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The understanding of the pathomechanism of myotonic dystrophy (DM) has been greatly improved since the recognition as an mRNA disease. Pre-mRNA containing repeats sequesters or activates proteins such as MBNL and CELF that bind to an mRNA motif similar to repeat. Consequently, the regulation of mRNA splicing, a normal function of these proteins, is perturbed. Over 30 miss-splicing events have been documented including muscle chloride channel which is responsible for myotonia. Such molecular events might serve as a target for therapeutic intervention. An important genetic feature of DM is the instability of expanded repeats between generations and organs. Since pathogenesis is connected to repeat length, manipulation of the repeat expansion size (somatic instability) might be also a potential therapeutic strategy. With accumulation of pathomechanistic studies, clinical trials are highly expected. Our recent survey in Osaka Japan revealed the need of standardized management employing currently available therapies, which should be prerequisite for trials. Clinical trials for DM will face challenges including lack of reliable outcome measures and enrollment of highly restricted cohort. Global initiative to form international DM registry have been taken to facilitate natural history studies and trials. In Japan, the development of DM registry has just started.

Myotonic dystrophy―from pathomechanism as a RNA disease to future clinical trials