A Wolff-Parkinson-White Gene
Abstract & Commentary
Synopsis: AMP-activated protein Kinase plays some key, but as yet unknown, role during cardiogenesis that favors development of the accessory AV connections that form the anatomic basis of the pre-excitation syndromes.
Source: Gollob MH, et al. N Engl J Med. 2001;344: 1823-1831.
Gollob and colleagues report the identification and characterization of a gene associated with a familial form of Wolff-Parkinson-White (WPW) syndrome. Gollob et al studied 2 separate families. In the first family, there were 23 affected individuals among 57 family members. In the second unrelated family, there were 8 affected members out of 13 members identified. In addition to an ECG pattern consistent with ventricular preexcitation, a number of other anomalies were observed. These included ventricular hypertrophy, sinus node dysfunction, atrioventricular (AV) conduction delays, and premature sudden death. Unfortunately, intracardiac electrophysiologic studies were only performed in 8 individuals so abnormalities that are not observable on the surface ECG (eg, concealed accessory pathway conduction, subtle AV conduction delays, etc) may have been missed. An autosomal, dominant pattern of inheritance with high penetrance was observed in both families. Genetic linkage analysis indicated an abnormality in the 7q34-36 region. Further studies showed a missense mutation involving substitution of adenine for guanine in the gene PRKAG2. No abnormalities in this gene were identified in a small number of patients with the WPW syndrome without a family history. This gene encodes the sequence for the g2 regulatory subunit of adenosine monophosphate (AMP)-activated protein kinase. AMP-activated protein kinase is a metabolic sensor which helps regulate adenosine triphosphate (ATP) production and use in several tissues. Gollob et al speculate that this protein plays some key, but as yet unknown, role during cardiogenesis that favors development of the accessory AV connections that form the anatomic basis of the pre-excitation syndromes.
Comment by John P. DiMarco, MD, PhD
Ever since the classic description of patients with a short PR interval, a widened electrocardiographic QRS wave with a slurred upstroke and paroxysmal tachycardia by Wolff, Parkinson, and White (the syndrome named after these scientists) has fascinated both cardiologists and electrophysiologists. The anatomical basis for the WPW ECG pattern is an accessory AV connection, believed to be residual muscular tissue that allows AV or ventriculoatrial (VA) electrical conduction independent from the AV node and His-Purkinje system. Most patients with WPW have no family history of the disorder, but familial patterns account for a small percentage of cases. In this paper, Gollob et al describe 2 families with WPW inherited in an autosomal, dominant pattern and describe a mutation in a gene PRKAG2 that encodes the protein AMP-activated protein kinase, an enzyme that modulates cellular energy balance. Unfortunately, Gollob et al emphasize the relationship to the WPW syndrome, but it seems much more probable that the WPW pattern seen in these individuals is only a small part of an overall picture of a cardiomyopathy with a broad spectrum of manifestations. In 2 earlier reports, families with WPW and mutations at this same locus were described.1,2 Like the families in this report, WPW was only one of a number of unusual findings. One family followed in Virginia has members who manifest various combinations of ventricular hypertrophy, AV-conduction disorders, preexcitation, and atria arrhythmias. The arrhythmia pattern depends on the relative properties of both the normal and the accessory conduction systems and changes during the patient’s lifetime. Various family members can show signs of conduction system disease and cardiomyopathy even if they have no clinical or invasive evidence for pre-excitation. These findings are not seen in patients with sporadic forms of WPW. Therefore, mutations in the PRKAG2 gene seem more likely to be the cause of a cardiomyopathy with diverse presentations rather than keys to the pathogenesis of the more commonly seen forms of WPW. In the latter patients, the failure of electrical septation is probably not under genetic control.
References
1. MacRae CA, et al. J Clin Invest. 1995;96:1216-1220.
2. Mehdirad AA, et al. J Cardiovasc Electrophysiol. 1999; 10:629-635.
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