Abstract
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3′-untranslated region (3′UTR) of the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the CNBP (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase.
Highlights
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, with an estimated prevalence of 1/8000 [1]
This study suggested that, as opposed to DM—type 1 (DM1), post-transcriptional silencing may not be a reasonable approach to treat DM2 because the downstream effects of the DM2 mutation seem to be different
Various approaches for miRNA intervention have been used or suggested: one is to inhibit miRNA by using synthetic antimiR. Products, such as Antisense oligonucleotides (ASOs) that are perfectly complementary to the specific miRNA target; a second approach is to use blockmiRs, which contain a sequence complementary to one of the messenger RNA (mRNA) sequences that serve as a binding site for a microRNA and sterically block the miRNA from binding to the same site, preventing degradation or transcription inhibition of the target; the third approach is to use miRNA sponges that contain several tandemly arranged miRNA target sequences; and the last one is using synthetic double strand miRNA mimics as replacement therapy
Summary
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, with an estimated prevalence of 1/8000 [1]. DM1 and DM2 are both nucleotide repeat expansion disorders and are thought to share the pathomechanisms involved in other neurodegenerative diseases, such as some forms of spinocerebellar ataxias and amyotrophic lateral sclerosis (ALS) [3]. DM1 is most common in individuals of European descent, but is present in Japan, China, India and the Middle East [4]. DM1 and DM2 share many clinical features but are caused by two different genes. We will have an overview of core clinical features in DM, the genetics of DM1 and DM2, postulated pathomechanisms in DM, and potential therapeutic approaches
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