Genetic factors that determine the severity of myotonic dystrophy type 1

Published Date
Laura Jacobs
Human DNA

Researchers involved in the OPTIMISTIC trial have published a scientific paper that identifies genetic factors that influence the severity of myotonic dystrophy type 1 (DM1). These findings help to explain variability between patients with DM1 and will inform the design of clinical trials in future.

DM1 is caused by a mutation in which a triplet of letters in the DNA – known as CTG – appears more times than it should. In the general population there are up to about 40 copies of the CTG repeat. However, in DM1 patients this triplet has expanded to more than 50 repeats, and can be as many as 1000 in some people.

In general, the higher the number of CTG repeats, the earlier that DM1 symptoms will appear and the more severe someone’s condition will be. The number of repeats nearly always increases when passed down from one generation to the next. This explains why younger generations are usually more affected than their parents. The number of CTG repeats also increases during the lifetime of the individual, which in addition to hastening disease onset, can complicate our ability to interpret the results of genetic testing.

In this new study, researchers at the University of Glasgow carefully analysed DNA samples provided by 255 participants of the OPTIMISTIC trial. This included patients from the Netherlands, France, Germany and UK. From these samples, the researchers were able to determine the number of CTG repeats that the patients had when starting the trial. They were also able to estimate how many CTG repeats the patients had inherited from their parents.

The results showed that the number of inherited CTG repeats determines the age at which symptoms first appear. This number also predicted participants’ muscle function, walking performance and capability to perform daily life tasks.

Although the majority of participants had a CTG expansion i.e. CTG-CTG-CTG-CTG-CTG, about 8% were revealed to have interruptions within the CTG repeats e.g. CTG-CTG-GGC-CTG-CTG. These interruptions seem to delay the first appearance of symptoms (typically by around a decade) and are associated with less severe DM1. Researchers think that these interruptions slow down the rate at which the CTG repeat grows during a patient’s lifetime.

This study helps us to understand why age of onset and disease severity differs between people with DM1, which has important implications for clinical trials. Using these findings, researchers could potentially group trial participants according to their genetic test results. This process – known as stratification – can make it easier to interpret outcomes from clinical trials.

Professor Darren Monckton, the OPTMISTIC lead at Glasgow University, said:

These results confirm the importance of carefully counting the number of CTG repeats as part of clinical trials in DM1 and increase prospects for detecting the effects of new treatments. In addition, our finding that the increasing number of CTG repeats contributes toward both the age at onset, and severity of the many of the progressive symptoms, reinforces the idea that stopping the repeat getting bigger during the lifetime of the patient would be therapeutically beneficial.

The study was published in the scientific journal, Neurology.

If you have any questions about this study or any other myotonic dystrophy research, please contact the MDUK Research Line on 020 7803 4813 or email

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