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Vol. 68. Issue 1.
Pages 71-73 (January 2015)
Vol. 68. Issue 1.
Pages 71-73 (January 2015)
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A New Mutation in the Ryanodine Receptor 2 Gene (RYR2 C2277R) as a Cause Catecholaminergic Polymorphic Ventricular Tachycardia
Una nueva mutación en el gen del receptor de la rianodina (RyR2 C2277R) como causa de taquicardia ventricular polimórfica catecolaminérgica
Diana Domingoa,b,c, Raquel López-Vilellaa, Miguel Ángel Arnaua, Óscar Canoa,b, Elena Fernández-Ponsb, Esther Zorioa,
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Corresponding author:
a Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
b Instituto de Investigación Sanitaria La Fe, Valencia, Spain
c Departamento de Medicina, Universidad de Valencia, Valencia, Spain
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Table. Clinical Characteristics of the Cohort of Eight Family Members Carrying the Mutation in RYR2
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To the Editor,

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable disease characterized by the appearance of polymorphic ventricular tachycardia during exercise, emotion, or catecholamine perfusion.1 This cardiopathy is considered a rare disease, with a prevalence of 1/10 000, and is a highly lethal entity (30% of sudden deaths in individuals under 40 years of age who are not undergoing treatment with beta-blockers2). It is usually characterized by autosomal dominant inheritance with 80% penetrance, and by mutations in the ryanodine receptor 2 gene (RYR2).3 Diagnosis usually requires an exercise stress test (EST) or adrenaline test.4–6

Our objective is to describe a kindred with 19 living members (Figure A), 4 with sudden death and 8 carriers of the new RYR2 C2277R variant (genotype+) (Figure B), 7 of whom exhibit the CPVT phenotype according to EST results (phenotype+).


A: Family tree; the arrow indicates the proband; the blue symbols represent patients with the catecholaminergic polymorphic ventricular tachycardia phenotype, and asterisks indicate heterozygous carriers of the RYR2 C2277R mutation. B: Electropherogram of the fragment of exon 45 of the RYR2 gene containing the mutation. C: Consecutive records (C1-C3) of the first minute of recovery following the exercise stress test in the proband, showing polymorphic ventricular arrhythmias (C1, ) and notable merging of the U-wave with the subsequent P wave (C2, §). CD, implantable cardioverter defibrillator; Dobl vent, ventricular doublets; m, month; NE, not evaluated; NSVT, nonsustained ventricular tachycardia; SD, sudden death; Vent big, ventricular bigeminy; Dobl vent, ventricular doublets; VEs, ventricular extrasystoles; y, years.


The proband (II: 1), aged 56, presented with syncope and palpitations. She reported the sudden death of 3 siblings, aged 11 and 15 years (due to physical exercise and an argument) and 1.5 months, and a daughter aged 29 years (while dancing, with previous syncope during exertion), although autopsy was only performed in the latter case, and was inconclusive. We applied the protocol approved by our ethics committee for family studies following sudden death in individuals with unknown cause, and all individuals gave informed consent. In the proband, the electrocardiogram and echocardiogram were normal. Her EST (Bruce protocol) showed ventricular arrhythmias at 100 bpm and above, and was diagnostic of CPVT (Figure C). This diagnosis was defined by the presence of ventricular doublets, sustained ventricular tachycardia, or non-sustained polymorphic ventricular tachycardia or > 10 premature ventricular contractions/min during the EST or adrenaline test.6 Six other members of the 19 tested showed a similar response, with different degrees of complexity of the ventricular arrhythmias (Figure A, Table). Suspecting autosomal dominant CPVT, we sequenced the 33 most frequently affected exons of the RYR2 gene in the proband. We identified a previously unreported heterozygous missense variant in exon 45 (C2277R), located in a hot spot encoding part of the calstabin-binding domain, which was classified as a mutation that is probably associated with the disease. The mutation cosegregated with the CPVT phenotype, although in 1 person (II: 9), who also underwent an adrenaline test (Mayo Clinic protocol), ventricular arrhythmias did not meet the diagnostic criteria. Thus, we obtained a cohort of 8 carrier subjects, 7 of whom were found by EST to have the CPVT phenotype (87.5% penetrance). Of the carriers, 75% were male, mean age 46 years (SD, 10), 37% reported prior arrhythmic symptoms, and 100% had a normal electrocardiogram at rest (heart rate, 63 [SD,10] bpm, QTc 400 [SD,27] ms). In the initial EST (duration 9 [SD,2] min), the maximum heart rate was 150 [SD,15] bpm, and the diagnosis was established at a heart rate of 132 (SD,11) bpm.


