Tan et al. (2001) studied a family who came to medical attention when the proband, a 3-year-old girl, experienced episodes of fainting during a febrile illness. Her 12-lead ECG showed characteristics of slow conduction throughout the atria and ventricles, including broad P waves, PR interval prolongation, and a wide QRS complex (see 113900). Continuous monitoring revealed episodes of severe bradycardia (25 beats/minute). During these slow periods the cardiac rhythm was maintained by infrequent atrioventricular nodal 'escape' impulses. Conduction disturbance persisted after the febrile illness, but there was no evidence of structural heart disease or systemic diseases associated with conduction defects in children. Therapeutic intervention with a dual-chamber pacemaker was initially limited by inability to pace the atrium (maximal stimulus: 10 V, 1 ms); however, this difficulty resolved with 1 week of empiric steroid treatment. During the 4 years following diagnosis, the patient continuously required dual-chamber pacing. The proband's 6-year-old sister was similarly affected and required pacemaker implantation, with episodes of noncapture that reproducibly resolved with corticosteroid therapy. Three other family members with no structural heart disease had ECG evidence of conduction slowing (prolonged PR and QRS intervals), but did not experience bradycardia or require pacemaker implantation. All affected family members had a G-to-T transversion in the first nucleotide of codon 514 in exon 12 of the SCN5A gene resulting in the replacement of glycine by cysteine (G514C). Biophysical characterization of the mutant channel showed that there were abnormalities in voltage-dependent gating behavior that could be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.
