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Paramytonica congenita - SCN4A

Clinical Features

Mutation in the SCN4A gene may cause various autosomal dominant, neuromuscular sodium channel disorders. The SCN4A gene is located on chromosome 17 (17q23.3) and codes for the alpha subunit of the voltage-dependent sodium channel. The various clinical phenotypes of the disease depend on the type, localization, and functional consequences of the particular disease-causing mutation. These include the following:

Paramyotonia congenita (PMC)
In contrast to chloride channel myotonias (mutations in the CLCN1 gene), there is no warm-up phenomenon, but rather an increase in muscle stiffness with repetitive strain ("paradoxical" myotonia). This form is also heavily temperature-dependent; there is an increase in muscle stiffness or paralysis (lasting from minutes to hours) after exposure to cold.

Hyperkalemic periodic paralysis (HYPP)
Leading clinical symptoms are episodic phases of muscle weakness or muscle paralysis (lasting from minutes to hours), often occurring in a period of rest following intense muscle activity or provoked by potassium-rich food, fasting, alcohol, or cold and accompanied by an increase in blood-potassium. Age of onset is typically in a patient's childhood or teenage years; EEG may reveal signs of a myotonic syndrome.

Potassium-sensitive myotonia (PAM, potassium-aggraved myotonia)
Clinically similar to chloride channel myotonias (mutations in the CLCN1 gene), this form shows various degrees of severity, typically without phases of paralysis or temperature-dependency. The symptoms of myotonia worsen with oral intake of potassium.

Hypokalemic periodic paralysis type 2 (HOKPP)
Episodic paralysis, frequently occurring in the morning (especially after physical activity on the previous day or after a meal rich in carbohydrates) and lasting longer than that of HYPP (lasting from hours to days), normally not accompanied by myotonia. Low blood potassium. Age of onset is typically in a patient's teens or twenties. This form is generally more common than HYPP. The most common cause is mutations in a muscular calcium channel gene (CACNA1S); in rare instances, mutations in a muscular potassium channel gene (KCNE3) are also responsible for causing the disease.

Diagnostic