Association Between Mutation Size and Cardiac Involvement in Myotonic Dystrophy Type 1

Abstract

Background— In myotonic dystrophy type 1, the association between mutation size (CTG expansion) and the severity of cardiac involvement is controversial. Methods and Results— We selected 855 patients with myotonic dystrophy type 1 (women, 51%; median age, 37 years), with genetic testing performed at the moment of their initial cardiac evaluation, out of 1014 patients included in the Myotonic Dystrophy Type 1-Heart Registry between January 2000 and December 2015. We studied the association between CTG expansion size and other baseline characteristics and (1) cardiac involvement at baseline and (2) the incidence of death, sudden death, and other cardiac adverse events. At initial presentation, the median CTG expansion size was 530 (interquartile range, 300–830). In multivariate analysis, larger expansions were associated with the presence at baseline of conduction defects on the ECG and left ventricular systolic dysfunction. In a median 11.5 years of follow-up period, 210 patients died (25%), including 32 suddenly (4%). Supraventricular arrhythmias developed over lifetime in 166 patients (19%), sustained ventricular tachyarrhythmias in 17 (2%), and permanent pacemakers were implanted in 181 (21%). In Cox regression analyses, larger CTG expansions were significantly associated with (1) total death, sudden death, and pacemaker implantation in a model, including CTG expansion size, age, sex, diabetes mellitus, and (2) all end points except sudden death in a model including all baseline characteristics. Conclusions— The size of the CTG expansion in the blood of myotonic dystrophy type 1 patients is associated with total and sudden deaths, conduction defects, left ventricular dysfunction, and supraventricular arrhythmias. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique Identifier: NCT01136330

Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat RNA

“…As a result, at-risk DM1 patients are often provided implanted pacemakers (Groh et al, 2002; Groh et al, 2008; Nazarian et al, 2011). DM1 patients experience an increased incidence of premature death, due in part to sudden cardiac death (SCD; de Die-Smulders et al, 1998; Mathieu et al, 1999; Groh et al, 2008; Chong-Nguyen et al, 2017), even in patients with pacemakers (Laurent et al, 2011; Chong-Nguyen et al, 2017; Wahbi et al, 2017). In spite of this, little is known regarding the precise biophysical and molecular mechanisms that underlie the ECG defects observed in DM1 patients and the specific pathogenic role of CUG exp RNA in the heart.…”

Repeats and Survival in Myotonic Dystrophy Type 1

“…In this issue of Circulation: Cardiovascular Genetics, Chong-Nguyen et al 17 provides evidence to support an association between repeat expansion size and cardiac outcomes in DM1. Out of 1014 patients, 855 underwent genotyping at the time of baseline evaluation.…”

Mutation analysis of multiple pilomatricomas in a patient with myotonic dystrophy type 1 suggests a DM1-associated hypermutation phenotype

“…Myotonic dystrophy type 1 (DM1, OMIM 160900) is an inherited and the most common neuromuscular disorder characterized genetically by an expansion of trinucleotide repeats within the 3’ untranslated region of the DMPK (DM1 protein kinase) gene [1–5]. The DNA-expansion within the DMPK gene is considered causative for the observed muscle weakness and cardiac disease [5,6]. Besides, affected patients develop early cataract as well as insulin resistance and cognitive impairment.…”