Myotonia congenita

Symptoms and signs

Prolonged muscle contractions occur most commonly in the leg muscles in recessive mutations, and more often in the hands, face, and eyelids in dominant mutations. These contractions are often enhanced by inactivity and relieved by repetitive movement, known as the warm-up effect, which diminishes quickly with rest. Some individuals are prone to falling due to hasty movements or inability to stabilize after loss of balance; during a fall, partial or complete rigid paralysis may occur but resolves quickly.

Falling into cold water can render the person unable to move for the duration of submergence. Children are more prone to falling than adults due to impulsivity. The two major types are distinguished by severity and inheritance: Becker disease appears later in childhood than Thomsen disease and causes more severe myotonia, muscle stiffness, and transient weakness. Cramps or myalgia may develop, and people with Becker disease often experience temporary attacks of muscle weakness in the arms and hands after rest, as well as mild permanent weakness over time; this weakness is not seen in Thomsen disease.

Early symptoms in a child may include difficulty swallowing, gagging, stiff movements that improve with repetition, frequent falling, and difficulties opening eyelids after strenuous contraction or crying (von Graefe's sign). Possible complications include aspiration pneumonia, frequent choking or gagging in infants, abdominal muscle weakness, chronic joint problems, and injury due to falls.

Mechanisms

Myotonia congenita is caused by loss-of-function mutations in the gene CLCN1, which encodes the ClC-1 chloride channel critical for normal skeletal muscle cell function. In the absence of sufficient functional chloride channels, the muscle fiber membrane becomes hyperexcitable and continues firing action potentials when stimulated for longer than normal, resulting in prolonged contraction and delayed relaxation. The dysfunctional chloride channels are located in the muscle fiber membrane and do not affect the motor nerve innervating the muscle.

Studies have shown that denervation of muscle fibers alters the resting membrane conductance, but whether this affects myotonia is debated and results are inconclusive. In skeletal muscle fibers, a large transverse tubule system with a high surface-area-to-volume ratio exists. The onset of muscle activity involves action potentials associated with an efflux of potassium into the extracellular fluid and transverse tubule system. As potassium accumulates in the transverse tubular system, its equilibrium potential becomes more depolarized.

The equilibrium potential for chloride is around -80 mV, equal to that of potassium at rest. During repeated action potentials, chloride moves toward its equilibrium potential while potassium moves toward a more depolarized potential, resulting in a slightly more depolarized membrane potential. Sodium conductance is elevated only briefly compared to potassium conductance during each action potential, so potassium largely determines the membrane potential, with chloride passively distributed at rest.

Diagnosis

Two types of myotonia congenita exist: an autosomal dominant form (Thomsen disease) and an autosomal recessive form (Becker disease, also called generalized myotonia or recessive generalized myotonia). The term congenital applies clinically from birth only to Thomsen disease, as Becker myotonia may have onset delayed until age 4 to 6 years; however, both forms are genetically present from birth. With genetic testing, some typically recessive mutations have been found to occur in a dominant fashion in some individuals, for reasons unknown.

Because several CLCN1 mutations can cause either form, doctors rely on characteristic signs and symptoms to distinguish them. Myotonia from CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel mutations (SCN4A) resulting in paramyotonia congenita. Congenital myotonia is more common in Finland and among ethnic Finns; a molecular study of 24 families in northern Finland showed that apparent dominant inheritance was actually recessive.

Differential diagnoses include sodium channel myotonias (SCN4A), potassium-aggravated myotonia, paramyotonia congenita, hyperkalemic periodic paralysis, myotonic dystrophy (type 1 and type 2), Andersen-Tawil syndrome, thyroid disorders, neuromyotonia, Schwartz–Jampel syndrome, stiff person syndrome, and Brody myopathy.

Research

Myotonia can be induced in intact isolated muscle preparations by administering 9-Anthracenecarboxylic acid, a chloride channel blocker, or by greatly lowering or removing extracellular chloride. During the 1970s, several murine models of myotonia appeared, including the adr mouse (arrested development of righting response), which displays myotonia due to lack of functional chloride channels and is widely used in scientific work with muscular dystrophy.

Did You Know?

• Some cases of myotonia congenita do not require treatment, or the risks of medication outweigh the benefits.
• Symptoms may be relieved with quinine, ranolazine, procainamide, flecainide, phenytoin, carbamazepine, mexiletine, and other anticonvulsant drugs.