Cardiac ryanodine receptor gene (hRyR2) mutation underlying catecholaminergic polymorphic ventricular tachycardia in a Chinese adolescent presenting with sudden cardiac arrest and cardiac syncope

Sudden cardiac death (SCD) in children and adolescents is uncommon and yet it is devastating for both victim's family and the society. Recently, it was increasingly recognized that SCD in young patients with structurally normal heart may be caused by inheritable primary electrical diseases due to the malfunction of cardiac ion channels, a disease entity known as the ion channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a specific form of ion channelopathy which can cause cardiac syncope or SCD in young patients by producing catecholamine-induced bi-directional ventricular tachycardia (BiVT), polymorphic VT and ventricular fibrillation (VF) during physical exertion or emotion.1–7 We reported here an index case of CPVT caused by cardiac ryanodine receptor gene (hRyR2) mutation which presented as cardiac syncope and sudden cardiac arrest in a Chinese adolescent female. CASE REPORT A 14-year-old girl with good past health suddenly collapsed with syncope after she boarded a bus. She regained consciousness but this was immediately followed by a second collapse and she remained comatose. When ambulance men arrived at the scene, their automatic external defibrillator recorded and successfully defibrillated a VF (Fig. 1A). Patient was put on mechanical ventilation and admitted to Paediatric Intensive Care Unit for further management. Nine months earlier she had suffered from a syncope after quarreling with her friend but she had not seeked any medical consultation. She had no history of drug abuse or consumption of Chinese herbal medicine. Her ECG recorded during sinus rhythm showed a normal QTc interval and no evidence of Brugada sign or pre-excitation. Serial serum cardiac troponin I levels were normal. Echocardiogram showed no structural heart disease. MR coronary angiograms ruled out any anomalous origin of her coronary arteries. MRI heart images were suboptimal due to patient's difficulty in breathholding during the examination. Computerized tomogram of her brain only revealed evidence of hypoxic brain damage. One night, she appeared agitated and cardiac monitor recorded multiple premature ventricular complexes (PVCs), polymorphic VT and runs of non-sustained BiVT (Fig. 1B) which were controlled by oral propranolol. After an informed consent was obtained from her parents, adrenaline provocation test was performed. Intravenous adrenaline infusion given at a dose of 0.6 μg · kg−1 · min−1 reproduced the PVCs, polymorphic VT and BiVT (Figs. 2 and 3) which rapidly subsided following the termination of adrenaline infusion. After other causes of BiVT were excluded, a clinical diagnosis of CPVT was established. There was no family history of sudden or premature death. Family screening by treadmill exercise test did not identify CPVT in other family members.Fig. 1.: (A) Ventricular fibrillation recorded by automatic external defibrillator. (B) Continuous single lead (lead II) Holter recording showing multiple runs of non-sustained bi-directional ventricular tachycardia induced by stress due to endotracheal suction.Fig. 2.: Serial single-lead (lead V4) ECG strips showing the results of adrenaline provocation test: (A) baseline sinus rhythm; (B) monomorphic premature ventricular complexes with a bigeminy rhythm; (C) polymorphic ventricular tachycardia; (D) bi-directional ventricular tachycardia (arrows); and (E) sinus rhythm following termination of adrenaline infusion.Fig. 3.: Bi-directional ventricular tachycardia recorded on precordial leads V1-V6 during adrenaline provocation test. Note that there is a right bundle branch block pattern with a beat-to-beat alteration of QRS axis (arrows) during the ventricular tachycardia.Genetic study was performed in our patient to look for mutation in CASQ2 and hRyR2 genes which were the only known genes implicated in CPVT.8,9 No mutation was found in her CASQ2 gene. However, a heterozygous missense mutation was found in exon 88 of her hRyR2 gene in chromosome No. 1 which resulted in an amino acid change from glycine to serine at the 3946th position (G3946S). As hRyR2 mutation underlying CPVT may have an autosomal dominant mode of inheritance, genetic screening of both parents of our patient was performed but none of them was found to carry the same mutation. Patient was treated with nadolol at a dose of 2 mg · kg−1 · d−1 and remained arrhythmia-free while on treatment. However, her post-resuscitative course was rather stormy. Although she was successfully weaned off from ventilator support, she developed spastic paraplegia and remained bed-ridden and non-communicable as a result of the severe hypoxic brain damage. After four months of hospitalization she suffered from empyema thoracis in her left lung which required surgical decortication. At seventh month she was complicated with septicaemic shock secondary to ischaemic large bowel perforation which necessitated an emergency bowel resection. DISCUSSION Since the first case series described by Coumel et al1 in 1978, it was increasingly recognized that CPVT may underlie SCD in children and adults without structural heart disease.1–7 To date, patients with CPVT reported in indexed medical literature were mostly Caucasians and less commonly Japanese.6 CPVT was reported in only one Chinese patient7 despite Chinese accounts for one-fifth of the global population. It was never reported in Hong Kong or mainland of China. This report provided both clinical and genetic evidence that CPVT can also be found in local Chinese population and thus served to alert medical professionals to this potentially lethal arrhythmogenic disorder that was rarely found in Chinese. Our patient in this report demonstrated the clinical and electrocardiographic hallmarks of CPVT, namely, the clinical presentation with cardiac syncope and sudden cardiac arrest related to physical or emotional stress and the development of polymorphic VT and the characteristic BiVT in the absence of any structural heart disease or baseline ECG abnormalities. BiVT