Coexistent Manifestations of the Andersen-Tawil and Brugada Syndromes

By Shandling, Adrian H Safani, Michael

Introduction The Andersen-Tawil syndrome (ATS) is a rare inherited disorder characterized by periodic paralysis, ventricular arrhythmias, skeletal developmental abnormalities, and in most cases, prolongation of the QT interval (or more correctly, the QU interval). The Brugada syndrome (BS) similarly is an inherited disorder manifested by the unique electrocardiographic (ECG) abnormality of ST-segment elevation in leads V^sub 1^ and V^sub 2^, ventricular arrhythmias, and sudden cardiac death. This report details an unusual patient with manifestations of both syndromes, who was treated by the implantation of a defibrillator (implanted cardioverter/defibrillator).

Case report

A 37-year-old woman was admitted to the hospital with an episode of upright syncope. Pounding in the chest preceded this event, and she woke immediately lucid. She experienced urinary incontinence but sustained no fall injuries. Her clinical history began 13 years prior, when she experienced 2 episodes of syncope. A prolonged QT interval and premature ventricular contractions (PVCs) were noted on ECG at that time. The result of electrophysiologic testing with standard programmed ventricular stimulation techniques was negative for arrhythmia induction. She was offered a defibrillator but refused. According to the patient, multiple antiarrhythmic medications were tried at that time to treat her palpitations, including quinidine, although precise details are lacking. The patient stated that most of these agents were ineffective in suppressing her symptoms. Moricizine was the only agent tolerated, and it was moderately effective. She had been on this medication with adequate medical control for the preceding 13 years until the current episode of syncope. At birth, the patient was diagnosed with the Pierre-Robin syndrome (micrognathia). More recently, the patient gave birth to her first daughter, who had a cleft palate as well as the Pierre-Robin syndrome. Chromosomal studies showed a mutation on the KCNJ^sub 2^ gene in chromosome 17 and confirmed the genetic diagnosis of the ATS in both mother and daughter. (Further chromosomal analysis is unavailable.)

The patient’s admission ECG showed right bundle branch block and unusually coved ST segments in V^sub 1^ and V^sub 2^, compatible with the diagnosis of the BS (Fig. 1). These ECG changes abated several days after the withdrawal of moricizine (Fig. 2). No electrolyte aberrations were detected. She had frequent multiform PVCs. Provocative antiarrhythmic drug testing to help confirm the diagnosis of the BS was refused. She underwent tilt-table testing during hospitalization, the result of which was negative. The result of echocardiography was normal. Because of her syncopal episode and the diagnosis of ATS and BS, a defibrillator was placed in the left pectoral region in a submuscular fashion. Continuing palpitations necessitated antiarrhythmic treatment. Mexilitine and beta-blockers were not tolerated, amiodarone was declined, and at the patient’s request, she was discharged on moricizine for her symptomatic ventricular ectopy. Approximately 1 month after implant, the defibrillator responded appropriately to an episode of polymorphic ventricular tachycardia. The ST segments in Vj and V2 were again elevated on the 12-lead ECG (Fig. 3). Moricizine was stopped, and amiodarone was initiated in view of highly symptomatic multiform PVCs.

