Myotonic dystrophy: time for evidence-based therapy

Abstract

This editorial refers to ‘Cardiac involvement in myotonic dystrophy: a nationwide cohort study’[†][1], by M. Lund et al. , on page 2158 . Lund and colleagues report on the association between cardiac disease and myotonic dystrophy using data derived from Danish patient registries.1 The major finding that myotonic dystrophy is strongly associated with cardiac disease throughout life emphasizes the importance of continuous cardiac follow-up and the urgent need for prevention and treatment of cardiac complications in this disease. The study also illustrates the value of research based on routinely collected healthcare data. Myotonic dystrophy is the most common muscular dystrophy in adults (incidence 1 in 8000 live births).2 There are two genetically distinct forms; myotonic dystrophy type 1 (DM1 or Steinert's disease) and the rarer myotonic dystrophy type 2. DM1 is caused by expansion of a repetitive trinucleotide sequence (CTG) in the 3'-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene which, when transcribed into CUG-containing RNA, forms aggregates of mutant transcripts that sequester RNA-binding proteins and cause abnormal splicing of downstream effector genes. In addition to this ‘RNA toxicity’ mechanism, other effects on protein translation and turnover and activation of cellular stress pathways have been observed2−7 ( Figure 1 ). Figure 1 Summary of pathophysiological pathways that may be involved in the cardiac manifestations of myotonic dystrophy type 1.2–7 The current disease paradigm for myotonic dystrophy type 1 is based on a toxic RNA gain-of-function hypothesis that results in gene missplicing, dysregulation of … [1]: #fn-2