported in the SCN4A gene. Exons 22 and 24 are recognized as 'hot spots' for paramyotonia congenita, particularly the T1313M mutation and amino acid substitutions at the R1448 position (Matthews et al., 2008b). The most common sodium channel myotonia mutations are V1589M and those at the G1306 position (Vicart et al., 2005).

Genetic Diagnosis

Although there are many clinical and electrophysiological indicators to help prioritize genetic testing in the non-dystrophic myotonias the difficulties described in distinguishing sodium channel myotonia from dominant myotonia congenita indicate that a proportion of patients will require screening of both the CLCN-1 and SCN4A genes (Trip et al., 2008). In some cases of recessive myotonia congenita, only one CLCN-1 mutant allele has been identified despite analysis of all coding exons (Trip et al., 2008). This indicates that mutations may be present in deeper intronic regions or possibly in promoter regions, although none have been reported. Another possibility is that there may be as yet unidentified large scale deletions in CLCN-1. Although it is recognized that some cases diagnosed clinically as non-dystrophic myotonia will have myotonic dystrophy type II, it is not known how frequent this is. Considering the importance of appropriate cardiac evaluation in myotonic dystrophy type II, we suggest that if CLCN-1 and/or SCN4A screening is negative, zinc finger protein-9 gene analysis should be undertaken.


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