Myotonic dystrophy: time for evidence-based therapy.

Lund and colleagues report on the association between cardiac disease and myotonic dystrophy using data derived from Danish patient registries. 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). 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 observed (Figure 1). Clinically,DM1 ischaracterizedbymyotonia, progressivemyopathy, and multiorgan involvement including cataracts, diabetes, thyroid dysfunction, hypogonadism, cognitive impairment, and gastrointestinal abnormalities. Pathological studies have shown that the heart in patients with DM1 is characterized by fibrosis and fatty replacement in the specialized conduction system and in both ventricles, and numerous clinical studies have reported progressive conduction disease, atrial and ventricular arrhythmia, and ventricular dysfunction. Yet, in spite of decades of study, three questions continue to trouble clinicians caring for patients with the disease. (i) What is the frequency of heart abnormalities in DM1? (ii) What is their impact on prognosis? (iii) Is it possible to treat and prevent cardiac complications and thereby improve survival. The answers to these questions are elusive because of the rarity of the disease and the lack of prospective data from large unselected patient populations. To date, the most informative data have come from a few large referral centres and systematic reviews of the literature. In a pooled analysis (comprising 1828 cases), the most frequent cardiac abnormalities were prolongation of the PR and QT intervals. With the exception of ventricular premature beats, atrial and ventricular arrhythmia were reported in ,10% of cases and left ventricular systolic impairment in only 7.2%. The estimated annual risks for pacemaker or implantable cardioverter defibrillator (ICD) implantation during follow-up were 1% and 0.2%, respectively. The study by Lund and colleagues is the first to use a National Patient Registry (NPR) to ascertain cases. The authors identified a cohort of .1000 patients diagnosed between 1977 and 2011 using the International Classification of Diseases 8 and 10 coding systems. These data were linked to various Danish health registers and the Civil Registration System (CRS) and were cross-referenced with information on genetic testing obtained directly from diagnostic laboratories. Information on incident cardiac disease and implantation of pacemakers and ICDs were also obtained from the NPR. During follow-up, 22.3% of the cohort died. The standardized incidence ratio (SIR) for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01–3.86], rising to 6.91 (95% CI 5.93–8.01) for any cardiac disease in the selected subgroups. The risk was particularly high in the first year after the diagnosis of myotonic dystrophy but remained elevated in subsequent years in all age categories. The results were similar in separate analyses of genetically confirmed DM1 patients. Unfortunately, the authors were unable to examine in detail the relationship between cardiac disease and survival or the impact of therapyonoutcomes. Previous studieshave reported anoverallmortality more than seven times higher than that of an age-matched reference population, with a mean age at death of 53 years. In most reports, respiratory failure and cardiovascular disease are the most common causes of death, accounting for 40% and 30% of fatalities,