is a very rare form of VT which may also be encountered in digitalis toxicity10 or herbal aconite poisoning.11 Both conditions were excluded in our patient. BiVT has a characteristic right bundle branch block pattern with a beat-to-beat alteration of right and left QRS axis (Fig. 3). When the BiVT degenerates into VF, CPVT patients will present with syncope or even SCD. CPVT was previously thought to be a rare disease limited to paediatric patients. However, subsequent studies reported young and older adult patients with CPVT who suffered from cardiac syncope or sudden cardiac arrest.2–4 The results of two recent molecular and clinical studies2,4 also suggested that CPVT is a common cause of SCD in patients without structural heart disease and its actual incidence in the general population may be much higher than it was previously thought. Thus although CPVT is essentially a paediatric disease, adults are not immune. More importantly, it may not rare in the community. At variance with the Brugada, congenital long QT or short QT syndromes which are the other inheritable ion channelopathies that can lead to SCD, patients with CPVT do not have a characteristic ECG in sinus rhythm to suggest the presence of the disease. Clinical diagnosis of CPVT relies on the use of exercise stress test3,5,6 and isoproterenol or adrenaline provocation tests4–6 to unmask the BiVT and/or polymorphic VT in CPVT. On the contrary, programmed electrical stimulation is not a useful diagnostic tool.3,5,6 In the adrenaline provocation test that our patient underwent, the emergence and disappearance of the BiVT and polymorphic VT following the initiation and termination of adrenaline infusion respectively confirmed the catecholaminergic nature of her ventricular arrhythmias and thus established the clinical diagnosis of CPVT. CPVT is an inheritable disease with an autosomal dominant3,5 and much less commonly autosomal recessive8,12 mode of inheritance. It may also be sporadic as exemplified by our case. Priori et al9 demonstrated that hRyR2 gene mutations underlie the autosomal dominant form of CPVT. They found these mutations in approximately 50% of their patients with CPVT.3 The hRyR2 gene encodes cardiac ryanodine receptor which plays a pivotal role in intracellular calcium ions homeostasis and excitation-contraction coupling process of the myocardium. It is postulated that hRyR2 mutations in the presence of high adrenergic tone can lead to leaking of intracellular calcium ions which then generate inwardly depolarizing membrane currents, delayed after-depolarizations and ventricular arrhythmias.13 The identification of this disease-causing gene has made the mutational analysis for the genetic diagnosis of CPVT possible in SCD victims,2 CPVT probands and their family members.3 Our patient was found to be heterozygous for a missense mutation G3946S in her hRyR2 gene and thus the genetic diagnosis of CPVT was also established. It was a de novo mutation as neither of her parents carried the same mutation. This mutation has been reported in at least two European families with CPVT in the medical literature3 and is associated with both BiVT and polymorphic VT. Moreover, this is hitherto the second time an hRyR2 mutation ever reported in Chinese following the first report of another hRyR2 mutation being found in a Taiwanese female with CPVT.14 Priori et al3 showed that the demographic characteristics of patients with CPVT due to underlying hRyR2 mutation (hRyR2 CPVT) and those with nongenotyped CPVT were remarkably different. While hRyR2 CPVT had a male preponderance, female was found to be predominant among nongenotyped CPVT. The patients with hRyR2 CPVT who had syncope were predominantly male and their first syncope occurred at a younger age than their counterparts with nongenotyped CPVT (8±2 vs 20±12 years). Our patient described in this report is a female who presented with her first syncope at the age of 14 years. Thus while our patient demonstrated the typical clinical features of CPVT, her demographic features were rather atypical of hRyR2 CPVT as described in medical literature. Patients with CPVT have a poor prognosis without treatment. Left untreated, the mortality of CPVT patients reached 30% — 35% by the age of 30 years.3,15 While Class I anti-arrhythmic agents and amiodarone appeared ineffective,5,6 β-blockers showed positive results in treatment of CPVT.3,5,6 Notwithstanding a discrepancy in the efficacy of β-blockers among various studies reported, these drugs are nowadays the cornerstone of therapy for patients with CPVT. Efficacy of treatment can be assessed by exercise stress test.3 As for our patient, the preliminary results suggest that nadolol given at a dose of 2 mg · kg−1 · d−1 is effective in suppressing the arrhythmias. World-wide experience in the use of implantable cardioverter-defibrillator (ICD) for treatment of CPVT is limited. Priori et al3 showed that among those patients with CPVT who received ICD implants after failing medical treatment, 50% received appropriate ICD shocks. Thus patients with CPVT who fail treatment with β-blockers should be considered for implantation of ICD. In conclusion, we reported in a Chinese adolescent female an index case of CPVT caused by a de novo missense mutation in her hRyR2 gene. Thus CPVT is newly recognized as a cause of SCD and cardiac syncope in Hong Kong and mainland of China. Although recent studies suggested that CPVT may not be a rare disease, the diagnosis of CPVT will remain elusive without the appropriate use of provocation tests. Medical professionals should therefore have a high index of suspicion to this disease when managing patients who present with sudden cardiac arrest or cardiac syncope related to physical or emotional stress. Patients suspected of CPVT should be referred to cardiologists for appropriate investigations. The highly malignant clinical course of CPVT underscores the importance of early diagnosis and treatment with β-blockers and appropriate use of ICD. Familial screening by exercise stress test or genetic study will help to identify affected family members who may benefit from prophylactic treatment with β-blockers.