The North Star Network has recently published a paper that describes, for the first time, differences in the way Duchenne Muscular Dystrophy progresses across patients. The lead author was Prof. Francesco Muntoni (pictured above with Duchenne UK's co-founder Alex and Emily).

The paper found that boys could be grouped into a series of similar progressions. They called these progressions over time ‘trajectories’ and provided evidence for four separate trajectories. 

An understanding of this grouping could lead to better analysis of clinical trial data. Variability complicates the interpretation of all clinical studies. By grouping DMD boys into these trajectories, rather than by their age, variability could be reduced, impacting clinical trial design and improving the clarity of results.

The analysis was conducted on the data collected by the NorthStar Clinical Network. 

We have written a summary of this paper, which you can read here.

The full paper can be accessed on PLOS ONE here. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221097 

Summary by Elinor George and David Bull, Duchenne UK

The overview:

Very recently, an article was published in which the authors, led by Prof Francesco Muntoni, tested the idea that boys with DMD did not follow totally random and independent progressions in loss of mobility. The authors showed that boys could be grouped into a series of similar progressions. They called these progressions over time ‘trajectories’ and provided evidence for at least four separate trajectories. The article went on to explore the relevance and potential value of understanding this grouping. In particular it is known that variability complicates the interpretation of clinical studies, so if variability can be ‘reduced’ by clustering it may impact clinical trial design and improve clarity.

The aims

The authors had three main aims in doing this work:

1. Assess whether patients with DMD could be clustered into groups sharing similar ambulatory trajectories over time (using NSAA scores)
2. Look for any patterns in the way skills are lost or gained at different ages
3. Look at the boys’ different genotypes and steroid therapies – how do they effect longitudinal progression of disease.

The data:

The group decided to use data from 395 patients (aged from 2 to 17 years) in the NorthStar Clinical Network database. For each of the boys they looked at the NorthStar Ambulatory Assessment (NSAA) over time – this type of measurement is called ‘longitudinal’ - and can provide a valuable picture of how change in mobility progresses. By combining all the data for all the boys onto a single graph, and by then using some pretty advanced statistical assessments, it is possible to see a general picture of change. Below we have included two important graphs from the article.                        

On the left, the mass of light grey lines are individual data from 395 boys. The single dark line is the statistical average. We can see the huge variation in scores over time. The authors then applied further statistics to the mass of data to see if there were patterns within the average. What they found was that the data fitted best when they assumed there were 4 different trajectories (groups of similarly responding boys) – any other number just didn’t work as well. This is shown on the right, and below are the sizes of the four groups:

• Class 1: 27% of patients - fastest
• Class 2: 34% of patients
• Class 3: 20% of patients 
• Class 4: 19% of patients - slowest

Using this approach, the research demonstrated that age was not the main determinant for the rate of disease progression.

Here are some of the other key findings from the report:

• There was no significant association between which cluster patients were grouped in and their type of dystrophin mutation. This highlights that the genotype is not the main cause of disease progression in patients.
• Another interesting result from the study is that patients who had faster disease progression had been prescribed glucocorticoids at an early stage. However, this is unlikely to be as a result of glucocorticoid treatment, but rather the result of a more severe rate of progression.
• The younger a patient with DMD is when he begins to lose the ability to walk, the lower will be his peak NSAA score, and age at which it is reached. Conversely, Patients with a slower disease progression will reach a higher peak NSAA score at a later age.

The conclusion

This piece of work has shown that the progression of DMD as determined by NSAA measurements fits best into four categories (trajectories). For example, twice as many boys acquiring more difficult skills (hop and jump) are in the slow trajectory versus the fast. This, and other functional measures, are more likely to be predictors of progression than is age.

Why does this matter? When clinical trials are designed to study new DMD treatments the inherent variability of boys’ NSAA scores (a frequent secondary measurement element along with a primary 6MWT) is always a complicating factor meaning many more boys are needed to improve the chances of seeing a real effect. By categorising boys into similar, less variable groups, we may improve our chances of seeing drug effects. Additionally, this information may boost the growing number of clinical trials employing NSAA as the primary outcome measure.

If you have any questions please email: [email protected]

View the paper here: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221097

NOTES FOR EDITORS

What is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease diagnosed in childhood. Children born with DMD cannot produce the protein dystrophin which is vital for muscle strength and function. Muscle weakness starts in early childhood. Many use a wheelchair by around the age of 12. As deterioration continues it leads to paralysis and early death, often in their 20s. It almost exclusively affects boys. There is no treatment or cure. In the UK there are around 2,500 boys affected and around 300, 000 worldwide. It is classified as a rare disease.

Who are Duchenne UK?

Duchenne UK is a lean, ambitious and highly focused charity with a clear vision: to fund and accelerate treatments and a cure for Duchenne muscular dystrophy.

We are investing millions of pounds in research right now to bring treatments and a cure to help this generation. Duchenne UK is the largest funder of DMD research in the UK. We are also committed to accelerating the pace of research. 90p in every £1 raised is committed to research.

Our president is HRH The Duchess of Cornwall. Our patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell. 

We need your help, because we need to keep funding promising new research.

How to donate?

Duchenne UK is entirely reliant on donations to fund research for treatments and a cure to DMD. This can be done via:

• Direct Debit – Duchenne Direct
• Individual Donation – Donate
• If you are a family or friend affected by DMD you can set up your own fund with Duchenne UK – Family and Friend Funds
• Take part in one of our fundraising events – Events
• Text DUCHENNE to 70085 to donate £5. This costs £5 plus a std rate msg.

For more information visit www.duchenneuk.org