DMPK CTG expansion length generally correlates with the severity of myotonic dystrophy type 1 (DM1), but is not fully prognostic of disease onset, course and severity. For congenital myotonic dystrophy (CDM), the apparent requirement for an epigenetic change upstream of the DMPK locus is apparently a co-requirement, along with a long CTG repeat. Moreover, the relationship between repeat expansion length and the cardiac phenotype in DM is a gap in our understanding of cardiac disease in DM1.

Multivariate Analysis of a Large Genetically Confirmed DM1 Cohort

Dr. Caroline Chong-Nguyen (Sorbonne Paris Cité University) and colleagues characterized the relationship between DMPK repeat expansion length and cardiac disease in a retrospective study of a cohort of 855 adult subjects from the DM1-Heart Registry. Subjects entered into the study had genetic analysis (Southern blot of peripheral blood) done at the time of their baseline cardiac investigations.

Genotyped patients were followed for a median of 11.5 years. The authors utilized a multivariate analysis that considered potential confounding factors, including age, sex, and diabetes mellitus.

Repeat Length is a Key Factor in Prognosis Even When Confounding Variables are Taken into Account

Survival of DM1 subjects was correlated with the quartile of CTG expansion size—37% mortality was reported in subjects with greater than 830 repeats. Across the range of repeat lengths studied, each 500 repeat increase was associated with 1.5-fold higher risk of death from all causes. Heart rate was higher and conduction system disease, left bundle branch block, and longer PR and QRS intervals were more prevalent in subjects with larger repeats. CTG length also associated with the presence of a permanently implanted pacemaker. Availability of extensive longitudinal data allowed the authors to report Kaplan–Meier estimates for survival, supraventricular arrhythmias, pacemaker implantation and sudden death.

This longitudinal study of a large cohort genotyped at the time of initial cardiac evaluation provides new insights into genotype-cardiac phenotype relationships in DM1. Overall, the authors showed that longer DMPK repeat expansions were correlated with the severity of cardiac involvement, including development of conduction defects, left ventricular dysfunction, supraventricular arrhythmias, the requirement for permanent pacing, sudden death and mortality. These findings support a more aggressive approach toward cardiac screening based on DMPK repeat length—the authors argue that care should be based on assessment of conduction system defects and other cardiac manifestations.

This peer-reviewed research article was accompanied by an editorial by Dr. Matthew Wheeler (Stanford University) in the same issue of the journal. This editorial is also referenced below.

References:

Association Between Mutation Size and Cardiac Involvement in Myotonic Dystrophy Type 1: An Analysis of the DM1-Heart Registry.
Chong-Nguyen C, Wahbi K, Algalarrondo V, Bécane HM, Radvanyi-Hoffman H, Arnaud P, Furling D, Lazarus A, Bassez G, Béhin A, Fayssoil A, Laforêt P, Stojkovic T, Eymard B, Duboc D.
Circ Cardiovasc Genet. 2017 Jun;10(3). pii: e001526. doi: 10.1161/CIRCGENETICS.116.001526.

Repeats and Survival in Myotonic Dystrophy Type 1.
Wheeler MT.
Circ Cardiovasc Genet. 2017 Jun;10(3). pii: e001783. doi: 10.1161/CIRCGENETICS.117.001783