New mutation in prkag2 syndrome and sudden cardiac death

Abstract

Background: Mutations in PRKAG2 have been described in patients (PT) with familial WPW syndrome and hypertrophic cardiomyopathy (HC). Conduction system disease, embolic stroke and heart failure can happen Tachyarrhythmias are frequent and can cause sudden cardiac death (SCD) and the predictive factors remain unknown. Objective: The purpose of this study is to describe the mechanism of aborted SCD in individuals affected by WPW in association with HC. Methods: A total of 18 (21%) PT selected from an 84-member family cohort were included retrospectively from March 2005 to March 2012 and submitted to ECG, 2D ECHO and 24h Holter. For a genetic analysis, it was collected blood samples (3ml) and used a commercial kit (Gentra System, Puregene), ExoSAP-IT, USB and directly sequenced in both directions using an ABI PRISM Automatic DNA Sequencer in a subgroup of 8 PT. Diagnosis of WPW was based on ECG with a shortened PR interval and a slurred upstroke to the QRS complex (delta wave). Diagnosis of HC was based on ECHO by demonstrating evidence of LVH, asymmetric in distribution, and with any diffuse or segmental pattern of left ventricular [LV] wall thickening ≥ 15 mm. Results: Eleven PT (61%) were female, with a mean age of 27±16. HC was detected in association with WPW in 11 (61.1%) PT, isolated WPW in 6 (33%) PT and HC only in one PT (5.6%). Main clinical findings: TIA (16.7%), spontaneous abortion (16.7%). Palpitations occurred in 12 (67%), chest pain in six (33.3%) and syncope in five (28%). Learning disabilities, retarded growth development were also observed in 3 males (16.7%). Five PT were submitted to pace-maker implantation due to total AV block. Main ECG findings: RBBB morphology (55.5%), LBBB (27.7%), atrial fibrillation (AF) (33.3%), atrial flutter (AFL) (16.7%), atrial tachycardia (11.1%), non-sustained VT (5.5%) and SVT in 12 (67%). ECHO showed generalized and diffuse LVH with septal thickness ≥15 mm and good contractility. Mitral valve insufficiency (50%) and diastolic dysfunction (61.1%). SCD occurred in 4=22% PT. Two PT had SCD at age 37 (f) and 27 (m). Three episodes of aborted SCD were documented in two PT with WPW in association with HC due to AF and AFL with anterograde conduction through the accessory pathway Direct sequencing of PRKAG2 revealed a missense mutation in exon 7 of PRKAG2, A869T (K290I). This mutation has not been previously described Conclusion: SCD had a high incidence in this cohort and the documented mechanism was AF and AFL with anterograde conduction through the accessory pathway. A new mutation in PRKAG2 was found in an initial study of subgroup.