Research progress in myotonic dystrophy

Myotonic dystrophy is one of the most common inherited muscle wasting conditions. It affects individuals of all ages and both sexes and is extremely variable in its presentation. It is characterised by muscle weakness and wasting (dystrophy), and muscle stiffness (myotonia). For example, people affected by myotonic dystrophy find it difficult to relax their hand grip. The muscle weakness becomes progressively worse over time and is most prominent in the head and neck, with drooping eye-lids, difficulty smiling and making other facial expressions, speaking and swallowing. As the condition progresses nearly all muscles are affected. Myotonic dystrophy also affects the heart, gut, eyes, hormonal system and brain. One of the most consistent symptoms of myotonic dystrophy is the development of early onset cataracts.

As the condition is passed from one generation to the next, the severity of the symptoms increases and the age of onset decreases. This unusual effect is known as anticipation. For example a grandfather who only shows mild symptoms of the condition later in life with cataracts being the only symptom, might have severely affected grandchildren who develop the condition from birth (congenital).

Myotonic dystrophy affects around 1 in 8,000 individuals and there are thought to be at least 9,000 individuals living with the condition in the UK. There are two forms of myotonic dystrophy: DM1 and DM2. Many clinical features are shared between the two forms however DM2 is generally milder.

The underlying defect causing DM1 is in a gene called DMPK. This gene contains a region with a three letter repeat that has become unstable in people with DM1. As a result the number of repeats increases from generation to generation. This has been an explanation for the progressive nature of the condition.

RNA is the short-lived intermediate that is necessary to translate the information carried in the DNA into a protein. When the long repeat in the DMPK DNA is copied into RNA, it forms an unusual shape and accumulates in the nucleus where it binds tightly to a protein called MBNL. MBNL has an important role in the cell in ensuring that the RNA copies of other genes are processed in the correct way. In individuals with DM1 the MBNL proteins that normally regulate this process are bound so tightly to the DMPK RNA that they do not function properly to regulate other genes. It is the disruption of these genes that leads to many of the symptoms in DM1.

Although the gene causing DM2 is different to the one causing DM1, it contains a very similar, repeat expansion (CCTG), which is likely to explain the clinical similarity of the two conditions.

Substantial research progress has been made in recent years in understanding DM. The use of animal models has proved invaluable. It has helped to assess the benefits of potential therapeutics. These current models, however, do not reflect the full range of the symptoms in humans and more work is needed to develop more useful models.

Currently there are only a limited number of treatment options for individuals with DM and most of them focus on treating the symptoms rather than the underlying genetic cause of the condition.

A lot of effort has been focused on reducing the amount of the toxic DMPK RNA in the nucleus by using molecular patches or antisense oligonucleotides. This approach has worked successfully in patient cells grown in the laboratory and in an animal model of the condition. Most excitingly, this approach has recently entered into clinical trials in humans. The initial trials have established that the antisense oligonucleotide is safe to administer to humans. Trials to determine if the drug has an effect on disease progression in DM1 patients were initiated in several centres in the USA in January 2015 (see below ISIS-DMPKRx).

Muscular Dystrophy UK has supported critical experiments that began to establish how the DM1 mutation leads to the diverse array of symptoms observed in patients. In particular, we funded research in Professor David Brook’s group at the University of Nottingham that was instrumental in establishing the role of the MBNL protein in the disease pathway. The group is now looking for drugs that have the effect of reducing the accumulation of the toxic DMPK RNA in the nucleus. The charity funded crucial research to develop a cellular test system that enables the researchers to test hundreds of compounds in a relatively short time.

In the last ten years the charity has supported several research projects into myotonic dystrophy. Some of this work, done by Professor Darren Monckton and his team at the University of Glasgow, has been crucial in better understanding the role of genetic variation in causing the great variability of symptoms seen in people with DM1. This information will be essential for improving the accuracy of prognostic information to patients and families and for improving the efficiency of clinical trials. This work has also revealed the critical role of genetic instability in the disease pathway highlighting new targets for therapeutic intervention.

We are currently funding another project in Professor Monckton’s laboratory aimed at further defining how genetic variation contributes towards the severity of symptoms associated with the condition, in a clinically well characterised cohort of Canadian patients. This is a collaboration with the clinical team at the University of Sherbrooke in Quebec.

We also co-fund a Clinical Research Fellow at the University of Glasgow, Dr Mark Hamilton, who is investigating how the genetic changes that occur in DM1 affect the severity of brain-related symptoms such as impairment of thinking and excessive sleepiness. Dr Hamilton will also be using state-of-the-art brain scanning techniques to understand how structural changes in the brain relate to function.

Finally, we provide support for the DM1 UK Patient Registry. The registry provides an invaluable resource for research teams and the pharmaceutical industry to recruit patients to clinical trials. Established in 2012, the registry has already been used to recruit UK patients to a number of new DM1 studies.

  • Tideglusib

This phase II clinical trial investigated whether a drug called tideglusib could be a potential treatment for congenital and childhood-onset myotonic dystrophy. Most participants who received the drug for 14 weeks had improved cognitive (brain) function and felt less fatigued (tired). The drug was also well-tolerated and safe. The company who sponsored the trial, AMO Pharma, is planning to further evaluate the efficacy of tideglusib in larger multi-site clinical trials in the US, Canada and UK. Read our news story for more information.

  • PhenoDM1

This observational study will help document the natural history of myotonic dystrophy type 1. This is important for doctors and researchers to understand as much as possible about the condition and how it affects people in different ways. The study is taking place at Newcastle-upon-Tyne Hospitals NHS Trust and is currently recruiting participants aged 18 and over. Find out more about the study, including how to take part, here. identifier: NCT02831504

  • Mexiletine

This phase II clinical trial in the US investigated the effects of a drug called mexiletine on muscle stiffness. It was completed in August 2017 and results are yet to be announced. identifier: NCT01406873


This phase I/II trial tested the safety, tolerability of an antisense oligonucleotide against the expanded repeat region of the DMPK RNA (called IONIS-DMPKRx). Although encouraging trends in certain biomarkers were observed and the drug was safe and well-tolerated, it was not very potent i.e. not enough got into the muscles to have a beneficial effect. For this reason, Ionis decided not to advance IONIS-DMPKRx further. The company has said that it will instead pursue the discovery of a more potent drug.

For more information, read this letter from Ionis

  • The OPTIMISTIC study

This EU funded international trial evaluated the potential benefits of exercise and cognitive behavioural therapy in reducing fatigue and increasing quality of life in DM1. It took place in the UK, Germany, France and Netherlands and results are yet to be announced. Find out more here.

Last updated March 2018.

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