Myotonia

Causes

Myotonia arises from different ion channel problems in the skeletal muscle cell membrane. In myotonic dystrophy, which comes in two forms (DM1 and DM2), a nucleotide expansion in one of two genes causes RNA to build up in the cell’s cytosol. This buildup disrupts the correct splicing of the mRNA for the ClC-1 chloride channel. Since this channel handles most of the chloride flow in skeletal muscle, reduced chloride conductance can trigger myotonia. Laboratory experiments that fixed the mRNA splicing restored ClC-1 function and eliminated the myotonia. Congenital myotonia includes two types: Becker’s disease and Thomsen’s disease. Both stem from mutations in the CLCN1 gene, which codes for the ClC-1 channel. Over 130 different loss-of-function mutations exist, each reducing chloride conductance to varying degrees. This lets potassium build up in the muscle’s transverse-tubules, leading to myotonia. The same genetic condition causes certain North American goats to faint when startled. Pregnant women with myotonia congenita report symptoms more often. Myotonia can also come from mutations in the SCN4A gene, which makes the Nav1.4 sodium channel. Some research hints that shifts in physiological pH might affect Nav1.4 channels and influence myotonic symptoms. Mutations in SCN4A can alter the channel’s behavior so it fails to inactivate properly, allowing spontaneous electrical signals after voluntary movement ends. This prolongs muscle relaxation or, if severe, causes paralysis. When the inability to relax worsens with exercise, it is called paradoxical myotonia. Paramyotonia is often set off by exercise, cold, or potassium.