Knowledge on rare diseases and orphan drugs

Given that the ECG pattern diagnostic for Brugada Syndrome is fluctuant, unlike other inherited arrhythmogenic syndromes, the data regarding the prevalence of the disease are controversial. According to a recent metanalysis, the worldwide prevalence of Brugada syndrome is estimated at 1/2,000, but it varies according to region and ethnicity. Brugada syndrome is rare in Hispanic and Caucasian populations and non-rare in Asian populations. By region, the prevalence is estimated at 1/20,000 in North America and 1/10,000 in Europe. Prevalence is higher in Asia and Middle East where estimates range between 1/270-625. The disease is observed more frequently in men than in women (8:1) and it is extremely rare in children.

Symptoms usually manifest in the third-fourth decade of life. Syncope, typically occurring at rest, is a common presentation. In some cases, tachycardia does not terminate spontaneously and leads to sudden death. Most frequently, the disease occurs in a normal heart, but subtle structural abnormalities of the right ventricle have been described in a subset of patients. Triggers for the onset of arrhythmias may include fever, abundant meals, some drugs (including antiarrhythmics and antidepressants). On ECG, three different patterns may be observed. Type 1, which is the only diagnostic pattern, is defined as a coved-type ST-segment elevation (0.2 mV) followed by a negative T wave. In type 2, ST-segment elevation has a saddleback appearance with a high-takeoff ST-segment elevation (0.2 mV), a trough (0.1mV) displaying ST elevation, and then either a positive or biphasic T wave. Type 3 has either a saddleback appearance or a coved-type ST-segment elevation (maximum 0.1mV). It is important to underline that only Type 1 ECG is diagnostic for the syndrome.

The gene SCN5A (3p22.2) is responsible for 30% of cases with a gene variant implicated. Other identified genes include CACNA1C (12p13.33), SCNN1A (12p13), SLMAP (3p14.3), SEMA3A (7q21.11), SCN2B (11q23.3). However, in nearly 70% of affected families the genetic cause is unknown.

The diagnosis is based on clinical examination and detection of type 1 ECG pattern using a 12-lead Holter ECG. In some cases, the ECG manifestations are not obvious or non-diagnostic (type 2, 3 and S ECG patterns). In such instances, a provocative test with the administration of class IC antiarrhythmic drugs (ajmaline, flecainide or procainamide) may be used to confirm/exclude diagnosis. Genetic testing is available after a clinical diagnosis has been established.

Disorders that could present the typical Brugada ECG pattern include isolated right bundle branch block, pectus excavatum, arrhythmogenic right ventricular cardiomyopathy, acute pericarditis, acute myocardial ischemia or infarction, and early repolarization.

Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance.

Implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest. Thus, correct risk stratification is a major goal for management. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients at risk of recurrence. Recently, epicardial ablation of the right ventricular outflow tract has emerged as a therapeutic option in patients at higher risk.

The majority of patients remain asymptomatic, 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death). Risk factors for cardiac arrest and sudden death are a spontaneously diagnostic ECG pattern and a history of syncope.

Last update: July 2020 - Expert reviewer(s): Dr Andrea MAZZANTI - Pr Silvia PRIORI