Wolff-Parkinson-White (WPW) syndrome is a conduction disorder that can make your heart beat too quickly or with an irregular rhythm. This is called an arrhythmia, and it can be life-threatening.

Electrical signals in your heart usually travel along certain pathways to tell the heart to beat regularly. People who have WPW syndrome are born with an extra electrical pathway that changes the way these signals travel. WPW syndrome is a rare condition, and most people who have this condition do not have any other heart problems.

Wolff-Parkinson-White syndrome is a condition characterized by abnormal electrical pathways in the heart that cause a disruption of the heart's normal rhythm (arrhythmia).

The heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. A specialized cluster of cells called the atrioventricular node conducts electrical impulses from the heart's upper chambers (the atria) to the lower chambers (the ventricles). Impulses move through the atrioventricular node during each heartbeat, stimulating the ventricles to contract slightly later than the atria.

People with Wolff-Parkinson-White syndrome are born with an extra connection in the heart, called an accessory pathway, that allows electrical signals to bypass the atrioventricular node and move from the atria to the ventricles faster than usual. The accessory pathway may also transmit electrical impulses abnormally from the ventricles back to the atria. This extra connection can disrupt the coordinated movement of electrical signals through the heart, leading to an abnormally fast heartbeat (tachycardia) and other changes in heart rhythm. Resulting symptoms include dizziness, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, and fainting (syncope). In rare cases, arrhythmias associated with Wolff-Parkinson-White syndrome can lead to cardiac arrest and sudden death. The most common arrhythmia associated with Wolff-Parkinson-White syndrome is called paroxysmal supraventricular tachycardia.

Complications of Wolff-Parkinson-White syndrome can occur at any age, although some individuals born with an accessory pathway in the heart never experience any health problems associated with the condition.

Wolff-Parkinson-White syndrome often occurs with other structural abnormalities of the heart or underlying heart disease. The most common heart defect associated with the condition is Ebstein anomaly, which affects the valve that allows blood to flow from the right atrium to the right ventricle (the tricuspid valve). Additionally, the heart rhythm problems associated with Wolff-Parkinson-White syndrome can be a component of several other genetic syndromes, including hypokalemic periodic paralysis (a condition that causes episodes of extreme muscle weakness), Pompe disease (a disorder characterized by the storage of excess glycogen), Danon disease (a condition that weakens the heart and skeletal muscles and causes intellectual disability), and tuberous sclerosis complex (a condition that results in the growth of noncancerous tumors in many parts of the body).

Wolff-Parkinson-White syndrome affects 1 to 3 in 1,000 people worldwide.

Wolff-Parkinson-White syndrome is a common cause of an arrhythmia known as paroxysmal supraventricular tachycardia. Wolff-Parkinson-White syndrome is the most frequent cause of this abnormal heart rhythm in the Chinese population, where it is responsible for more than 70 percent of cases.

Normal Function

The PRKAG2 gene provides instructions for making one part (the gamma-2 subunit) of a larger enzyme called AMP-activated protein kinase (AMPK). This enzyme helps sense and respond to energy demands within cells. It is active in many different tissues, including heart (cardiac) muscle and muscles used for movement (skeletal muscles). AMP-activated protein kinase is likely involved in the development of the heart before birth, although its role in this process is unknown.

AMP-activated protein kinase regulates chemical pathways involving the cell's main energy source, a molecule called adenosine triphosphate (ATP). The breakdown of ATP releases energy to drive many types of chemical reactions. AMP-activated protein kinase is activated during times of cellular stress (such as low oxygen levels or muscle exercise), when ATP is broken down rapidly to produce energy. If ATP levels become too low, the enzyme restores the balance of energy by limiting chemical reactions that require ATP and stimulating pathways that generate ATP.

Studies suggest that AMP-activated protein kinase may play a role in controlling the activity of other genes, although many of these genes have not been identified. The enzyme may also regulate the activity of certain ion channels in the heart. These channels, which transport positively charged atoms (ions) into and out of heart muscle cells, play critical roles in maintaining the heart's normal rhythm.

Health Conditions Related to Genetic Changes

Wolff-Parkinson-White syndrome

At least seven mutations that cause Wolff-Parkinson-White syndrome have been identified in the PRKAG2 gene. Some people with these mutations also have features of hypertrophic cardiomyopathy, a form of heart disease that enlarges and weakens the heart (cardiac) muscle. Researchers are uncertain how PRKAG2 mutations lead to the development of these heart conditions. Research suggests that these mutations alter the activity of AMP-activated protein kinase in the heart, disrupting the enzyme's ability to respond to changes in cellular energy demands. It is unclear, however, whether the genetic changes overactivate the enzyme or reduce its activity.

Studies indicate that changes in AMP-activated protein kinase activity allow a complex sugar called glycogen to build up abnormally within cardiac muscle cells. The accumulation of this substance enlarges these cells, which may lead to hypertrophic cardiomyopathy. Researchers continue to investigate whether an abnormal buildup of glycogen in the heart is also responsible for the problems with electrical signaling that are characteristic of Wolff-Parkinson-White syndrome.

Other studies have found that altered AMP-activated protein kinase activity is related to changes in the regulation of certain ion channels in the heart. These changes may help explain the increased risk of abnormal heart rhythms (arrhythmias) in people with Wolff-Parkinson-White syndrome.

