<unk>  is caused in humans by loss-of-function mutations in the gene CLCN1. This is the gene encoding the protein CLCN1, that forms the ClC-1 chloride channel, critical for the normal function of skeletal muscle cells. This gene is also associated with the condition in horses, goats, and dogs. In short, in lack of sufficient functional chloride channels, the muscle fiber membrane becomes hyper-excitable and continues to be electrically active (firing action potentials) when stimulated, for longer periods of time, than a normal muscle fiber. This results in prolonged contraction/delayed relaxation of the muscle. The dysfunctional Cl− channels are located in the muscle fiber membrane and do not affect the motor nerve innervating the muscle. However, many studies have shown that denervation of muscle fibers alter the resting membrane conductance, but whether this affects myotonia in the muscle has been subject to heavy debate, and results from experiments are inconclusive. In skeletal muscle fibers, a large transverse tubule system with a high surface-area to volume ratio exists. The onset of skeletal muscle activity is associated with the initiation and propagation of action potentials again associated with an efflux of K+ to the extracellular fluid and transverse tubule system. When many action potentials are elicited subsequently more K+ is expelled from the cell into the transverse tubular system. As K+ accumulates in the transverse tubular system the equilibrium potential for K+ (EK+) normally around -80 mV, becomes more depolarized (depolarization), according to the Nernst equation. In skeletal muscle fibers the equilibrium potential for Cl− is around -80 mV, equal to that of K+ at rest. Cl− moves towards its equilibrium potential around -80 mV, while potassium moves towards its equilibrium potential more depolarized than -80 mV during activity. This results in a slightly more depolarized membrane potential of the fiber during repeated action potentials, see Goldman equation. The Na+ conductance is only elevated shortly compared to the K+ conductance during each action potential, which is why K+ largely determines the membrane potential (Cl− is passively distributed during rest). In the case of<unk> , the chloride channels that allow Cl− to move across the membrane towards its equilibrium potential are defective, thus K+ is the only ion determining the membrane potential, and as more and more K+ accumulates in the transverse tubular system with each subsequent action potential the fiber depolarizes until the membrane potential comes close enough to the action potential threshold for spontaneous activity to ensue Spontaneous action potentials can arise for several seconds, leading to the delayed relaxation that is the hallmark of myotonia. Cessation of spontaneous activity is associated with sodium channel inactivation (Nav1.4).
Myotonia congenita
Myotonic dystrophy
Paramyotonia congenita
Periodic paralysis
Klumpke paralysis
Quadrigia
Cardiofaciocutaneous syndrome
Hyperkalemic periodic paralysis