Genetic Forms of Wolff-Parkinson-White

Introduction

Wolff-Parkinson-White (WPW) syndrome is one of a classification of preexcitation disorders that have been found to have a genetic component. Recent research has identified the gene (PRKAG2) with WPW associated with hypertrophic cardiomyopathy (HCM) and conduction system disease. The current research states there may be a glycogen and ion channel mutation in conjunction with the accessory pathways that are the hallmark of this syndrome. WPW syndrome is in extensive research at this time to identify the components of the genetic mutation and its relation to other disease processes. The invasive and pharmacological protocols impact the course of treatment for patients with this syndrome. Ethical standards are incorporated in the evaluation and consideration of testing and treatment for these patients.

Background

The conduction anomaly known as Wolff-Parkinson-White syndrome was first discussed in 1930 by Louis Wolff, Sir John Parkinson, and Paul Dudley White. Their observations included patients that presented on electrocardiography (ECG) with a bundle branch block pattern, a shorter PR interval of <120 msec, and tachycardia.¹ The common wave that occurred on ECG was the delta wave. In 1967, the accessory pathways were mapped and found to be the cause of the conduction system bypassing the atrioventricular node (AVN).² WPW syndrome affects 0.1 to 0.2% of the population. It can be found in males and females, with a higher predominance in men. Most patients with this syndrome may be unaware; thus, the incidence may be higher. The syndrome can occur at any age, but is most often seen in childhood or in the third or fourth generation of life. The mortality rate can be elevated with this syndrome due to sudden cardiac death (SCD) that can occur, especially in adolescents. Patients can be asymptomatic, have occasional tachycardic episodes, or have episodes suggesting reentrant tachycardia and require radiofrequency ablation procedures.

Pathophysiology

In WPW, the heart’s cardiomyocytes develop fibrous tissue between the atria and ventricle during the gestational stages of the seventh and twelfth week. The normal process of closure between the atria and ventricle does not occur and these accessory fibers allow conduction to occur between the two, outside of the normal pathway of the AVN.² In normal conduction through the AVN there is a delay; however, there is no such delay in the conduction system of a patient with WPW, in which the conduction through the accessory pathway can be anterograde, retrograde, or both. This leads to ventricular preexcitation, which may lead to tachycardia (orthodromic/antidromic reentrant tachycardia or atrial fibrillation). WPW is the second most common cause of SVT in the western world, and the most common cause in China.² The atrial fibrillation that occurs with WPW creates a shorter refractory time for the diastolic filling of the ventricle. This can allow atrial rates to reach 300 beats and conduct to the ventricles which, in turn, may lead to rapid ventricular rates and ventricular fibrillation. This commonly occurs in patients with SCD, and is also often why adolescent WPW patients die suddenly during strenuous activity. This age group is normally not aware of the affliction of WPW or other preexcitation disorders until it is too late.³ There is a 0.15–0.39% incidence of SCD over 3–10 years in patients with WPW.⁴ According to Blomström-Lundqvist and colleagues, “studies of WPW syndrome patients who have experienced a cardiac arrest have retrospectively identified a number of markers that identify patients at increased risk. These include 1) a shortest pre-excited R-R interval less than 250 ms during spontaneous or induced AF, 2) a history of symptomatic tachycardia, 3) multiple accessory pathways, and 4) Ebstein’s anomaly. A high incidence of sudden death has been reported in familial WPW.”⁴ While 60–70% of WPW patients show no underlying organic heart disease, there is a correlation between WPW and hypertrophic cardiomyopathy.³ This association with HCM has led to an increased interest in the genetics of WPW and accessory pathways.

Patterns of Inheritance

Isolated Nonsyndromic Presentation.¹ In the vast majority of cases, WPW has no clear familial involvement. In this manner, WPW is inherited as a simple or isolated trait of preexcitation. Except in syndromic situations as described in the next section, any genetic influence on preexcitation would result not from a single disease gene but from the action of multiple genes altering individual susceptibility. Indeed, Griggs et al have shown that 46% of PR interval variation in probands can be attributed to shared genetic and familial factors.⁵ When compared to the incidence of preexcitation in the general population of 0.15%, Vidaillet el⁶ found that 3.4% of first-degree relatives of patients with accessory pathways had evidence of accessory pathways. Furthermore, patients with this familial preexcitation had higher incidence of multiple accessory pathways, possible increase in sudden death incidence, and pattern of inheritance was likely autosomal dominant.

Syndromic Presentation.¹ Syndromic presentations of WPW account for a minority of inherited forms of preexcitation and include congenital Ebstein’s anomaly, familial hypertrophic cardiomyopathy, HCM & WPW & conduction system disease, metabolic myopathies and storage disorders, and mitochondrial syndromes. These syndromes are summarized in Table 1.

