State of the art in hereditary muscle channelopathies

Abstract

A combination of electrophysiological and genetic studies has resulted in the identification of several skeletal muscle disorders to be caused by pathologically functioning ion channels and has led to the term channelopathies. Typical hereditary muscle channelopa thies are congenital myasthenic syndromes, non-dystrophic myotonias, periodic paralyses, malignant hyperthermia, and central core disease. Most muscle channelopathies are commonly considered to be benign diseases. However, life-threatening weakness episodes or progressive permanent weakness may make these diseases severe, particularly the periodic paralyses (PP). Even in the typical PP forms characterized by episodic occurrence of weakness, up to 60% of the patients suffer from permanent weakness and myopathy with age. In addition, some PP patients present with a predominant progressive muscle weakness phenotype. The weakness can be explained by strongly depolarized fibers that take up sodium and water and that are electrically inexcitable. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression.

Figure 1.

Transient weakness in a patient with recessive myotonia congenita. Upper trace: surface EMG recorded over biceps brachii muscle. Lower trace: Concurrent isometric force generated by elbow flexors. Note ~5-6 s of diminished electrical and force activity followed by gradual recovery. N, Newton [from Lehmann-Horn et al., 2004 (1), mod.].

Figure 2.

Currents through the central pore of normal and mutant Na_v1.4 channels. Macroscopic (A, C) and single-channel (B, D) sodium currents of normal and mutant Na_v1.4 channels are shown. The currents were elicited by a depolarization step from a holding potential of -120 mV to +30 mV. Re-openings were more frequent for mutant channels, thereby leading to a small persistent current as verified by the tail current at the end of the pulse (C) [from Lehmann- Horn et al., 2004 (1), mod.].

Figure 3.

The voltage-gated sodium channel of skeletal muscle, Na_v1.4. The alpha-subunit is composed of 4 highly homologous repeats (I-IV) each consisting of 6 transmembrane segments (S1-S6). When inserted in membrane, the 4 repeats of the protein fold to generate a central pore, whereby the S5-S6 loops form the ion-selective pore. The S4 segments contain positively charged residues conferring voltage dependence to the protein. Repeats are connected by intracellular loops; one of them, the III-IV linker, contains the inactivation particle of the channel. The sketch gives an overview of locations of known Na_v1.4-mutations [from Jurkat-Rott, et al. 2010 (32) mod.].

Figure 4.

Leak currents through mutant voltage sensors. (A) A replacement of the outermost arginine (left) by a smaller amino acid e.g. glycine (center), opens a conductive pathway at hyperpolarized potentials, resulting in an inward cation current (arrow). At depolarized potentials at which the S4 segment moves outward (right), the conductive pathway is closed and the cation current ceases. (B) Schematic of cation currents through sodium channels carrying charge-neutralizing substitutions in S4 voltage sensors. Note the large inward current in the hyperpolarized potential range corresponding to the resting state of the leaky S4 voltage sensor [from Jurkat-Rott, et al. 2010 (32) mod.].