Europace Advance Access originally published online on May 4, 2007
Europace 2007 9(8):597-600; doi:10.1093/europace/eum071
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BASIC SCIENCE
A familial form of conduction defect related to a mutation in the PRKAG2 gene
1 Université Pierre et Marie Curie-Paris 6; Inserm UMR621; AP-HP, Hôpital Pitié-Salpêtrière, Département de Cardiologie, Paris, France; 2 Service de Cardiologie, Hôpital Léon Binet, Provins, France; 3 Fédération de Génétique, UF Cardiogénétique, Hôpital Pitié-Salpêtrière, Paris, France
Manuscript submitted 27 November 2006. Accepted after revision 19 March 2007.
* Corresponding author. Tel: +33 1 42 16 28 98 fax: +33 1 42 16 30 26. E-mail address: philippe.charron{at}psl.aphp.fr
 |
Abstract |
|---|
 Top Abstract IntroductionCase reportDiscussionReferences |
|---|
We describe four members of the same family with a very similar ECG pattern characterized by conduction defects (right bundle branch block, frequent left anterior hemiblock, atrial hypertrophy, and sometimes severe nodal dysfunction) contrasting with a short PR interval. Significant clinical events were reported only after 60 years of age. A mutation in the
2 subunit of the AMP activated protein kinase gene (PRKAG2) was identified in the four members of the family, with an autosomal dominant inheritance. The phenotype observed in this family appears different from that previously described as associated with this gene as neither left ventricular hypertrophy nor Wolff–Parkinson–White syndrome was present. These findings extend the phenotype associated with the PRKAG2 gene and emphasize an additional cause of familial conduction defect.
Key Words: Conduction defect, PRKAG2 gene, Preexcitation, AMP activated protein kinase
|
Introduction |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
The familial and genetic origin of cardiac conduction defects are increasingly recognized although still considered quite rare. Familial conduction defects can be isolated, such as progressive conduction defects caused by mutations in the SCN5A gene, or associated with myocardial abnormalities (dilated cardiomyopathy), such as mutations of the LMNA gene.1
,2 We describe here the members of a family with cardiac conduction defects and a specific ECG pattern, without myocardial abnormalities (Figure 1).
|
|
Case report |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
A 66-year-old woman was admitted because of several episodes of dizziness and severe paroxysmal sinusal dysfunction (with a rhythm <35 bpm), requiring the implantation of a dual pacemaker (subject II-1 on Figure 1). She had a history of hypertension controlled with hydrochlorothiazide and captopril without any hypokaliemia. The ECG performed for the first time on admission exhibited sinus rhythm with complete right bundle branch block (RBBB), left anterior hemiblock (LAHB), and short PR interval (0.10 s) but no delta wave (Figure 2). Echocardiography was normal at that time. Eleven years later at the age of 77, hospitalization was required for congestive heart failure favoured by rapid atrial fibrillation, and a small troponin elevation with limited apical defect on scintigraphy.
|
There was no history of cardiac disease in her parents: the father (I-1) died at 96 years old and the mother (I-2) died of asthma at 57.
Her brother (II-2) experienced sudden death due to ‘heart attack’ when he was 60 years old (no cardiac examination); and her sister (II-3) committed suicide. Electrocardiograph of their own children (III-3 and III-4) were normal.
The first daughter (III-1) of the propositus (II-1) was investigated when she was 41 years old because of palpitations (Figure 3). Electrocardiograph was characterized by short PR (0.10 s) without delta wave, RBBB, LAHB, and pseudo bi-atrial enlargement (bi-atrial hypertrophy on ECG contrasting with normal atrial diameter on echocardiography). Invasive electrophysiological investigation was then carried out. AH and HV intervals were 60 and 40 ms, respectively. Wenckeback point was raised without post-stimulation abnormal response, an auriculo-hisian accessory pathway was present, without decremental conduction, as well as frequent supraventricular extrasystoles and sinus bradycardia. She required a treatment with cibenzolin and remains asymptomatic after 11 years of follow-up, with unchanged ECG and a normal echocardiography.
|
The second daughter (III-2) is asymptomatic but ECG at 48 years of age displays an incomplete pattern of electrocardiographic abnormalities (see Figure 4) with pseudo bi-atrial hypertrophy and short PR interval (0.11 s). Echocardiography revealed only mild mitral regurgitation with normal atrial and ventricle dimension.
|
At 22 years old, the daughter of III-1 (IV-2) had some palpitations related to supraventricular extrasystoles. Electrocardiograph pattern was similar to those within the family, with short PR interval, RBBB and pseudo bi-atrial hypertrophy (see Figure 5).
|
The brother of IV-2 (known as IV-1) who is 26 years of age is asymptomatic, with a normal ECG.
No significant echocardiographic left ventricular hypertrophy or Wolff–Parkinson–White (WPW) syndrome or clinical muscular dystrophy was observed in the family (Table 1). Serum levels of creatine kinase were normal.
