Hypokalemic periodic paralysis

Genetics

Mutations in SCN4A or CACNA1S cause hypokalemic periodic paralysis by altering voltage-gated sodium or calcium channels. The SCN4A gene encodes the Nav1.4 sodium channel; mutations affect arginine residues in the S4 voltage sensor, disrupting normal pore opening. CACNA1S encodes the Cav1.1 calcium channel; mutations in domains II and IV produce loss-of-function effects. These changes reduce channel excitability, so signals from the central nervous system cannot adequately depolarize the muscle, impairing contraction.

Low extracellular potassium worsens the condition because it accelerates repolarization, making sustained calcium conductance harder to achieve. An association with KCNE3 has been described but is disputed and excluded from the disease definition in OMIM. Mutations in KCNJ2 cause a related form with cardiac arrhythmias called Andersen–Tawil syndrome. The condition is hypokalemic because it manifests when potassium is low, not because it causes hypokalemia.

Diagnosis

The long exercise test, a specialized electromyographic procedure, is the current standard for diagnosis. It measures compound muscle action potential amplitude for 40 to 50 minutes after exercise; affected patients show a progressive decline. Standard EMG only detects abnormalities during a full attack. Provoking an attack with exercise and diet followed by oral potassium can be diagnostic but is dangerous because hyperkalemic periodic paralysis has similar symptoms but different treatment.

The old glucose-insulin challenge is life-threatening and should never be used. Serum potassium during an attack is low normal or low. Genetic testing is often unreliable because only common gene locations are tested, and 20–37% of clinically diagnosed individuals have no known mutation in SCN4A or CACNA1S. Misdiagnosis as conversion disorder or hysterical paralysis is common because weakness is muscle-based and does not follow nerve or spinal root distributions; epinephrine release during fight-or-flight situations further encourages this error.

Treatment

Preventive treatment includes avoiding carbohydrate-rich meals, strenuous exercise, and other triggers, along with acetazolamide or another carbonic anhydrase inhibitor. Some patients use potassium-sparing diuretics such as spironolactone to maintain potassium levels. Acute paralysis attacks are managed by drinking potassium salts dissolved in water; potassium chloride and bicarbonate are common choices. Rapidly absorbed liquid potassium is typically needed, though some patients use time-released tablets.

Intravenous potassium is rarely justified unless swallowing is impossible. Daily potassium dosage may reach 100–150 mEq. Perioperatively, prevention involves avoiding neuromuscular blockade, excessive hyperventilation, glucose infusions, and diuretics; warming the patient, providing adequate hydration, and monitoring the electrocardiogram for hypokalemia are recommended. Normal saline is preferred over glucose-containing solutions.

Prognosis

Life span is expected to be normal, but attacks can lower potassium enough to cause life-threatening breathing problems or heart arrhythmia. Overactivity, a diet not low in sodium and carbohydrates, or an unfortunate gene mutation can lead to chronic low-level weakness called an abortive attack or to permanent muscle damage. Abortive attacks may respond to extra potassium, cutting carbohydrates, rest, increased medication, and gentle daily exercise.

Permanent muscle weakness involves vacuoles and tubular aggregates that destroy healthy tissue, observable via muscle biopsy, and is irreparable even with anabolic steroids. Muscle strength is stated to be normal between attacks, but patients often report lower baseline strength.

Muscle pain and cognitive problems occur during attacks. Migraines affect up to 50% of patients and may include phantom smells, light and sound sensitivity, or loss of words. Because many gene mutations exist, treatments that work for one patient may not work for another.

Did You Know?

• The Scottish physician Dr Mary Walker first recognized the association between familial periodic paralysis and hypokalaemia in 1935.
• Attacks can be triggered by a viral illness or certain medications.
• Some people develop symptoms only due to hyperthyroidism, a condition called thyrotoxic periodic paralysis.