Clinical Spectrum of PRKAG2 Syndrome (Journal Review and Synopsis)
by Misti Blu Day McDermott
PRKAG2 genetic mutations result in PRKAG2 syndrome (PS), which involves episodes of supraventricular arrhythmias and cardiac hypertrophy. This is also known as ventricular pre-excitement syndrome and can lead to advanced heart blocks, early pacemaker or ICD implantation, heart failure, or even sudden cardiac death. The objective is to describe the features and clinical implications involving PS in order to improve diagnosis, prevent sudden cardiac death, and to better manage the comorbidities of the disease.
A collection of 55 studies, 24 of which were observational, resulted in a total of 193 genetically confirmed patients and discovering 13 different mutations of PRKAG2 gene. The inheritance pattern is autosomal dominant and the mutations are suspected to alter the tridimensional structure of Adenosine Monophosphate-Activated Protein Kinsae (AMPK), which affects the enzyme activity then impairs the myocardial glycogen uptake. Glycogen-filled myocytes interfere with the AV septation, leading to ventricular pre-excitation, thus inducing arrhythmias. It was also demonstrated that cardiac hypertrophy is caused by an enhanced insulin sensitivity and protein kinase B activation. A study on mice demonstrated that mutated AMPK led to an unbalanced phosphorylation state of cardiac troponin and myocardial contractility, resulting in heart failure.
ECG features of PS patients commonly demonstrate short PR interval, present in 68% of patients, along with a bundle branch block (mostly RBBB). Additionally, delayed QRS depolarization and delayed intraventricular conduction of > 120 msec are commonly reported clinical abnormalities. The left ventricle may demonstrate cardiac hypertrophy with both diastolic and systolic heart failure. Cardiac transplant may be necessary if restrictive mitral inflow doppler pattern, hemodynamically significant LV outflow tract obstruction, and dilation progressions are present. Supraventricular tachycardia (SVT) is typically the first sign and can include complications resulting in stroke or sudden cardiac death due to cardiogenic shock. Electrophysiological studies have also indicated different types of accessory pathways. It is noted that the third or forth decade of age will likely lead to the patient (43% of PS patients) receiving a pacemaker implantation due to advanced AV blocks, bradycardia, or sinus blocks. Heart failure was reported in 12% of PS patients and sudden cardiac death was reported in 8.7% of 171 patients.
In conclusion, proper diagnosis and early recognition of mutations in PRKAG2 is important; it is often misdiagnosed as hypertrophic cardiomyopathy and/or Wolff-Parkinson-White syndrome, where the golden standard ablation (of accessory pathways) will likely be ineffective for PS (Aggarwal). Aberrant conduction in PS is due to swollen glycogen accumulated in cardiomyocytes rather than an accessory pathway. PS should be suspected and considered in autosomal dominant HCM with WPW syndrome, and a negative sarcomeric mutation. Table 3 in Clinical Spectrum of PRKAG2 Syndrome feature cardiomyopathies associated with WPW syndrome or short PR and should be considered to prevent misdiagnosis. Currently, there is no cure for PS, only to promptly manage symptoms and to prevent catastrophic events.
The possibility of gene therapies should be explored in order to prevent sudden cardiac death in PS patients. Cardiac event monitoring is also essential to evaluate arrhythmias. A loop monitor implantation is a long-term monitoring option that allows the physician to keep a close eye on the electrophysiological aspect of the patient. Early ICD implantation can prevent catastrophic events, as it would be less of a gamble than waiting for a serious cardiac event to occur. Familial screening and genetic testing are important tools for diagnosis and counseling. In a published article, genome editing with CRISPR/Cas9 corrected PRKAG2 syndrome in postnatal mice (Xie, 2016).
*A link to the PDF of the reviewed journal can be found at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704128/pdf/nihms-716203.pdf
Aggarwal, V., Dobrolet, N., Fishberger, S., Zablah, J., Jayakar, P., & Ammous, Z. (2015). PRKAG2 mutation: An easily missed cardiac specific non-lysosomal glycogenosis. Annals of pediatric cardiology, 8(2), 153–156. https://doi.org/10.4103/0974-2069.154149
Xie, C., Zhang, Y. P., Song, L., Luo, J., Qi, W., Hu, J., Lu, D., Yang, Z., Zhang, J., Xiao, J., Zhou, B., Du, J. L., Jing, N., Liu, Y., Wang, Y., Li, B. L., Song, B. L., & Yan, Y. (2016). Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell research, 26(10), 1099–1111. https://doi.org/10.1038/cr.2016.101
Porto, A. G., Brun, F., Severini, G. M., Losurdo, P., Fabris, E., Taylor, M., Mestroni, L., & Sinagra, G. (2016). Clinical Spectrum of PRKAG2 Syndrome. Circulation. Arrhythmia and electrophysiology, 9(1), e003121. https://doi.org/10.1161/CIRCEP.115.003121