Clinical Characteristics of the Cohort of Eight Family Members Carrying the Mutation in RYR2

Case  Sex  Age at diagnosis, years  Previous symptoms  Baseline ECG  Maximum arrhythmia in the initial EST  Treatmenta  Events during evolutionb 
II:1 (proband)  56  Syncope and palpitations  SB, prominent U  VE, Big, D, NSVTc  Nadolol 20 mg/24 h + Fl + ICD  Presyncope 
II:3  53  No  Normal  VE, Big, NSVT  Nadolol 80 mg/24 h + Fl  No 
II:6  43  No  Normal  VE, Big, NSVT  Atenolol 50 mg/12 h + Fl  No 
II:8  55  No  SB  VE, Big, D  Nadolol 80 mg/24 h + Fl  No 
II:9  50  Palpitations  Normal  VEd  Atenolol 100 mg/12 h  No 
II:15  49  No  Normal  VE, Big, Trig  Atenolol 100 mg/12 h + Fl  No 
III:4  35  No  Normal  VE, Big, D  Nadolol 20 mg/24 h + Fl  No 
III:9  27  Syncope and palpitations  SB  VE, Big, D  Nadolol 10 mg/día  No 

Big, bigeminy; D, doublets; ECG, electrocardiogram; EST, exercise stress test; F, female; Fl, flecainide; ICD, implantable cardioverter defibrillator; M, male; NSVT, nonsustained ventricular tachycardia with 180° change of axis; SB, sinus bradycardia; Trig, trigeminy; VE, ventricular extrasystoles.


Treatment at end of follow-up when the manuscript was submitted.


Sudden death, arrhythmic symptoms, or appropriate defibrillator discharge. Mean follow-up, 34 months (standard deviation, 4).


The initial exercise stress test was carried out while undergoing treatment with beta-blockers.


Ventricular extrasystoles not diagnostic of catecholaminergic polymorphic ventricular tachycardia.

The carriers were treated with beta-blockers at the maximum tolerated dose, and while the ventricular arrhythmias disappeared during the follow-up EST in 3 subjects (37%), in the remaining 5 (63%) the arrhythmic burden (frequent ventricular premature beats, bigeminy, doublets, nonsustained ventricular tachycardia) persisted enough to add flecainide to the treatment regime, as previously proposed1 (Table). The proband was implanted with a defibrillator due to presyncope with nonsustained ventricular tachycardia during the EST, despite maximum treatment with beta-blockers (before starting the use of the flecainide treatment in this clinical context1). Finally, at 34 (SD,4) months follow-up, all patients were asymptomatic, without arrhythmia or remarkable clinical events (sudden death, syncope, or appropriate defibrillator discharge).

In summary, for the first time we describe the RYR2 C2277R mutation as a cause of CPVT, in a family with high lethality in younger individuals, with a good diagnostic yield using EST and an excellent response to treatment with beta-blockers, with and without flecainide.


This work was funded by the Instituto de Salud Carlos III (PI14/01477 y RD12/0042/0029), Prometeo 2011/027, the Sociedad Española de Cardiología (Pedro Zarco Scholarship) and the Agence Nationale de la Recherche (ANR-13-BSV1-0023-03).


We are grateful for the kind cooperation of the patients, and the working group on sudden infantile death of Spanish Association of Pediatrics, and for technical support from the La Fe Biobank (PT13/0010/0026).

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Copyright © 2014. Sociedad Española de Cardiología
Revista Española de Cardiología (English Edition)

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