The Multifaceted Cardiac Sodium Channel
The Multifaceted Cardiac Sodium Channel
Loss-of-function Na channelopathies are a group of diseases with a loss or reduction of Na channel function and are caused by mutations in SCN5A and its associated genes. The prototype of this group of diseases, BrS, was initially described as a clinical entity in 1992, with the earliest report of an underlying genetic mutation in 1998. There are currently more than 300 known SCN5A BrS related mutations, accounting for up to 21% of BrS probands. These mutations lead to a loss of Na channel function through several mechanisms, including trafficking defects, generation of truncated proteins, faster channel inactivation, shift of voltage dependence of steady state activation towards more depolarised membrane potentials or slower recovery from inactivation. Apart from SCN5A, mutations in Na channel β-subunits (SCN1B and SCN3B), L-type calcium channels (CACNA1C, CACNB2b, and CACNA2D1), glycerol-3-phosphate dehydrogenase 1-like enzyme gene, KCNE3, KCNJ8, KCND3, ankyrin-G, and MOG1 have also been implicated in BrS related phenotypes.
The hallmark of BrS is the presence of a coved-type ST segment elevation in the anterior precordial leads (V1 to V3) on the ECG, termed type 1 ECG. Frequently, and particular so when aberrant sodium channels are involved, conduction abnormalities in all cardiac departments are present as well. Drug challenge with sodium channel blockers such as flecainide or ajmaline is quite often used to unmask the type 1 ECG in affected patients (figure 3). While BrS typically manifests as ventricular fibrillation and SCD in middle aged men, individuals of all ages and both sexes may be affected. Infants and young children (<2 years of age) typically present with rapid wide complex (monomorphic) ventricular tachycardia or with evidence of prolonged conduction intervals. Fever, which is an established arrhythmia trigger in BrS patients, often plays a significant role in exposing infants and young children harbouring loss-of-function Na channelopathies.
(Enlarge Image)
Figure 3.
Twelve lead ECG tracings in a 5-year-old male patient with Brugada syndrome. Resting ECG (A) shows saddleback-type ST segment elevation in V2 (red arrow); ECG (B) after intravenous administration of flecainide unmasks the diagnostic type 1 ECG with coved-type ST segment elevation (red arrow).
Cardiac conduction disease, originally described by Lenègre and Lev in elderly patients, is characterised by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, eventually leading to complete atrioventricular block, syncope, and sudden death. An SCN5A mutation that segregates with cardiac conduction disease in an autosomal dominant manner was first reported in 1999. Apart from the Na channel genes SCN5A and SCN1B, the LMNA (lamin A/C) gene has been implicated in a complex phenotype of conduction disease associated with dilated cardiomyopathy. Dilated cardiomyopathy, in combination with atrial and ventricular arrhythmias and conduction disease, was then identified as a manifestation of SCN5A mutations. Sick sinus syndrome refers to diseases of the sinus node (brady-tachy syndrome, sinus bradycardia, sinus arrest). It may be associated with loss-of-function Na channelopathies and is especially severe in patients with compound heterozygous mutations (figure 4). SCN5A mutations or rare variants have recently been implicated in familial atrial fibrillation, the most common arrhythmia in clinical practice.
(Enlarge Image)
Figure 4.
Twelve lead ECG tracing in a 14-year-old female patient with loss-of-function cardiac sodium channelopathy (compound heterozygous). Sinus bradycardia (53 beats/min), prolonged PR interval (225 ms), prolonged QRS duration (154 ms), and right bundle branch block morphology are see
The Na channel genes implicated in loss-of-function channelopathies are SCN5A, SCN1B, SCN2B, and SCN3B. While each disease phenotype poses a unique clinical entity, there is also convincing evidence to suggest that all these disorders may represent a spectrum or continuum of conduction abnormalities in a given patient. Moreover, genetic studies in affected families have shown these mutations, in particular in SCN5A, to have variable penetrance and disease expression, manifesting with varying severity and phenotypes across members of the same or different generations, referred to as 'overlap syndromes'. The nature of the SCN5A mutation, namely truncation and severe missense mutations with total loss of function, was found to underlie a more severe phenotype when compared with other missense mutations where some of the channel function was preserved.
