Hyperkalemic periodic paralysis

Signs and symptoms

Hyperkalemic periodic paralysis causes episodes of extreme muscle weakness, often beginning in childhood. Attacks may increase or stabilize until the fourth or fifth decade, after which they may cease, decline, or continue into old age depending on the type. Triggers include rest after exercise, potassium-rich foods, stress, fatigue, weather changes, certain pollutants such as cigarette smoke, and fasting.

Muscle strength typically improves between attacks, though many affected individuals experience increasing bouts of weakness over time, known as abortive attacks. Some people also have muscle stiffness and spasms (myotonia) in affected muscles, triggered by the same factors that cause paralysis. During attacks, blood potassium levels may be elevated (hyperkalemia) or normal (normokalemia); ingesting potassium can trigger attacks even without a rise in blood potassium.

Genetics

The most common genetic cause in humans is one of several point mutations in the SCN4A gene, which codes for the voltage-gated sodium channel Nav1.4 at the neuromuscular junction. The condition is inherited in an autosomal dominant pattern, meaning one copy of the altered gene is sufficient to cause it. Normally, action potentials from the central nervous system cause end-plate potentials at the neuromuscular junction, allowing sodium ions to enter through Nav1.4 and depolarize muscle cells.

This depolarization triggers calcium release from the sarcoplasmic reticulum, leading to muscle contraction. To prevent sustained contraction, the channel has a fast inactivation gate that plugs the sodium pore shortly after opening. Mutations altering the structure or function of this channel disrupt regulation of muscle contraction, causing episodes of severe weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV that form the fast inactivation gate, as well as on cytoplasmic loops between S4 and S5 helices of domains II, III, and IV, which are binding sites for the inactivation gate.

In patients with SCN4A mutations, not all copies of the channel inactivate after an action potential, resulting in a sodium leak and failure to return to the original resting membrane potential. In the presence of hyperkalemia, which causes additional chronic depolarization, this sodium leak raises the membrane potential enough that all sodium channels—including those from the wild-type allele and mutant channels that did inactivate—fail to release from inactivation, entering depolarization block. With the motor end plate depolarized, further signals to contract have no effect, producing paralysis.

Treatment

To manage an attack, giving glucose or other carbohydrates may lessen its severity. Intravenous calcium can quiet sodium channels and potentially halt sudden episodes.

Diuretics like furosemide, acetazolamide, or chlorothiazide may also stop attacks. A combination of intravenous glucose and insulin encourages potassium entry into cells via the Na-K ATPase pump, easing weakness without lowering total body potassium. A high-carbohydrate diet is often advised, and known triggers should be avoided.