6th March 2024

Genetic Syndromes

Brugada syndrome

This predominant sodium channelopathy is autosomal dominant with the SCN5A gene affected in 20% of cases. The heart is structurally normal but patients are at risk of sudden cardiac death from VT or VF. Presentation may be with cardiac arrest or with incidental finding of typical ECG changes including coved ST elevation of at least 2 mm in at least 2 precordial leads from V1-3. ECG changes may be transient and tests such as a flecainide (Na channel blocker) challenge can be used to reveal the characteristic ST changes. 

Management 

Management is with the insertion of an ICD device.

Arrhythmogenic right ventricular cardiomyopathy (ARVC)

Patients develop fibrofatty infiltration within the right ventricle, resulting in dilation of the right ventricle. ARVC fibrofatty infiltration is not limited to the RV and can occur in the left heart as well. The condition is autosomal dominant in inheritance and, thus, there may be a family history of sudden death. The changes predispose to failure or arrhythmias which can lead to sudden cardiac death. Young patients may initially present with symptoms of palpitations, syncope, or sudden cardiac death. 

Diagnosis 

The ECG will show either T wave inversion in V1-3 and or an epsilon wave in V1, resembling a blip at the end of the QRS complex. Cardiac MRI is the imaging of choice and often shows fibrosis of the RV, regional wall motion abnormalities and pseudoaneurysmal changes. 

Management depends on risk stratification; low risk patients are started on an antiarrhythmic, typically sotalol. ICDs are implanted in patients with high-risk features (e.g., family history of sudden death or previous syncope).

Congenital Long QT Syndrome (LQTS)

These consist of numerous, mainly autosomal dominant, genetic defects encoding for ion channel proteins, which prolong ventricular repolarisation, resulting in prolongation of the QT interval (QTc >440ms in men and >460ms in women). This is achieved by reduced outflow of potassium or prolonged inflow of sodium. Prolonging of the QT interval may result in a polymorphic VT with the typical characteristic of Torsades de Pointes. This may be triggered by increased sympathetic activity such as exercise or emotional stress. There are three main genetic subtypes shown in Table 4:

Table 4: Genetic subtypes of LQTS

The long QT may be identified after the patient presents with symptoms of palpitations or syncope. The Schwartz score helps to offer the likelihood that a patient has LQTS. Beta-blockade is used in these patients and ICD is implanted in high-risk patients. It is worth mentioning that there are eponymous syndromes including ‘Jervell and Lange-Nielsen’ and ‘Romano-Ward’ with which patients have LQTS but with associated hearing loss or no-hearing loss respectively.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

Patients will have episodes of bidirectional ventricular tachycardia, clinically presenting as syncope during exercise or emotional stress. Structurally, they have normal hearts and resting ECG is also normal. There is potential for the VT to progress to VF and lead to sudden cardiac death. Approximately 30% of patients will have one episode of cardiac arrest. 

Diagnosis

Exercise testing is useful in revealing the characteristic bidirectional VT. Genetic testing can also be used, the genes affected are involved in intracellular calcium handling including the ryanodine receptor (RYR2) and calsequestrin receptor (CASQ2). Treatment is with beta-blockers to prevent syncopal episodes and consideration of ICD in high-risk individuals or those with refractory symptoms.  

References

• Ginks MR, Lane DA, McGavigan AD, et al. Cardiac Arrhythmias. Oxford Textbook of Medicine. Oxford University Press. 2020 January. 3 (6th ed.): 179-218. Available at https://oxfordmedicine.com/view/10.1093/med/9780198746690.001.0001/med-9780198746690-chapter-346/ 
• Cadogan M, Buttner R. Epsilon Wave. Life in the Fast Lane. Last updated February 4th 2022. Available at https://litfl.com/epsilon-wave-ecg-library/
• Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. Gene Reviews. Last updated October 13th 2016. Available at https://www.ncbi.nlm.nih.gov/books/NBK1289/