Loss-of-function Na Channelopathies
Loss-of-function Na channelopathies are a group of diseases with a loss or reduction of Na channel function and are caused by mutations in SCN5A and its associated genes. The prototype of this group of diseases, BrS, was initially described as a clinical entity in 1992, with the earliest report of an underlying genetic mutation in 1998. There are currently more than 300 known SCN5A BrS related mutations, accounting for up to 21% of BrS probands. These mutations lead to a loss of Na channel function through several mechanisms, including trafficking defects, generation of truncated proteins, faster channel inactivation, shift of voltage dependence of steady state activation towards more depolarised membrane potentials or slower recovery from inactivation. Apart from SCN5A, mutations in Na channel β-subunits (SCN1B and SCN3B), L-type calcium channels (CACNA1C, CACNB2b, and CACNA2D1), glycerol-3-phosphate dehydrogenase 1-like enzyme gene, KCNE3, KCNJ8, KCND3, ankyrin-G, and MOG1 have also been implicated in BrS related phenotypes.
The hallmark of BrS is the presence of a coved-type ST segment elevation in the anterior precordial leads (V1 to V3) on the ECG, termed type 1 ECG. Frequently, and particular so when aberrant sodium channels are involved, conduction abnormalities in all cardiac departments are present as well. Drug challenge with sodium channel blockers such as flecainide or ajmaline is quite often used to unmask the type 1 ECG in affected patients (figure 3). While BrS typically manifests as ventricular fibrillation and SCD in middle aged men, individuals of all ages and both sexes may be affected. Infants and young children (<2 years of age) typically present with rapid wide complex (monomorphic) ventricular tachycardia or with evidence of prolonged conduction intervals. Fever, which is an established arrhythmia trigger in BrS patients, often plays a significant role in exposing infants and young children harbouring loss-of-function Na channelopathies.
(Enlarge Image)
Figure 3.
Twelve lead ECG tracings in a 5-year-old male patient with Brugada syndrome. Resting ECG (A) shows saddleback-type ST segment elevation in V2 (red arrow); ECG (B) after intravenous administration of flecainide unmasks the diagnostic type 1 ECG with coved-type ST segment elevation (red arrow).
Cardiac conduction disease, originally described by Lenègre and Lev in elderly patients, is characterised by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, eventually leading to complete atrioventricular block, syncope, and sudden death. An SCN5A mutation that segregates with cardiac conduction disease in an autosomal dominant manner was first reported in 1999. Apart from the Na channel genes SCN5A and SCN1B, the LMNA (lamin A/C) gene has been implicated in a complex phenotype of conduction disease associated with dilated cardiomyopathy. Dilated cardiomyopathy, in combination with atrial and ventricular arrhythmias and conduction disease, was then identified as a manifestation of SCN5A mutations. Sick sinus syndrome refers to diseases of the sinus node (brady-tachy syndrome, sinus bradycardia, sinus arrest). It may be associated with loss-of-function Na channelopathies and is especially severe in patients with compound heterozygous mutations (figure 4). SCN5A mutations or rare variants have recently been implicated in familial atrial fibrillation, the most common arrhythmia in clinical practice.
(Enlarge Image)
Figure 4.
Twelve lead ECG tracing in a 14-year-old female patient with loss-of-function cardiac sodium channelopathy (compound heterozygous). Sinus bradycardia (53 beats/min), prolonged PR interval (225 ms), prolonged QRS duration (154 ms), and right bundle branch block morphology are see
The Na channel genes implicated in loss-of-function channelopathies are SCN5A, SCN1B, SCN2B, and SCN3B. While each disease phenotype poses a unique clinical entity, there is also convincing evidence to suggest that all these disorders may represent a spectrum or continuum of conduction abnormalities in a given patient. Moreover, genetic studies in affected families have shown these mutations, in particular in SCN5A, to have variable penetrance and disease expression, manifesting with varying severity and phenotypes across members of the same or different generations, referred to as 'overlap syndromes'. The nature of the SCN5A mutation, namely truncation and severe missense mutations with total loss of function, was found to underlie a more severe phenotype when compared with other missense mutations where some of the channel function was preserved.
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