Hypokalemic periodic paralysis is a condition that causes episodes of extreme muscle weakness typically beginning in childhood or adolescence. Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Attacks cause severe weakness or paralysis that usually lasts from hours to days. Some people may have episodes almost every day, while others experience them weekly, monthly, or only rarely. Attacks can occur without warning or can be triggered by factors such as rest after exercise, a viral illness, or certain medications. Often, a large, carbohydrate-rich meal or vigorous exercise in the evening can trigger an attack upon waking the following morning. Although affected individuals usually regain their muscle strength between attacks, some develop persistent muscle weakness later in life.

People with hypokalemic periodic paralysis typically have reduced levels of potassium in their blood (hypokalemia) during episodes of muscle weakness. Researchers are investigating how low potassium levels may be related to the muscle abnormalities in this condition.

Mutations in the CACNA1S or SCN4A gene can cause hypokalemic periodic paralysis. These genes provide instructions for making proteins that play essential roles in muscles used for movement (skeletal muscles). For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of certain positively charged atoms (ions) into muscle cells. The CACNA1S and SCN4A proteins form channels that control the flow of these ions. The channel formed by the CACNA1S protein transports calcium ions into cells, while the channel formed by the SCN4A protein transports sodium ions.

Mutations in the CACNA1S or SCN4A gene alter the usual structure and function of calcium or sodium channels. The altered channels are "leaky," allowing ions to flow slowly but continually into muscle cells, which reduces the ability of skeletal muscles to contract. Because muscle contraction is needed for movement, a disruption in normal ion transport leads to episodes of severe muscle weakness or paralysis.

A small percentage of people with the characteristic features of hypokalemic periodic paralysis do not have identified mutations in the CACNA1S or SCN4A gene. In these cases, the cause of the condition is unknown.

A clinical diagnosis of HOKPP is based on:

• a history of episodes of paralysis
• low levels of potassium during attacks, but not between attacks
• the identification of typical "triggers" (i.e., rest after exercise, prolonged immobility)
• a family history consistent with autosomal dominant inheritance. The diagnosis cannot be established by clinical findings alone in the absence of a known family history of the condition.

Various types of tests including blood tests, urine tests, and/or electromyograms may be used to differentiate between primary HOKPP and other possible causes of symptoms.

Of all individuals who meet diagnostic criteria and have genetic testing, approximately 60% have mutations in the CACNA1S gene, approximately 20% in the SCN4A gene, and approximately 3.5% in the KCNJ18 gene. No other genes have yet been found to cause HOKPP, suggesting that other, unidentified genes may be responsible for the condition.

Although its exact prevalence is unknown, hypokalemic periodic paralysis is estimated to affect 1 in 100,000 people. Men tend to experience symptoms of this condition more often than women.