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New Treatments for Sodium Channelopathies

Disorders of the α-subunit of the muscle sodium channel result in four major distinct disorders: hyperkalemic periodic paralysis, hypokalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonias. There is some phenotypic overlap of the sodium channelopathies, suggesting that they may be a continuum of disorder rather than rigidly demarcated clinical entities. Previous literature also includes normokalemic and myotonic periodic paralyses in this category, but since most, if not all, of these are potassium sensitive in exactly the same way as hyperkalemic periodic paralysis, it is likely that they represent sodium channel disorders.

Paramyotonia Congenita

This disease is autosomal dominant, inherited with complete penetrance. The predominant symptom is paradoxical myotonia, usually present from birth and persisting throughout life. The myotonia is paradoxical because unlike classical myotonia, it increases with repetitive movements. Cold temperature exacerbates myotonia and can cause weakness. The myotonia particularly affects the face, neck, and forearm. Typically on relief of the myotonia, either spontaneously or on warming, there is a variable degree of weakness that persists for several hours. In a warm environment patients may have no symptoms at all. In some families with this disorder, there is a tendency for attacks of paralysis to occur independently of the myotonia. In many patients, these attacks are precipitated by potassium ingestion, in much the same way as hyperkalemic periodic paralysis. Occasional patients, usually adolescents, are weakened by hypokalemia.

Hyperkalemic Periodic Paralysis

As with paramyotonia congenita, hyperkalemic periodic paralysis normally appears in infancy or early childhood with frequent episodes of paralysis that are generally brief and mild, lasting between 15 minutes and 4 hours. Attacks are often precipitated by rest following exercise, by ingestion of potassium-rich foods, or by administration of potassium compounds. They commonly start in the morning before breakfast. Stress tends to make the attacks more easily provoked. Weakness is mainly proximal, but distal muscles can be involved. There is usually no ocular or respiratory muscle weakness. Examination of a patient during a severe attack reveals a flaccid tetraparesis with absent reflexes and normal sensory examination. The potassium may rise during the attack but not necessarily above the upper limit of normal range and rarely to levels that cause cardiac arrhythmia. Generally between attacks, patients maintain normal strength, but in a few cases there is persistent mild weakness.