Discussion

The Anderson-Tawil syndrome was first described in 1971. The syndrome is linked to mutations of the KCNJ^sub 2^ gene on chromosome 17. This gene encodes for the inward rectifier potassium channel.1 A reduction in Kir 2.1 prolongs the terminal phase of the cardiac action potential and thereby the QT interval. It also induces delayed afterdepolarizations with consequent spontaneous arrhythmias.1 Andersen-Tawil syndrome is unique among ion channelopathies due to the combination of both a skeletal and a cardiac muscle phenotype. The concurrence of periodic paralysis and a prolonged QT in the same individual suggests a shared ion channel defect.1 Periodic paralysis has been reported in 64% of ATS cases. The serum potassium level with periodic paralysis is most often low but can be normal or elevated. No trigger, such as carbohydrate loading, has been identified.1,2 Characteristic dysmorphic physical features include low-set ears, hypertelorism, micrognathia, clinodactyly, digit webbing, cleft palate, short stature, and scoliosis. The heart is typically morphologically normal with a prolonged QT interval in 71 % of cases. Prominent U waves and abnormal anterior T waves are seen.1,2 A characteristic TU pattern has been described recently.3 This TU pattern consists of a prolonged terminal T-wave downslope with biphasic U waves in the limb leads and enlarged U waves in V^sub 2^ and V^sub 3^. These findings cannot be convincingly seen in the tracings of this patient, perhaps due to the increased heart rate. Right bundle branch block has also been reported in one instance, but it is unclear whether ST-segment elevation was present or whether the diagnosis of BS was even considered in this article.1 Fatal sudden cardiac death appears very uncommon when compared with the traditional long QT syndrome, although syncope and a case of nonfatal cardiac arrest have been reported.3 Arrhythmia inducibility by electrophysiologic programmed stimulation has been noted in a single prior case.4

Fig. 1. The ECG shows sinus rhythm, first-degree AV block, right axis deviation, and a prolonged QT interval. Bizarre coving of the ST segment is present in V^sub t^.

Fig. 2. The ST-segment coving in V^sub 1^ is gone (after withdrawal of moricizine).

Fig. 3. Coving of the ST segment in V^sub 1^ has returned after reinitiation of moricizine.

Brugada syndrome is a genetically heterogeneous disorder first reported in 1992.5 It is increasingly recognized as an inherited autosomal dominant trait, with 18% to 30% of cases involving an SCN5A mutation.6’7 This particular gene type was first identified in 1998 and occurs with a higher frequency in males.8 A second locus on chromosome 3 was established in 2002, and subsequently, a new causative mutation in the glycerol-3-phosphate dehydrogenase 1-like gene has been identified.9,10 The prevalence of expression of the latter gene mutation in the BS population remains undetermined. There is a distinct baseline or sodium channel blocker-induced ECG finding of ST-segment elevations in the precordial leads (V^sub 1^ and V^sub 2^). These elevations can take the form of coving or “saddlebacking.”11,12 The QT interval can be prolonged, but this is limited to the right precordial leads.13 It is associated with syncope, malignant arrhythmias, and sudden cardiac death.14 These clinical and ECG manifestations tend to predominate in the fourth decade of life, and this may explain the age of presentation of clinical and ECG manifestations in this case. The ST-segment elevation in V^sub 1^ and V^sub 2^ is dynamic and can be accentuated or unmasked by pharmacologie agents that block cardiac sodium channels, including flecainide, propafenone, procainamide, disopyramide, and ajmaline. Certain tricyclic antidepressants and phenothiazines have been associated with a transient Brugada pattern on the ECG. Flecainide, procainamide, and ajmaline may be used as pharmacologic challenges and can occasionally uncover the Brugada type 1 ECG pattern for diagnostic purposes.12 Sodium channel blockade can induce ventricular premature beats, eliciting VT/VF in patients with BS.15 Quinidine, another sodium channel blocker, appears to be an exception and may be beneficial in those patients with BS.16,17 This paradoxical effect appears to be related to blockade of the transient outward current resulting in normalization of the ST segment and may lead to prevention of VT/VF.16 Despite encouraging limited data, there is not enough clinical experience with the use of quinidine or other related agents to recommend its use in preference to an ICD.18 The ACC/ AHA/ESC 2006 guidelines offer a weak recommendation (Class lib, grade C) for the use of quinidine for the treatment of electrical storm in those with BS.19 Nevertheless, antiarrhythmic drugs may have a role in patients with an ICD who continue to have frequent arrhythmic events. Inducibility of ventricular fibrillation at the time of electrophysiologic testing can be seen in almost half of cases,11 but in a recent study, programmed electrical stimulation showed very little accuracy in predicting future outcome.14

