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

Animal Models

There are several animal models of myotonia congenita. The myotonic goat was bred by Dr H. H. Mayberry in Tenessee in the 1800s. This myotonic goat has been shown to harbour an alanine to proline substitution in the carboxyl terminus of the chloride channel (Beck et al., 1996). Other animal models include the arrested development of righting mouse which is caused by an insertion of a transposon element (Steinmeyer et al., 1991). More recently two different myotonic canine models have been described; the miniature Schnauzer and the Australian cattle dog with recessive missense mutations in CLCN-1 (Rhodes et al., 1999; Finnigan et al., 2007). The small size of the myotonic mouse makes it a difficult model upon which to undertake in vivo electrophysiology. Muscles from myotonic goats were very useful in the early experiments to elucidate the pathophysiology of myotonia congenita. However, in view of the substantial resource implications of goat care, goats are not considered ideal as a potential model for therapeutic trials. The maintenance of the myotonic dog models is also a major undertaking, but since many other canine models of disease have been extensively studied, greater technical experience is available indicating that myotonic dogs may be a more attractive model for future studies including therapeutic trials.

Hyperkalaemic periodic paralysis has been described in quarter horses. A single point mutation has been identified in the equine skeletal muscle sodium channel gene that substitutes a phenylalanine for a leucine in the DIV/S3 segment of the protein (Rudolph et al., 1992). Recently a mouse model of hyperkalaemic periodic paralysis was successfully engineered by introducing the equivalent of the common human M1592V mutation into the murine SCN4A gene (Hayward et al., 2008). The mouse was shown to display similar clinical and biopsy findings to those seen in human cases of hyperkalaemic periodic paralysis validating it as a reasonable animal model. New insights into the beneficial effects of elevated extracellular calcium levels and detrimental effects of impairing the sodium/potassium pump in the pathophysiology of hyperkalaemic periodic paralysis have already been determined (Hayward et al., 2008). This knock-in mouse offers potential for developing an increased understanding of the pathophysiology of hyperkalaemic periodic paralysis and possibly the development of future therapies.

Although hyperkalaemic periodic paralysis is allelic to paramyotonia congenita and sodium channel myotonia, no such phenotypes have been described in animal models. Myotonia does occur in horses but in conjunction with multisystem defects; the phenotype seems more like one of equine myotonic dystrophy (Reed et al., 1988).


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