Correlation between cardiac involvement and CTG trinucleotide repeat length in myotonic dystrophy

OBJECTIVES: Because sudden death due to complete atrioventricular (AV) block or ventricular arrhythmias is the most dramatic event in myotonic dystrophy, we assessed the relation of cardiac disease to cytosine-thymine-guanine (CTG) triplet mutation in adults affected with myotonic dystrophy. BACKGROUND: The myotonic dystrophy mutation, identified as an unstable deoxyribonucleic acid (DNA) sequence (CTG) prone to increase the number of trinucleotide repeats, produces clinical manifestations of the disease in skeletal muscle, the heart and many organ systems. METHODS: Forty-two adult patients underwent electrocardiography and echocardiography; in addition, signal-averaging electrocardiography was performed in 22, and 24-h Holter monitoring was recorded in 32. The diagnosis was established by neurologic examination, electromyography, muscle biopsy and DNA analysis. The patients were then classified into three subgroups on the basis of the number of CTG trinucleotide repeat expansions: E1 = 18 patients with 0 to 500 CTG repeats; E2 = 12 patients with up to 1,000 repeats; E3 + E4 = 10 patients with up to 1,500 repeats and 2 patients with > 1,500 repeats. RESULTS: The incidence of normal electrocardiographic (ECG) results was found to be significantly different in the three subgroups (55%, 50%, 17% in E1, E2, E3, + E4, respectively, p = 0.04), with the highest values in the group with fewer repeat expansions. The incidence of complete left bundle branch block was also significantly different among the groups (5% in E1, 0% in E2, 42% in E3 + E4 p = 0.01) and was directly correlated with the size of the expansion. A time-domain analysis of the signal-averaged ECG obtained in 12 patients in E1, 4 in E2, 5 in E3 and 1 in E4 showed that abnormal ventricular late potentials were directly correlated with CTG expansion (33% in E1, 75% in E2, 83% in E3 + E4, p = 0.05). Moreover, the incidence of ventricular couplets or triplets showed a positive correlation with size of CTG expansion (0 in E1, 0 in E2, 29% in E3 + E4, chi square 0.02). CONCLUSIONS: Our findings suggest that the involvement of specialized cardiac tissue, accounting for severe AV and intraventricular conduction defects, is related to CTG repeat length. In addition, the presence of abnormal late potentials directly correlates to CTG expansion. Abnormal late potentials, caused by slowed and fragmented conduction through damaged areas of myocardium, represent a substrate for malignant reentrant ventricular arrhythmias. In the future, therefore, molecular analysis of DNA should identify patients with cardiac disease at high risk for development of AV block or lethal ventricular arrhythmias.