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

Molecular Pathophysiology

In a normal muscle fibre, a single nerve stimulus depolarizes the sarcolemma propagating a single action potential that results in a single muscle contraction followed by rapid relaxation. Myotonia results from an increased excitability of the muscle fibre membrane such that a single electrical stimulus triggers a repetitive train of action potentials.

In myotonia congenita, the enhanced excitability is due to reduced sarcolemmal chloride conductance and was initially demonstrated in muscles of myotonic goats (Lipicky et al., 1966; Bryant., 1969) and later in humans (Lipicky et al., 1971). Compared with other excitable cells, skeletal muscle has an unusually high chloride conductance, accounting for up to 85% of the resting membrane conductance (Bryant et al., 1971). The high chloride conductance is especially important in view of the large size of the muscle fibers which require the T-tubule system to propagate an action potential into the depth of the cell to initiate a synchronous contraction. Although T-tubules are directly connected to the extracellular space, they represent a significant diffusion barrier. Consequently with repeated membrane discharges, a build-up of potassium ions within the T-tubule system due to the repolarizing potassium ion currents increases the probability of additional spikes. The membrane depolarization as a consequence of potassium ion accumulation in the T-tubules is normally counteracted by the chloride conductance.

The chloride channel is an antiparallel assembled homodimer consisting of two identical subunits each with their own ion conducting pore (Fig. 5A). There are two main gating modes referred to as the fast gate, which can open and close the two pores independently, and a slow gating mechanism or 'common gate' which causes deactivation of both pores simultaneously. While all chloride channel mutations lead to loss of function, recessive mutations usually exert their effect by loss of function of the mutated subunit, while the mutant subunit in dominant disease tends to have an adverse effect on the function of the co-expressed wild-type subunit, i.e. a dominant negative effect (Pusch et al., 1995). The majority of dominant myotonia congenita mutations shift the voltage dependence of CLCN-1 to more positive voltages (Pusch et al., 1995; Kubisch et al., 1998). Using a mathematical model, Barchi (1975) showed that decreasing the chloride conductance to 20% is sufficient to trigger myotonic discharges following a single stimulus. A similar hyperexcitability threshold of 25% was predicted by graded pharmacological inhibition of muscle CLCN-1 conductance (Kwiecinski et al., 1988). Clinically, a reduction to 50% does not seem to cause myotonia as evidenced by the majority of asymptomatic carriers of recessive myotonia congenita mutations. However, this assumes a 1:1 allelic expression in these cases, which may not always be the case (Chen et al., 1997). Supplementary Table 3 outlines details of known functional effects of all reported CLCN-1 mutations.

Figure 5.

Diagramatic representation of (A) CLCN-1 and (B) Nav1.4 channels.

In contrast to the chloride channel, the voltage gated skeletal muscle sodium channel comprises a single ion conducting pore formed by the interaction between four homologous domains (Fig. 5B). All of the mutations associated with paramyotonia congenita and sodium channel myotonia produce 'gain of function' defects either by impaired inactivation or enhanced activation of the Nav1.4 channel (see Table 2 Supplementary Data). Impaired inactivation can either involve delayed inactivation or incomplete inactivation. Delayed inactivation of the skeletal muscle sodium channel causes increased excitability of the muscle fibre membrane and myotonia (Yang et al., 1994). The increased availability of sodium channels immediately after an action potential renders the fibre susceptible to sustained trains of repetitive discharges (Cannon, 2000), the electrophysiological hallmark of myotonia. In contrast to the repetitive firing seen in myotonia, the paralytic attacks experienced in paramyotonia congenita and in the allelic disorder hyperkalaemic periodic paralysis, are caused by episodic loss of fibre excitability. This sustained depolarization of the resting potential is due to sodium channels that do not inactivate completely, thereby conducting a persistent inward sodium current that depolarizes the fibre. (Bendahhou et al., 2002; Cannon, 2006).

Sodium channels also undergo a second, mechanistically distinct form of inactivation on a much slower time scale of seconds termed slow inactivation. Defects of slow inactivation increase the propensity for depolarization-induced attacks of weakness, and missense mutations of SCN4A that disrupt slow inactivation always result in a paralytic phenotype (Hayward et al., 1999).


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