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

Genotype–Phenotype Correlations

Marked phenotypic heterogeneity is common in the skeletal muscle channelopathies even in kindreds with the same mutation. Clinical and electrophysiological findings can help to distinguish between dominant and recessive myotonia congenita but since the same mutation can be inherited in a dominant or recessive manner this doesn't necessarily narrow the possible genotypes. From a genetic point of view, non-sense mutations, small deletions and insertions leading to frameshift or mutations interrupting splice sites are usually associated with recessive myotonia congenita. However, missense mutations can lead to either recessive or dominant myotonia congenita depending on their location and the effect of the amino acid substitution on channel gating. Dominant mutations are clustered around the dimer interface of the channel (Duffield et al., 2003; Fialho et al., 2007) but are also found in other regions of the channel. R894X is the most studied mutation causing recessive and dominant myotonia congenita in different families. It is a non-sense mutation located within the C-terminus of the channel. Due to its location within the last exon of the CLCN-1 gene the mRNA does not undergo the usual non-sense mediated decay typically induced by earlier premature stop-codons. Duno et al. (2004) compared two families with dominant myotonia congenita and two families with recessive myotonia congenita carrying the R894X mutation. There was no direct relation between levels of CLCN-1 mRNA and inheritance type excluding differential allelic expression as an explanation for the varying inheritance mode. However, the most severely affected dominant case expressed more than twice the amount of mutant mRNA compared to the recessive families raising the possibility that this may contribute to phenotypic variability particularly within dominant pedigrees (Duno et al., 2004).

Paramyotonia congenita and sodium channel myotonia can usually be reliably distinguished from each other by the presence or absence of weakness from clinical and EMG findings. This narrows down the likely genotype to a certain degree but within each group there are still a number of possibilities. Supplementary Table 2 outlines the phenotypes reported for each mutation.

Now, there is evidence that certain SCN4A genotypes are associated with a severe neonatal phenotype. A fatal case of myotonia with significant respiratory muscle involvement was described in an infant with a de novo N1297K mutation (Gay et al., 2008). We observed the I693T mutation linked to spontaneously resolving neonatal hypotonia with variable feeding and respiratory difficulties in four unrelated families (Matthews et al., 2008a). The recognition that sodium channelopathies may present in such a way is important in order to provide appropriate pre-natal advice for mothers known to carry these mutations and neonatal care for their children.

A further example of the phenotypic variability that can be observed with the same genotype is provided by G1306E mutation. The original phenotype reported with this was so severe the individual suffered permanent myotonia that included the respiratory muscles and which lead to hypoxia and acidosis requiring ventilatory support (Lerche et al., 1993). In contrast, a more recent report observed that although affected individuals had relatively severe myotonia they did not exhibit respiratory involvement and were able to carry out daily activities including work without treatment (Colding-Jorgensen et al., 2006). See Supplementary Table 2 for more detail of phenotypes reported in different kindreds with the same SCN4A mutation.

One limitation in studying genotype–phenotype correlations has been the lack of availability of sufficient numbers of individuals carrying each mutation. The large multicentre natural history trial currently being run by the Consortium for Clinical Investigation of Neurological Channelopathies aims to address these issues.


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