Myotonia Congenita - Cause

Cause

Myotonia congenita is most commonly caused in humans by mutations in the gene CLCN1. CLCN1 is the genetic code for the protein CLCN1, that is critical for the normal function of skeletal muscle cells. This gene is also associated with the condition in horses and goats. The protein affected by this gene is used to make skeletal muscle chloride ion channels. In normal individuals, cessation of muscle contraction is initiated when the chloride channels open and shunt chloride ions into the muscle to halt the processes inducing the contraction. In people with myotonia congenita, the chloride channel is defective and the open gate probability potentials are shifted by a number of millivolts either in the positive or negative direction. In some mutations, the mutated proteins/channels are unstable and deteriorate quickly, or a defective endoplasmic reticulum exists, meaning the protein/channel cannot be transported efficiently to the cell surface. In other mutations, the mutated chloride channels are less permeable to chloride ions and more permeable to other ions. The result is prolonged muscle contractions, which are the hallmark of myotonia.

The two forms of myotonia congenita caused by CLCN1 mutations have different patterns of inheritance. Thomsen disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases of Thomsen Myotonia Congenita, an affected person has one parent with the condition. However some individuals may be so mildy affected that they do not notice the symptoms, while others may be very severely affected.

Becker disease is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene, but do not show signs and symptoms of the disorder. The condition in horses is also thought to be an autosomal recessive.

With the advent of genetic testing, it has recently been found that some recessive mutations may occur in a dominant fashion in some individuals. The reason for this is not known.

Because several CLCN1 mutations can cause either Becker disease or Thomsen disease, doctors usually rely on characteristic signs and symptoms to distinguish the two forms of myotonia congenita. However, myotonia caused by CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel SCN4A mutations.

SCN4A mutations have been recognized as causing an atypical form of myotonia congenita not categorized as either Becker or Thomsen. Atypical myotonia congenita is also known as acetazolamide-responsive myotonia, a form of potassium-aggravated myotonia.

A so-called Finnish heritage disease, congenital myotonia is more common in Finland and among ethnic Finns. A molecular study of the CLCN1 gene in 24 families in northern Finland, including 46 affected individuals, showed that although the inheritance appeared to be dominant (Thomsen type), in fact it is recessive (Becker type).