Repeats and Survival in Myotonic Dystrophy Type 1.

The myotonic dystrophies are multisystem disorders characterized by progressive skeletal muscle weakness, myotonia, cataracts, endocrine abnormalities, cognitive impairment, and cardiomyopathy. Myotonic dystrophy type 1 (DM1) is the most common of the myotonic dystrophies. The cardiac-specific phenotypes of DM1 include progressive atrioventricular conduction delay, atrial and ventricular arrhythmias, impaired left ventricular diastolic and systolic dysfunction, impaired contractile reserve, and mesocardial fibrosis. Cardiac conduction abnormalities in patients with DM1 range from asymptomatic preclinical conduction system disease to complete heart block or ventricular arrhythmias leading to sudden death. In addition, DM1 patients are at increased risk for left ventricular dysfunction, ranging from impaired global longitudinal strain and impaired contractile reserve with preserved resting ejection fraction to overt left ventricular systolic dysfunction leading to overt heart failure. See Article by Chong-Nguyen et al Much concerning the pathogenesis of DM1 has been elucidated. Abnormal repeat expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene (dystrophia myotonica protein kinase)1 leads to accumulation of mutant transcripts in the nuclei of cells that in turn lead to dysregulated splicing and altered transcription.2,3 Sequestration of RNA-binding proteins including MBNL1 by DMPK mRNA CUG repeats and compensatory upregulation and activation of CUGBP1 (CUG-binding protein) lead to altered splicing of multiple transcripts.4–6 In addition to splicing defects, reduction of the DM protein kinase itself may contribute to the cardiac conduction defect seen in patients with DM1.7,8 Aberrant differential splicing of the SCN5A mRNA, with switching of exon 6 from the adult exon 6B to fetal 6A, is likely contributory to reductions in cardiomyocyte excitability and increased atrioventricular conduction delay.9 There is extensive evidence of a relationship between age-dependent neuromuscular dysfunction and DMPK CTG repeat length in DM1. Indeed, clinical phenotypes of late-adult-onset, classical-adult-onset, childhood-onset, …