Understanding the Familial Forms of WPW and PRKAG2

Previous studies believed that an accessory pathway was congenital, but it was unclear because symptoms may not have occurred until later in life. Recent research, however, has identified the gene that is responsible for a significant minority of WPW in association with HCM and conduction system disease. The gene is autosomal dominant, meaning that the controlling gene alleles are located on an autosomal chromosome and the trait is expressed regardless of whether the person is homozygous or heterozygous for the dominant allele.⁸ There is a 50% chance of an offspring having WPW when there is familial correlation.² The gene is registered with the Online Mendelian Inheritance of Man (OMIM) as: Location: 7q36.1; Phenotype: Wolff-Parkinson-White Syndrome; Phenotype MIM number: 194200; Gene/Locus: PRKAG2; Gene/Locus MIM number: 602743.⁹ The PRKAG2 gene encodes for a protein AMPK (AMP-activated protein kinase). Six mutations in this gene have been found, and patients with these mutations are shown to have conduction abnormalities and cardiac hypertrophy. PRKAG2 encodes for gamma-2 subunit of AMPK and contains 16 exons (the region of the gene that is translated into amino acids), which total 569 amino acids. Only one amino acid must be changed.² AMPK is a catabolic enzyme and is activated in times of stress, energy shortage, low oxygen, ischemia, excessive physical activity, and food deprivation.² The research into this metabolic protein has been overwhelming since it appears to have cardiac ramifications, and recent research is underway for the study of how glycogen storage in the myocardium is caused by the PRKAG2 gene. Excess glycogen storage in the myocardium can cause a slowing of the conduction system, heart blocks, and can be toxic to the system itself. This toxicity, in turn, creates preexcitation, and slowing of the system causes cellular growth to increase, therefore, creating hypertrophy.² There is evidence that both a gain and loss in AMPK activity can result from PRKAG2 mutations,⁷ thus highlighting the complexity of interpretation of PRKAG2 mutations on cardiac function.

In addition to the cardiomyocyte fiber growth and glycogen storage of PRKAG2, there is another factor of this gene being researched. Current information suggests that the sodium channels involved in cardiac function may be altered by the PRKAG2 gene as well. This may play a factor in the prolonged QT interval and, as such, play a major role into ventricular arrhythmias that may occur in patients with WPW.⁷

Current Treatment

There are two main treatments for patients with WPW: electrical/ablative and pharmacological. Since most patients are unaware of the syndrome they may be carrying, there is usually no treatment obtained until arrhythmias occur. Most present in atrial fibrillation or SVT. Treatment may include the use of medications such as adenosine and/or electrical cardioversion. The causes of death in most patients with WPW are the dangerous tachyarrhythmias that can occur or the proarrhythmic effects of medications used to treat these arrhythmias. Patients with WPW are treated very differently than patients without WPW when presenting with tachyarrhythmias. Most medications used for this syndrome fall under the Class IA and IC classification; however, the use of any antiarrhythmics with WPW associated with structural heart disease should be with caution. Amiodarone and sotalol affect the AVN and accessory pathways. Verapamil and IV lidocaine can increase the ventricular rate during atrial fibrillation. Intravenous verapamil can precipitate ventricular fibrillation with rapid ventricular response during atrial fibrillation. Cathecholamines can shorten the refractory time of the accessory pathway and reverse the effects of some antiarrhythmic medications. The common approach to treat WPW tachyarrhythmias is first to try vagal maneuvers, then move to adenosine, IV verapamil, or diltiazem. With atrial fibrillation and/or flutter, the choice is to use procainamide and propranolol. Flecainide can also be used, but only in patients with no organic or structural cardiac disease.³ Given the risks of SCD with WPW, the indication for EP studies and subsequent ablation have liberalized; electrophysiology studies (and possible ablation) can be performed to determine the presence/participation of accessory pathways. This approach may eliminate the need for further medications and is used in cases in which tachyarrhythmias occur frequently in patients.

Physicians are becoming more aware of the genetic testing that can be performed on patients to recognize a host of diseases and disorders. With familial WPW, testing can be performed on patients, siblings and offspring to check for their risk of developing AV block and cardiac hypertrophy. This is even more important with the current research into glycogen storage and sodium ion channels. The syndrome of WPW is also commonly found in other diseases such as Pompe disease, Ebstein’s anomaly, Danon disease, tuberous sclerosis complex, Leber’s hereditary optic neuropathy (LHON), as well as diabetes and deafness presenting as subtle features of mitochondrial disease. When the gene mutations are reviewed, there is a common correlation between them.

Patients with preexcitation abnormalities and those with AV block should be evaluated for WPW. In addition, an ECG screen of first-degree relatives should also be performed to rule out WPW or other conditions. The secondary screenings may include echocardiography, since many of these patients will have cardiomyopathy and eventually develop left ventricular systolic dysfunction.¹ Figure 1 depicts a simplified flowchart of patient management that may help guide care when familial preexcitation is suspected.

Ethical Issues Related to Testing and Treatment

Ethical issues may develop in familial WPW if there is an occurrence of sudden cardiac death. Families may proceed with genetic testing to identify those that are carrying the trait, as well as to see if their offspring is afflicted. The ethical issue would more than likely raise awareness to seek more aggressive medical measures to treat WPW preexcitation and abnormalities. The dilemma may occur when, through genetic testing, it is found that a patient may have a more serious disease such as Danon disease. This may lead to ethical decisions being made regarding offspring. Further research will determine the implications of the gene mutation and drive the genetic testing for accompanying disorders and conditions of this syndrome.

Patient Teaching and Genetic Counseling

Counseling and patient teaching should focus on the recognition of the symptoms of this syndrome to include palpitations, syncope, fatigue, hypotension, and regular physical checkups to include a yearly ECG if WPW is found. Referral to a cardiac specialist should be made in all patients found to have WPW so that appropriate medical or invasive treatment courses of action can be made. Genetic counseling should focus on the presenting syndrome as well as accompanying conditions that may precipitate the need for genetic testing to be performed and adequate follow-up to be performed regarding those results.

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