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Familial hypertrophic cardiomyopathy

MedlinePlus Genetics provides information about Familial hypertrophic cardiomyopathy

Other disorders

Several mutations in the PRKAG2 gene have been found in people with other heart conditions. For example, a specific mutation in this gene is responsible for a very severe form of heart disease called lethal congenital glycogen storage disease of the heart. People with this mutation are born with extremely enlarged hearts (cardiomegaly) and abnormal electrical signaling within the heart. These abnormalities lead to respiratory distress and heart failure early in life. The mutation responsible for this condition changes a single protein building block (amino acid) in the gamma-2 subunit of AMP-activated protein kinase. Specifically, this mutation replaces the amino acid arginine with the amino acid glutamine at position 531 (written as Arg531Gln or R531Q). Studies suggest that this severe disorder may be related to the abnormal buildup of glycogen within cardiac muscle cells.

Other mutations in the PRKAG2 gene have been associated with disorders affecting both cardiac and skeletal muscle. These mutations change single amino acids in the gamma-2 subunit of AMP-activated protein kinase. Individuals with these genetic changes typically experience muscle pain and stiffness, particularly following exercise, in addition to hypertrophic cardiomyopathy and abnormal electrical signaling within the heart. It is not known why the effects of some PRKAG2 mutations appear to be confined to the heart, while other mutations cause signs and symptoms affecting both cardiac and skeletal muscles.

Other Names for This Gene

• AAKG
• AAKG2
• AAKG2_HUMAN
• AMP-activated protein kinase gamma2 subunit
• AMPK gamma2
• CMH6
• H91620p
• protein kinase, AMP-activated, gamma 2 non-catalytic subunit
• WPWS

Genomic Location

Most cases of Wolff-Parkinson-White syndrome occur in people with no apparent family history of the syndrome. These cases are described as sporadic, meaning they are not inherited. In these cases, it is possible that a combination of genetic and environmental causes are responsible for the development of the syndrome.

People who have a genetic change (mutation or pathogenic variant) in PRKAG2 causing Wolff-Parkinson-White syndrome have an inherited form of the syndrome. In these cases, the syndrome is inherited in an autosomal dominant manner. This means that only one copy of the PRKAG2 gene is changed for a person to have symptoms of the syndrome. We inherit one copy of each gene from our mother and the other from our father. When a person with Wolff-Parkinson-White syndrome that is caused by a pathogenic variant in PRKAG2 has children, for each child there is a:

• 50% chance to inherit the changed copy of the PRKAG2 gene, meaning he or she will have Wolff-Parkinson-White syndrome
• 50% chance to inherit the working copy of the PRKAG2 gene, meaning he or she will not have Wolff-Parkinson-White syndrome.

A doctor may determine if other family members are at risk to have symptoms of Wolff-Parkinson-White syndrome by taking a detailed family history. If no other family members have symptoms of the syndrome, it is most likely that the syndrome is sporadic and is not caused by a pathogenic variant in PRKAG2.

Symptoms of Wolff-Parkinson-White syndrome occur because the heart’s normal rhythm is disrupted. This is called an arrhythmia. The most frequent type of arrhythmia associated with Wolff-Parkinson-White syndrome is paroxysmal supraventricular tachycardia. This means that there is a rapid heart rate (tachycardia) that originates from the area above the two lower chambers of the heart (supraventricular), and that the abnormal rhythm occurs intermittently (paroxysmal). Other symptoms of Wolff-Parkinson-White syndrome may include dizziness, a feeling of an irregular heartbeat (palpitations), shortness of breath, low blood pressure (hypotension), and fainting. Rarely, the arrhythmia associated with Wolff-Parkinson-White syndrome can cause the heart to stop (cardiac arrest).

Some people with Wolff-Parkinson-White syndrome also have other heart abnormalities, most commonly the Ebstein anomaly. The Ebstein anomaly affects the tricuspid valve, which connects the right upper chamber of the heart (atrium) to the right lower chamber (ventricle). However, some people with Wolff-Parkinson-White syndrome do not have any other heart abnormalities, and some people have no symptoms of the syndrome at all.

People who do develop symptoms of Wolff-Parkinson-White syndrome may have them beginning at any time of life. These symptoms may occur in episodes that start and stop abruptly. The frequency of episodes can vary. Some people may have only a few episodes in a lifetime, while others may have more than one episode a week.

The treatment for Wolff-Parkinson-White syndrome may depend on whether a person has any symptoms of the syndrome. For people who do have symptoms, medications such as antiarrhythmic drugs may be recommended. In other cases, a doctor may recommend a surgical procedure to determine the location of the extra electrical pathway, followed by a catheter ablation. During this procedure, a catheter is used to direct radiofrequency energy at the location of the extra electrical pathway in the heart, which destroys the tissue. This procedure can help restore a regular heart rhythm with a high success rate.

If a person with Wolff-Parkinson-White syndrome does not have any symptoms, a doctor may recommend monitoring of the heart to see if symptoms will develop. The exact treatment recommendation depends on the symptoms of each person as well as family history information and other health problems that a person may have. In some cases, surgery may be recommended, even for people who have never had symptoms of the syndrome.

If left untreated, WPW syndrome can cause the following problems:

• Heart failure
• Serious arrhythmias, including atrial fibrillation
• Cardiac arrest, which can be fatal and is more common in boys and men and in people who have other heart conditions