Myotonic dystrophy type 1 mimics and exacerbates Brugada phenotype induced by Nav1.5 sodium channel loss-of-function...

Myotonic dystrophy type 1 (DM1), a muscular dystrophy due to CTG expansion in the DMPK gene, can cause cardiac conduction disorders and sudden death. These cardiac manifestations are similar to those observed in loss-of-function SCN5A mutations, which are also responsible for Brugada syndrome (BrS).

The purpose of this study was to investigate DM1 effects on clinical expression of a loss-of-function SCN5A mutation causing BrS.

We performed complete clinical evaluation, including ajmaline test, in 1 family combining DM1 and BrS. We screened the known BrS susceptibility genes. We characterized an SCN5A mutation using whole-cell patch-clamp experiments associated with cell surface biotinylation.

The proband, a 15-year-old female, was a survivor of out-of-hospital cardiac arrest with ventricular fibrillation. She combined a DMPK CTG expansion from the father's side and an SCN5A mutation (S910L) from the mother's side. S910L is a trafficking defective mutant inducing a dominant negative effect when transfected with wild-type Nav1.5. This loss-of-function SCN5A mutation caused a Brugada phenotype during the mother's ajmaline test. Surprisingly, in the father, a DM1 patient without SCN5A mutation, ajmaline also unmasked a Brugada phenotype. Furthermore, association of both genetic abnormalities in the proband exacerbated the response to ajmaline with a massive conduction defect.

Our study is the first to describe the deleterious effect of DM1 on clinical expression of a loss-of-function SCN5A mutation and to show a provoked BrS phenotype in a DM1 patient. The modification of the ECG pattern by ajmaline supports the hypothesis of a link between DM1 and Nav1.5 loss of -function.