Familial Atrial Enlargement, Conduction Disorder and Symmetric Cardiac Hypertrophy Are Early Signs of PRKAG2 R302Q

Abstract

PRKAG2 cardiac syndrome (PS) is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome (WPWs), conduction system lesions and myocardial hypertrophy. It can also lead to serious consequences, such as sudden death. But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult. Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations. Gene analysis identified a missense mutation (Arg302Gln) in the five affected subjects of the family. The electrocardiograph performance of the five was composed of sinus bradycardia (SB), WPWs, right bundle branch block (RBBB), atrioventricular block (AVB), left bundle branch block (LBBB), supraventricular tachycardia (SVT) and atrial premature beat (APB). Among them, the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old; two members progressed over time to serious conduction damage, and the proband received a pacemaker at the age of 27 due to AVB. Besides, according to cardiac magnetic resonance and echocardiography, the youngest one showed symmetric hypertrophy; three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy; all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage. In conclusion, the conduction system disorder, familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.

Keywords

arrhythmia / atrial enlargement / cardiac hypertrophy / PRKAG2 syndrome / R302Q mutation

References

[1] GollobMH, GreenMS, TangASL, et al.. Identification of a gene responsible for familial wolff-parkinson-white syndrome. N Engl J Med, 2001, 344(24): 1823-1831

[2] GollobMH, GreenMS, TangAS, et al.. PRKAG2 cardiac syndrome: Familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy. Curr Opin Cardiol, 2002, 17(3): 229-234

[3] OfirM, HochhauserE, VidneBA, et al.. AMP-activated protein kinase: How a mistake in energy gauge causes glycogen storage. Harefuah (Hebrew), 2007, 146(10): 770-775813–814

[4] SidhuJS, RajawatYS, RamiTG, et al.. Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. Circulation, 2005, 111(1): 21-29

[5] AradM, BensonDW, Perez-AtaydeAR, et al.. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest, 2002, 109(3): 357-362

[6] ThornSL, GollobMH, HarperM, et al.. Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model. EJNMMI Res, 2013, 3(1): 48

[7] AustinSL, ChiouA, SunB, et al.. Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation. Mol Genet Metab, 2017, 120(1–2): 96-100

[8] ZhangBL, XuRL, ZhangJ, et al.. Identification and functional analysis of a novel PRKAG2 mutation responsible for Chinese PRKAG2 cardiac syndrome reveal an important role of non-CBS domains in regulating the AMPK pathway. J Cardiol, 2013, 62(4): 241-248

[9] YangKQ, LuCX, ZhangY, et al.. A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation. Sci Rep, 2017, 7(1): 2407

[10] ThevenonJ, LaurentG, AderF, et al.. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace, 2017, 19(4): 651-659

[11] LiuY, BaiR, WangL, et al.. Identification of a novel de novo mutation associated with PRKAG2 cardiac syndrome and early onset of heart failure. PLoS One, 2013, 8(5): e64603

[12] WolfCM, AradM, AhmadF, et al.. Reversibility of PRKAG2 Glycogen-Storage cardiomyopathy and electrophysiological manifestations. Circulation, 2008, 117(2): 144-154

[13] KellyBP, RussellMW, HennessyJR, et al.. Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation. Pediatr Cardiol, 2009, 30(8): 1176-1179

[14] LaforetP, RichardP, SaidMA, et al.. A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Neuromuscul Disord, 2006, 16(3): 178-182

[15] BayrakF, Komurcu-BayrakE, MutluB, et al.. Ventricular pre-excitation and cardiac hypertrophy mimicking hypertrophic cardiomyopathy in a Turkish family with a novel PRKAG2 mutation. Eur J Heart Fail, 2006, 8(7): 712-715

[16] BurwinkelB, ScottJW, BuhrerC, et al.. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-Subunit of AMP-Activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet, 2005, 76(6): 1034-1049

[17] SternickEB, OlivaA, MagalhaesLP, et al.. Familial Pseudo-Wolff-Parkinson-White syndrome. J Cardiovasc Electrophysiol, 2006, 17(7): 724-732

[18] LiT, JiangS, YangZ, et al.. Targeting the energy guardian AMPK: another avenue for treating cardiomyopathy?. Cell Mol Life Sci, 2017, 74(8): 1413-1429

[19] AradM, MoskowitzIP, PatelVV, et al.. Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation, 2003, 107(22): 2850-2856

[20] BanerjeeSK, WangDW, AlzamoraR, et al.. SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy. J Mol Cell Cardiol, 2010, 49(4): 683-692

[21] BanerjeeSK, McGaffinKR, HuangXN, et al.. Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation. Biochim Biophys Acta, 2010, 1802(2): 284-291

[22] KimM, HunterRW, Garcia-MenendezL, et al.. Mutation in the γ2-Subunit of AMP-Activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circ Res, 2014, 114(6): 966-975

[23] YuanL, XieM, ChengTO, et al.. Left ventricular noncompaction associated with hypertrophic cardiomyopathy: echocardiographic diagnosis and genetic analysis of a new pedigree in China. Int J Cardiol, 2014, 174(2): 249-259

[24] MonserratL, Hermida-PrietoM, FernandezX, et al.. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Eur Heart J, 2007, 28(16): 1953-1961

[25] TanHL, van der WalAC, CampianME, et al.. Nodoventricular accessory pathways in PRKAG2-dependent familial preexcitation syndrome reveal a disorder in cardiac development. Circ Arrhythm Electrophysiol, 2008, 1(4): 276-281

[26] LightPE, WallaceCH, DyckJR. Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation, 2003, 107(15): 1962-1965

[27] LightPE. Familial Wolff-Parkinson-White syndrome: a disease of glycogen storage or ion channel dysfunction?. J Cardiovasc Electrophysiol, 2006, 17(s1): S158-S161