To our knowledge, there is no prior report that documents the coexistence of these 2 syndromes. There are 2 reports of QT prolongation combined with ST-segment elevation, but neither of these related to ATS.20,21 It is conceivable that the ATS responds to moricizine with Brugada-type ECG effects because moricizine is a phenothiazine derivative with class 1C electrophysiologic and hemodynamic effects.22 This has not been previously reported, however. Moricizine, like other class 1C antiarrhythmic agents, prolongs the PR and QRS intervals without significant prolongation of the JT or QT intervals.23 It depresses the rapid inward sodium current and interferes with sodium-calcium exchange. Moricizine does have some additional limited potassium single-channel blocking effect.24 The role of moricizine in treatment of those with BS has not been studied. Treatment of this patient’s symptomatic ectopy is complicated when one considers the mode of action of the various antiarrhythmic drugs on each of the syndromes. Type Ia (perhaps with the exception of quinidine) and Ic agents should preferably be excluded from use (type Ia agents prolong the QT interval, and Ic agents are proarrhythmic in BS). Type III antiarrhythmic agents such as sotalol and dofetilide prolong the QT interval and as such are contraindicated. The use of flecainide in long-term suppression of malignant arrhythmias in 2 siblings with ATS was recently reported.25 Flecainide, a class 1C agent, with proarrhythmic pharmacologie properties would not be indicated in presence of BS, and its mechanism of action in ATS is unknown at the present time. Amiodarone, also predominantly a type III antiarrhythmic agent with a weak propensity to prolong the QT interval, has been used successfully for the treatment of the ATS syndrome.26 In patients with BS who have a reasonable expectation of survival with a good functional capacity for more than 1 year, the ACC/AHA/ESC 2006 guidelines recommend an ICD if there is a history of previous cardiac arrest (Class I, grade C) or if there is evidence of spontaneous ST-segment elevation in V^sub 1^, V^sub 2^, or V^sub 3^ and syncope with or without mutations demonstrated in the SCNSA gene (Class IIa, grade C).19 Intracardiac radiofrequency ablation may represent another feasible therapeutic option.27

Calcium channel loss of function associated with a familial sudden cardiac death syndrome was recently described.28 This report demonstrated an association between loss-of-function mutations in the alpha^sub 1^ and beta^sub 2b^ subunits of the cardiac L-type calcium channel and the BS phenotype combined with shorter-than- normal QT interval. Additional research in cardiac ion channelopathies will likely lead to further identification of the genetic causes of BS.

In summary, we report a patient in whom the diagnoses of both the Anderson-Tawil syndrome and the BS occur concurrently. Manifestations of each syndrome are discussed and therapeutic options presented.

Acknowledgment

We would like to thank Neepa Rai, PharmD, for her valuable contribution relating to the relevant literature search. Thank you to Melanie Edwards for her editorial assistance.

Mimicking acute coronary syndrome

Artifact-mimicking acute coronary syndrome. The patient presented himself at a rheumatologist complaining of left shoulder pain. The above ECG was recorded, and the patient was referred to a coronary care unit. Neither lead I nor the chest leads show the extreme QT lengthening associated with the repolarization abnormalities in the inferior leads. It is impossible for the QT interval to differ by 300 milliseconds between leads. Electrode movement should be suspected when seeing an ECG such as this.

Janos Tomcsanyi, MD, PhD, and Bela Bozsik, MD

Budapest, Hungary

doi:10.1016/j.jelectrocard.2008.02.015

References

1. Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir 2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001;105:511.

2. Tristani-Firouzi M, Jensen J, Donaldson M, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQTS (Andersen syndrome). J CHn Invest 2002;110:381.

3. Zhang L, Benson DW, Tristani-Firouzi M, et al. Electrocardiographic features in Anderseri-Tawil Syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 2005;111:2720.

