Hypokalemic periodic paralysis (HPP) is a rare genetic disorder characterized by episodes of muscle weakness or paralysis, often accompanied by low potassium levels in the blood (hypokalemia). These episodes typically occur suddenly and can last from a few hours to a few days. HPP is one of several forms of periodic paralysis, each with distinct features. The prevalence of the disease is estimated to be between 1-9 cases per 100.000. The onset of hypokalemic periodic paralysis may be in childhood or adolescence, around the second decade of life.
Hypokalemic periodic paralysis genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Hypokalemic Periodic Paralysis include:
- Episodic Weakness or Paralysis: Individuals with HPP experience episodes of muscle weakness or paralysis, typically involving the limbs. The weakness may range from mild to severe, and various factors can trigger the episodes, including rest after exercise, high-carbohydrate meals, stress, and certain medications.
- Hypokalemia: During episodes of weakness, blood potassium levels drop below the normal range. However, between episodes, potassium levels generally return to normal.
- Triggers: Certain factors can trigger episodes of weakness, and these triggers can vary among individuals. Common triggers include rest after exercise, consuming high-carbohydrate meals, stress, alcohol consumption, and certain medications.
- Onset and Duration: The onset of symptoms often occurs in adolescence or early adulthood. The duration of episodes can vary; some individuals may have infrequent episodes, while others may experience them more frequently.
- Family History: Hypokalemic periodic paralysis is often inherited in an autosomal dominant manner. This means that a person with HPP has a 50% chance of passing the condition to each of their children. In some cases, HPP can also occur sporadically without a family history.
HPP is primarily caused by mutations in genes that encode ion channels in muscle cells, particularly the CACNA1S and SCN4A genes. These mutations disrupt the normal function of ion channels, leading to abnormal potassium movement in and out of muscle cells, contributing to episodes of weakness.
The management of Hypokalemic Periodic Paralysis involves preventing and managing episodes of weakness. This may include dietary modifications, such as avoiding high-carbohydrate meals and, in some cases, potassium supplementation. Medications such as acetazolamide may be prescribed to help prevent episodes by altering the acidity in muscle cells.
Lifestyle modifications like regular exercise and avoiding triggers are essential to managing HPP. Genetic counseling is recommended for affected individuals and their families to understand the inheritance pattern and make informed decisions about family planning. Regular follow-up with a healthcare provider, particularly a neurologist or a specialist in neuromuscular disorders, is essential for ongoing care and management.
More Information
Hypokalemic periodic paralysis is a disorder with variable penetrance, especially in females, that belongs to a group of muscle diseases involving abnormal ion channel function. Sporadic cases and de novo mutations have also been reported.
Approximately 70% of cases are associated with mutations in the CACNA1S gene, which codes for the alpha 1 subunit of the calcium channel, and 10% of cases are linked to mutations in the SCN4A gene, which codes for the alpha subunit of the sodium channel.
Within the CACNA1S gene, the following hypoPP-causing mutations stand out: c.3716G>A (p.Arg1239His), c.3715C>G (p.Arg1239Gly), c.1583G>A (p.Arg528His) and 2691G>T (p.Arg897Ser). These amino acid changes alter the electrophysiological properties of the ion channel and its permeability, causing membrane depolarization.
Among the mutations described in the SCN4A gene, c.3472C>T (p.Pro1158Ser), c.2006G>A (p.Arg669His), c.2015G>A (p.Arg672His), c.3395G>A (p.Arg1132Gln) and c.664C>T (p.Arg222Trp) stand out. Most disease-causing variants in the SCN4A gene are characterized by exchanging an arginine (positively charged) for other uncharged amino acids. This substitution alters the ion channels' conductance properties, causing the disease's pathophysiology.
Hypokalemic periodic paralysis genetic testing analyzes the 5 most frequent pathogenic mutations of the CACNA1S gene and the 12 most frequent pathogenic mutations of the SCN4A gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
