Ventricular Fibrillation, Paroxysmal Familial, 1

A number sign (#) is used with this entry because of evidence that paroxysmal familial ventricular fibrillation (VF1) is caused by heterozygous mutation in the cardiac sodium channel gene SCN5A (600163) on chromosome 3p21. One such patient has been reported.

Description

Ventricular fibrillation (VF) is said to cause more than 300,000 sudden deaths each year in the US alone. In approximately 5 to 12% of cases, there are no demonstrable cardiac or noncardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). Patients with a distinct form of VF called Brugada syndrome (see 601144) present with a characteristic electrocardiographic pattern, with right bundle branch block (RBBB) and elevation of ST segment in leads V1 to V3 and may account for 40 to 60% of all IVF cases (review by Chen et al., 1998). Mutations in the SCN5A gene were identified in patients with Brugada syndrome-1 (601144).

Genetic Heterogeneity of Paroxysmal Familial Ventricular Fibrillation

Another familial form of VF (VF2; 612956) is caused by mutation in the DPP6 gene (126141) on chromosome 7q26.

Clinical Features

McRae et al. (1974) described a family in which 3 brothers had syncopal attacks and died suddenly at ages 17, 12, and 12 years. Autopsy in 2 of them showed no abnormality. A fourth brother had syncopal episodes and proved paroxysmal ventricular fibrillation. Important electrocardiographic changes were short PR interval and prominent gamma wave. Fibrillation was induced by stressful emotional stimuli, but could not be induced by exercise. Propranolol was found to be effective prophylactic medication. The mother had experienced 25 episodes of syncope between ages 15 and 25. Each episode was precipitated by an emotionally stressful event causing fright or anger. The mother, like her son, had a short PR interval. Because of the EKG changes, this family may have had a repolarization abnormality.

Viskin and Belhassen (1990) reviewed the literature dealing with sudden death and identified 19 articles in which ostensibly healthy patients with documented VF unrelated to any known cardiac or noncardiac etiology were reported. Fifty-four patients fulfilled the criteria for IVF. The mean age of patients in studies that reported age data was 36 years, with a male-to-female ratio of 2.5 to 1. Over 90% of the patients required resuscitation, while syncope due to nonsustained VF occurred in the rest. Diagnosis of VF was preceded by syncope in one-fourth of the patients. Holter monitoring and exercise stress tests were often unrewarding. Available electrophysiologic data revealed a 69% inducibility rate of sustained ventricular tachyarrhythmias using nonaggressive protocols of ventricular stimulation in most cases. Induced tachyarrhythmias were poorly tolerated, and were mostly of polymorphic configuration. Class IA antiarrhythmic agents were highly effective in preventing reinduction of these arrhythmias. Available figures suggested an 11% rate of sudden death with 1 year of diagnosis. Appropriate antiarrhythmic therapy appeared to improve prognosis. The authors concluded that IVF represents an underestimated cause of sudden cardiac death in ostensibly healthy patients.

Diagnosis

Viskin et al. (1997) reviewed the electrocardiograms of patients with IVF. Documentation of the onset of spontaneous arrhythmias was available for 22 VF episodes in 9 patients (6 men and 3 women, aged 41 +/- 16 years) with IVF. In all instances, spontaneous VF followed a rapid polymorphic ventricular tachycardia, which was initiated by premature ventricular complexes (PVCs) with very short coupling intervals. The PVC initiating VF had a coupling interval of 302 +/- 52 msec and a prematurity index of 0.4 +/- 0.07. These PVCs occurred within 40 msec of the peak of the preceding T wave. Pause-dependent arrhythmias were never observed. Viskin et al. (1997) concluded that cardiac arrest among patients with IVF has a distinctive mode of onset. Documentation of a polymorphic ventricular tachycardia that is not pause dependent is of diagnostic value.

Molecular Genetics

Akai et al. (2000) screened 25 Japanese patients with idiopathic ventricular fibrillation, in whom the diagnosis was based on the occurrence of at least 1 episode of syncope and/or cardiac arrest as well as documentation of ventricular fibrillation. Structural heart disorders were excluded; 18 of the patients were diagnosed with Brugada syndrome. In a 39-year-old man who was admitted to the hospital for recurrent syncope and suffered an episode of spontaneous ventricular fibrillation while hospitalized, the authors identified a heterozygous missense mutation in the SCN5A gene (S1710L; 600163.0014). The patient did not have Brugada syndrome, and an implanted cardiac defibrillator prevented further attacks of palpitation or syncope. His paternal grandfather and a paternal uncle had died suddenly in their sixth decade of unknown cause; his parents and sibs were asymptomatic.

Associations Pending Confirmation

Bezzina et al. (2010) performed a genomewide association study for ventricular fibrillation complicating acute myocardial infarction in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at chromosome 21q21 (rs2824292, odds ratio = 1.78, 95% confidence interval 1.47-2.13, p = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (odds ratio = 1.49, 95% confidence interval 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR (602621), which encodes a viral receptor implicated in myocarditis and dilated cardiomyopathy and which has been identified as a modulator of cardiac conduction.