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

Clinical Electrophysiology

Recently, specialized clinical neurophysiology protocols have aided precise diagnosis in muscle channelopathies by directing genetic testing based on channel-specific electrophysiological patterns. Sarcolemmal excitability can be measured indirectly as the variability of the compound muscle action potential (CMAP) following different stimuli. The CMAP size varies in skeletal muscle channelopathies in response to short (10–20 s) or long (3–5 min) exercise tests (Streib, 1982; McManis et al., 1986). Using these exercise protocols in combination with muscle cooling, distinct electrophysiological patterns—termed patterns I, II and III—are now recognized for each of the non-dystrophic myotonia groups (Fournier et al., 2004, 2006). For clinical diagnosis the repeat short exercise test with muscle cooling is of great value in the non-dystrophic myotonias.

Patients with chloride channel myotonia can show one of two patterns. The most common is pattern II (Fournier et al., 2004) in which at room temperature there is an immediate CMAP decrement after exercise which recovers quickly and diminishes with repetition, reflecting the transient weakness observed clinically (Fig. 1). This pattern is most frequently seen in recessive myotonia congenita but can be observed in any muscle ion channel disorder in which there is a loss of sarcolemmal chloride conductance. It is therefore also seen in dominant myotonia congenita and in both myotonic dystrophy types I and II. That this pattern may be seen in myotonic dystrophy types I and II is not unexpected as there is now clear evidence that the myotonia in these dystrophies is secondary to reduced chloride conductance (Charlet et al., 2002). In recessive myotonia congenita cooling has little further effect (Fig. 1). However, in dominant myotonia congenita, the CMAP decrement may be worsened or only seen with cooling (Fournier et al., 2006) making it essential to perform the short exercise test at both room temperature and with the muscle cooled (Fig. 2). Occasional patients with dominant myotonia congenita show a normal response [pattern III (Fournier et al., 2006)] to all provocative tests, even with muscle cooling which is indistinguishable electrophysiologically from sodium channel myotonia (Fig. 3).

Figure 1.

Autosomal recessive myotonia congenita: short exercise test (mean CMAP amplitudes) at room temperature and after cooling.

Figure 2.

Autosomal dominant myotonia congenita: short exercise test (mean CMAP amplitudes) at room temperature and after cooling.

Figure 3.

Sodium channel myotonia: short exercise test (mean CMAP amplitudes) at room temperature and after cooling

Patients with paramyotonia congenita typically have a gradual and prolonged decrement in CMAP after exercise, termed pattern I (Fournier et al., 2004). This decrement is exacerbated with repeat testing and muscle cooling (Fig. 4) reflecting the clinically observed cold- and exercise-induced weakness. Some genotypes only display this typical pattern when the short exercise test is performed with the muscle cooled (Fournier et al., 2006) again emphasizing the importance in diagnosis of performing a short exercise test at both room temperature and with the muscle cooled.

Figure 4.

Paramyotonia congenita: short exercise test (mean CMAP amplitudes) at room temperature and after cooling.

The sodium channel myotonias are separated clinically from paramyotonia congenita by their lack of weakness. This is illustrated by pattern III, normal responses to all provocative tests (Fig. 3) with EMG myotonia as usually the only positive electrophysiological finding. This is the characteristic finding in sodium channel myotonia but is not absolute and there are some variations for certain genotypes (Fournier et al., 2006). It is notable that this is the same pattern observed in a minority of cases with dominant myotonia congenita.

The similarities between sodium channel myotonia and dominant myotonia congenita can lead to difficulty in prioritizing genetic testing. Clinical history and examination considered in conjunction with EMG findings (see Table 1) can improve the ability to distinguish between the two and guide genetic analysis, but in some cases screening of both the CLCN-1 and SCN4A genes will be required.

Variability exists in the response of the non-dystrophic myotonia subgroups to exercise testing and where muscle cooling has already proven useful in improving diagnosis, repetitive nerve stimulation may have a future role to play in distinguishing the sub-types of non-dystrophic myotonia. There is some evidence that a reduction in CMAP may be provoked by repetitive nerve stimulation in certain cases of recessive myotonia congenita where exercise testing even with the muscle cooled has failed to produce any such decrement (Michel et al., 2007). In this way, repetitive nerve stimulation may become an additional future tool to guide the genetic analysis towards recessive myotonia congenita, in cases that may otherwise be thought to be dominant myotonia congenita or sodium channel myotonia. There is currently no distinguishing electrophysiological test for myotonic dystrophy type II and this diagnosis should be considered for patients with a myotonic disorder in whom no mutations are found in CLCN-1 or SCN4A.


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