What is the clinical evidence from this study?

Study design: Case Report. Population: Lethal arrhythmias (torsades de pointes) (n=1). Intervention: M1766L-SCN5A mutation. Primary outcome: Sodium channel expression and late sodium current.

August 1, 2002Open Access

A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine

Key Result

The novel M1766L-SCN5A mutation caused a significant decrease in sodium channel expression and a 10-fold increase in persistent late sodium current, which was partially rescued by mexiletine in vitro.

Study Design

Type

Case Report (n=1)

Structured PICO

Does mexiletine rescue the expression defect of the M1766L SCN5A mutation in vitro?

Population

1 infant presenting shortly after birth with self-terminating torsades de pointes, followed by postmortem molecular and in vitro analysis.

Exposure

In vitro incubation with mexiletine, co-expression with beta1 subunit, and low temperature

Outcome

Sodium channel expression and persistent late sodium current measured by voltage clampsurrogate

The novel M1766L SCN5A mutation causes a loss of function and increased late sodium current, representing the first sodium channelopathy whose expression defect is rescued by mexiletine in vitro.

Abstract

OBJECTIVE: Mutations in the cardiac sodium channel gene, SCN5A, cause congenital long QT syndrome (LQT3), Brugada syndrome, idiopathic ventricular fibrillation, and conduction disease by distinct cellular and clinical electrophysiological phenotypes. METHODS: Postmortem molecular analysis of SCN5A was conducted on an infant who presented shortly after birth with self-terminating torsades de pointes. The infant was treated with lidocaine, propranolol, and mexiletine and was stable for 16 months manifesting only a prolonged QT interval. The infant collapsed suddenly following presumed viral gastroenteritis, was found in 2:1 AV block, and was subsequently declared brain dead. Genomic DNA was subjected to SCN5A mutational analyses and DNA sequencing revealing a novel, spontaneous germline missense mutation, M1766L. The M1766L mutation was engineered into the hH1a clone by site-directed mutagenesis, transfected into embryonic kidney cells (HEK-293), and studied by voltage clamp. RESULTS: The M1766L mutation caused a significant decrease in the sodium channel expression. Co-expression with beta1 subunit, incubation at low temperature, and most effectively incubation with mexiletine partially 'rescued' the defective expression. In addition to this pronounced loss of function, M1766L also showed a 10-fold increase in the persistent late sodium current. CONCLUSIONS: These findings suggest that M1766L-SCN5A channel dysfunction may contribute to the basis of lethal arrhythmias, displays an overlapping electrophysiological phenotype, and represents the first sodium channelopathy rescued by drug.