![]() ![]() The mutation causes a marked reduction in INa density and a positive shift of the voltage-dependence of activation leading to atrial and ventricular conduction slowing and bradycardia by slowing the diastolic depolarization rate and dereasing the upstroke velocity of the sino-atrial action potentials. The SCN5A E161K mutation was identified in two non-related families with symptoms of bradycardia, sino-atrial node dysfunction, generalized conduction disease and BrS, or combinations thereof (Smits et al., 2005). Heterozygous SCN5A mutations (T220I, P1298L, delF1617) occur in patients diagnosed with congenital SSS during the first decade of life, suggesting that congenital SSS segregates as a recessive disorder of the cardiacNa+ channel. Three mutations exhibited mild to moderate dysfunction (T220I, P1298L, delF1617), while the R1632H allele was more severely impaired. Two mutations (G1408R, R1623X) produce nonfunctional sodium channels the remaining alleles were functional when expressed heterologously in cultured mammalian cells and exhibited impaired inactivation and slowed recovery from inactivation. The disorder progressed from bradycardia to atrial inexcitability during the first decade of life, but none of the patients had other evidence of heart disease. Compound heterozygous SCN5A mutations (T220I, P1298L, G1408R, delF1617, R1623X, and R1632H) were found in five individuals from three families, indicating that congenital SSS may, in some families, segregate as a recessive disorder of the cardiac sodium channel. ![]() (2003) reported 5 children (2 to 9 years of age) with autosomal recessive SSS characterized by sinus bradycardia, absent P waves, atrial inexcitability, prolonged QRS duration, prolonged His-ventricle conduction time, and ventricular escape rhythms. Additionally, impaired sodium channel function may cause a conduction block within the cardiac conduction system, referred to as AV block or bundle branch block (BBB).īenson et al. The molecular basis for SSS resulting from SCN5A mutations is an exit block at the peripheral sino-atrial node caused by decreased conduction velocity from the central sino-atrial node (Butters et al., 2010). Affected individuals also manifest abnormal ventricular depolarization (prolonged QRS) and delayed His-ventricle conduction. Loss-of-function mutations in the SCN5A gene result in decreased sarcolemmal expression of mutant channel proteins, expression of non-functional channels or gating disturbances (i.e., delayed activation, hyperpolarizing shift in voltage-dependent inactivation) (Benson et al., 2003 Veldkamp et al., 2003 Lei et al., 2008) that reduce myocardial excitability in some forms of congenital SSS. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder (Benson et al., 2003). Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common. The ECG typically shows sinus bradycardia, sinus arrest, and/or sino-atrial block. However, patients often are asymptomatic or have subtle or nonspecific symptoms related to the decreased cardiac output that occurs with the bradyarrhythmias or tachyarrhythmias. Patients may experience syncope, pre-syncope, palpitations, dizziness, fatigue or vertigo. It is characterized by inappropriate sinus bradycardia, sino-atrial block, sinus arrest with or without junctional escape, or chronotropic incompetence, atrial tachyarrhythmias (atrial fibrillation with slow ventricular response), and alternating bradyarrhythmias and tachyarrhythmias. The term "sick sinus syndrome"(SSS) encompasses a variety of conditions caused by sino-atrial node dysfunction.
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