Mutations in the SCN5A gene, which encodes the pore-forming alpha-subunit of cardiac sodium channels, can lead to a number of cardiac phenotypes: long-QT syndrome (LQT) type 3, Brugada syndrome, cardiac conduction disease, sick sinus syndrome (SSS), and atrial fibrillation (AF) with or without dilated cardiomyopathy.
The prevalence of SCN5A mutations and the genotype-phenotype relationships in 445 patients with hereditary arrhythmias was investigated by Makiyama and colleagues at Kyoto University. Key findings were:
- LQTS: 16 mutations in 21 of 232 patients (9%).
- Brugada Syndrome: 12 mutations in 13 of the 105 patients (11%).
- Familial SSS: 6 mutations in 6 of the 15 patients (40%).
- Familial atrial fibrillation: 1 mutation in the 1 patient.
The mutations in the LQTS tend to aggregate in the intracellular region of the cardiac sodium channel. Some of the mutations found in Brugada syndrome and familial SSS can be classified as a missense, which are commonly found in the pore-forming regions. These forms produce non-functioning sodium channels.
Case Reviews
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Figure 1. A 2-day old infant with long QT syndrome with a 2:1 AV block and a QTc of 720 ms.
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Figure 2. Late sodium currents and action potential duration prolongation were identified in the 2-day-old infant with long QT syndrome.
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Figure 3. A 33-year-old man with Brugada syndrome and familial sick sinus syndrome, who experienced syncope from ventricular fibrillation when febrile.
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Figure 4. A novel gain-of-function SCN5A phenotype was indentified in the setting of familial atrial fibrillation.
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A 2-day old infant with LQTS with a 2:1 AV block and a QTc of 720 ms was found to have a heterozygous SCN5A mutation (N17740) (Figure 1). Late sodium currents resulted in gain-of-function and action potential duration prolongation (Figure 2).
A 33-year-old man with Brugada syndrome and familial SSS experienced syncope from ventricular fibrillation when he was febrile (Figure 3). His mother had SSS and an implanted pacemaker. An SCN5A mutation (T187I) was found in the patient and his mother. A non-functional channel was revealed on functional analysis.
Patients with Brugada syndrome and an SCN5A mutation are at high risk for a bradyarrhythmia; 5 of the 13 Brugada patients identified with an SCN5A mutation had an underlying bradyarrhythmia that produced non-functional channels.
A 53-year old man with SSS had a pacemaker implanted because of a prolonged sinus pause. His mother had atrial standstill and an implanted pacemaker. A heterozygous SCN5A gene missense mutation (K1859E) was identified in both. A loss-of-function modulation was determined as a result of a 40% reduction in sodium channel density in the mutant channels compared to the wild-type channels and a negative shift of 9.2 mV in the INa/peak INa.
In Japanese patients with familial SSS, SCN5A mutations are common as shown by the 40% prevalence. Interestingly, 4 of the 6 patients with SCN5A-linked SSS had an additional overlapping sodium channelopathy, Brugada syndrome and Long QTS.
A novel gain-of-function SCN5A phenotype that manifested as familial AF was identified in this study (Figure 4). The 8 affected family members had a similar clinical course. In their teens, PACs began that later progressed to AF. No structural heart disease or ECG abnormalities were found. The novel M1875T mutation perfectly matched the clinical phenotypes of family members. On functional assay, their inward channels showed slower inactivation compared to wild-type channels. A significantly larger peak sodium channel density was also found in the mutant channels. A marked depolarized shift of 16.4 mV of fast inactivation in the mutant channels was observed. Increased automaticity and irritability in the right atrium was identified with radiofrequency ablation in the probands.
In closing, Makiyama stated that SCN5A mutations were identified in a substantial portion of patients with various inherited arrhythmias, suggesting the diversity and complexity of cardiac sodium channelopathies.
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