|
Blood sampling was obtained from all investigated members of the family, after written informed consent, and DNA was extracted from lymphocytes. After PCR amplification, coding regions and boundaries of the PRKAG2 gene were analysed (GenBank accession number ENSG1066178) by direct sequencing with BigDye terminator chemistry on the ABI PRISM 3100 genetic analyser (Applied Biosystems, Foster City, CA, USA). We identified a missense heterozygous mutation (G-to-A transition at nucleotide 995 of the PRKAG2 gene), leading to the substitution of arginine by glutamine at codon 302 of the protein R302Q (or p.Arg302Gln), in the four family members with ECG abnormalities (II-1, III-1, III-2, and IV-2), but not in the relative (IV-1) with a normal ECG. The mutation was not found in a control and ethnic-matched (European origin) population of 200 chromosomes (Figure 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
The PRKAG2 gene (7q36.1) encodes the
2 subunit of adenosine monophosphate (AMP) activated protein kinase (AMPK). Adenosine monophosphate kinase is a heterotrimer consisting of a catalytic alpha subunit and two regulatory (beta and gamma) subunits. This ubiquitous enzyme is a key regulator of ATP levels in all tissues and appears to act as a cellular ‘fuel gauge’, monitoring the AMP/ATP ratio.3 An increase of this ratio is observed in various cellular stresses that deplete ATP and consequently increase AMP. This situation triggers the AMPK with subsequent phosphorylation of a number of downstream targets switching on catabolic energy-generating pathways, and switching off many non-essential ATP-consuming processes, thus restoring the energetic balance.
Mutations in the PRKAG2 gene have been described since 2001 in patients with hypertrophic cardiomyopathy (HCM) and/or WPW syndrome.4,5 The phenotype evaluated from four major studies is heterogeneous with ventricular preexcitation (defined as short PR interval and a delta wave or widened QRS complex) in 50–100%, HCM on echocardiography in 26–78%, severe conduction defect requiring pace maker implantation in 30–76% of patients older than 30 years, paroxysmal atrial fibrillation or flutter in 20–75%, and myalgia or clinical myopathy in 0–15%.4–7 The global rate of cardiac death was estimated to be high in the initial reports.4,5
Several mutations have been identified in the PRKAG2 gene but the pathophysiological consequences are still poorly understood. Some experimental studies suggest that mutations lead to constitutively active AMPK, with a gain-of-function, whereas other studies observed a loss-of-function effect.8,9 Whatever the precise mechanism, the final common pathway probably leads to a disequilibrium of the energetic balance. Moreover, histological studies performed in human and in animal transgenic models exhibited vacuoles containing amylopectin, a glycogen-derived substance, in cardiomyocytes,8 as observed in glycogen storage disorders including Pompe disease. These animal studies also revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. This suggests that ventricular preexcitations could be related to microscopic atrioventricular connections rather than conventional morphological distinct bypass tracts.8
In the present study, we describe a family with a mutation in the PRKAG2 gene and a particular phenotype characterized by (i) no echocardiographic hypertrophy; (ii) no WPW syndrome; (iii) but conduction defects, including RBBB, LAHB, and possible severe sinusal dysfunction (in one patient); (iv) pseudo atrial hypertrophy on ECG probably related to intra-atrial conduction defect (in the absence of echocardiographic morphologic substrate) which has never been described previously in PRKAG2 mutation carriers; (v) short PR interval; and (vi) mild progression with no significant clinical event before 60 years of age. Supraventricular arrhythmia was observed in some patients, but no clinical myopathy. The phenotype present in the family appears therefore different from that previously reported in the literature. In addition, and surprisingly, the R302Q mutation that we identified here has been previously reported in several families, with a classical phenotype characterized by cardiac hypertrophy on echocardiography and/or WPW syndrome on ECG.4,6,7 This finding suggests a novel level of complexity about phenotype–genotype relationships, possibly related to interacting factors such as modifier or environmental factors.
Finally, important practical implications can be drawn from the present observation. First, the presence of conduction defect and pseudo atrial hypertrophy contrasting with short PR interval (even in the absence of delta wave/WPW syndrome or left ventricular hypertrophy) should raise the suspicion of a PRKAG2 mutation. Second, the confirmation of a mutation in this gene should lead to a specific cardiac follow-up because of the risk of cardiac sudden death, and early pacemaker implantation should be considered.
In conclusion, we describe a family with conduction defects and short PR interval related to a mutation the PRKAG2 gene. These findings extend the phenotype which might be associated with mutations in this gene and emphasize an additional cause of familial isolated conduction defect.
|
References |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
[1] Roberts R. Genomics and cardiac arrhythmias. J Am Coll Cardiol (2006) 47:9–21.
[2] Sarkozy A, Brugada P. Sudden cardiac death and inherited arrhythmia syndromes. J Cardiovasc Electrophysiol (2005) 16(Suppl. 1):S8–20.[CrossRef][Web of Science][Medline]
[3] Oliveira SM, Ehtisham J, Redwood CS, Ostman-Smith I, Blair EM, Watkins H. Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. J Mol Cell Cardiol. (2003) 35:1251–5.[CrossRef][Web of Science][Medline]
[4] Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, et al. Identification of a gene responsible for familial Wolf Parkinson White Syndrome. N Engl J Med (2001) 344:1823–31.
[5] Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, et al. Mutations in the gamma 2 subunit of AMP- activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet (2001) 10:1215–20.
[6] Arad M, Benson DW, Perez-Atayade AR, McKenna WJ, Sparks EA, Kanter RJ, et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest (2002) 109:357–62.[CrossRef][Web of Science][Medline]
[7] Murphy RT, Mogensen J, McGarry K, Bahl A, Evans A, Osman E, et al. Adenosine monophosphate activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolf–Parkinson–White syndrome. J Am Coll Cardiol (2005) 45:922–30.
[8] Arad M, Moskowitz IP, Patel VV, Ahmad F, Perez-Atayde AR, Sawyer DB, et al. Transgenic mice overexpressing mutant PRKAG2define the cause of Wolff–Parkinson–White syndrome in glycogen storage cardiomyopathy. Circulation (2003) 107:2850–6.
[9] Sidhu JS, Rajawat YS, Rami TG, Gollob MH, Wang Z, Yuan R, 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) 111:21–9.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||