4. Hosaka Y, Hanawa H, Washizuka T, et al. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen’s syndrome. J Mol Cell Cardiol 2003;35:409.

5. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographie syndrome. J Am Coll Cardiol 1992;20:1391.

6. Smits JP, Eckardt L, Probst V, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 2002;40:350.

7. Antzelevitch C. Brugada syndrome. Pacing CHn Electrophysiol 2006; 29:1130.

8. Matsuo K, Akahoshi M, Nakashima E, et al. The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram. A population-based study of four decades. J Am Coll Cardiol 2001;38:765.

9. Weiss R, Barmada MM, Nguyen T, et al. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus chromosome 3. Circulation 2002;105:707.

10. London B, Sanyal S, Michalec M, et al. A mutation in the glycerol-3-phosphate dehydrogenase 1-like gene (GPDlL) causes Brugada syndrome. (abstract)Heart Rhythm 2006;3:S32.

11. Wilde A, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002; 106:2514.

12. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second Consensus Conference. Circulation 2005;111:659.

13. Pitzalis MV, Anaclerio M, lacoviello M, et al. QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome. J Am Coll Cardiol 2003;42:1632.

14. Eckardt L, Probst V, Smits JP, et al. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation 2005;111:257.

15. Monta H, Morita S, Nagase S, et al. Ventricular arrhythmias induced by sodium channel blockers in patients with Brugada syndrome. J Am Coll Cardiol 2003;42:1624.

16. Belhassen B, GHck A, Viskin S. Efficacy of quinidine in high- risk patients with Brugada syndrome. Circulation 2004; 110:1731.

17. Belhassen B, Viskin S, Fish R, et al. Effects of electrophysiologicguided therapy with class IA anti-arrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999: 1301.

18. Priori S, Aliot E, Blomstrom-Lundqvist C, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J 2001;22:1374.

19. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death-executive summary. Circulation 2006;114:1088.

20. Bezzina C, Veldkamp MW, Van den Berg MP, et al. A single NA+ channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999;85:1206.

21. Priori SG, Napolitano C, Schwartz PJ, et al. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation 2000;102:945.

22. Vaughan Williams E. Classification of the anti-arrhythmic action of moricizine. J Clin Pharmacol 1991;31:216.

23. Rosenshtraukh L, Anyukhovsky EP, Nesterenko V, et al. Electrophysiologic aspects of moricizine HCl. Am J Cardiol 1987;60:27F.

24. Dorian P, Echt D, Mead R, et al. Ethmozine: electrophysiology, hemodynamics, and anti-arrhythmic efficacy in patients with lifethreatening ventricular arrhythmias. AM Heart J 1986; 112:327.

25. Bokenkamp R, Wilde A, Schalij J, et al. Flecainide for recurrent malignant ventricular arrhythmias in two siblings with Anderson-Tawil syndrome. Heart Rhythm 2007;4:508.

26. Junker J, Haverkamp W, Shulze-Bahr E, et al. Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology 2002;59:466.

27. Haissaguerre M, Extramiana F, Hocini M, et al. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation 2003;108:925.

28. Antzelevitch C, Ollevick PGD, Cordeiro JM, et al. Loss-of- function mutations in cardiac calcium channel underlie a new clinical entity characterized by ST segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007;115:442.

Adrian H. Shandling, MD,a Michael Safani, PharmD(b,*)

a Memorial Heart and Vascular Institute and Department of Pharmacy Services, Long Beach Memorial Medical Center, University of California,

Irvine, CA, USA

b University of California, San Francisco, CA, USA

Received 5 April 2007; accepted 28 September 2007

* Corresponding author. Long Beach Memorial Medical Center, PO Box 1428, Long Beach, CA 90801-1428, USA.

Copyright Churchill Livingstone Inc., Medical Publishers Mar/Apr 2008

(c) 2008 Journal of Electrocardiology. Provided by ProQuest Information and Learning. All rights Reserved.