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#apaperaday: Longitudinal data of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Longitudinal data of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy

Today’s pick is from Muscle Nerve by Awano et al on a natural history study in a historic cohort of 337 Japanese Duchenne patients most of whom are not on steroids. DOI: 10.1002/mus.28073

Duchenne is a progressive muscle wasting disease. Natural history data is important. Authors reason that perhaps in the future natural history can be used instead of placebo data. Maybe, but it is also important to allow proper design and powering of clinical trials.

Most natural history data are from White patients from north-America/Europe. Authors correctly point out it is important to also study other races as the trajectories may differ and this has consequences for trial design. Here they did a retrospective study in Japanese patients.

Authors included patients who visited clinics between 1991 and 2019 with a confirmed genetic diagnosis. Follow up was until patients were 20 years, or until patients were loss for follow up (77% on average at age 12).

Authors had medical data from 337. 56% had a deletion, 10% a duplication and 21% a nonsense variant. Authors do not report the number of small exonic variants. Not sure whether these are the 13% not accounted for, or whether they are part of the deletion/duplication group.

i.e. a 1 bp deletion is also a deletion, just like a deletion of a whole exon. Authors point out that 21% nonsense mutations is higher than the average reported for other cohorts (usually around 10-13%).

Authors also looked into exon skippable groups: 44 (5%), 45 (10%), 51 (10%) and 53 (11%). Note that 2% of patients had a deletion of exon 52 and these are mentioned in both exon 51 and exon 53 skipping groups (good that authors point this out).

Patients on average first visited at age 5 and there was 6 year follow up. 15% of patients were on steroids (very low amount) and 19% had heart medication. 3% of patients died before age 21. Creatine kinase serum levels (marker for muscle damage) was high at diagnosis.

CK levels increased until age 6 and then dropped with time. This is as expected because patients will lose muscle, so even though they get worse, muscle damage markers will go down because there is less muscle to leak from.

Motor function also increased until age 4-6, then plateaued and declined for the 10 meter walk/run and the rise from floor until patients lost the ability. For forced vital capacity patients peaked at age 9 and then started to decline.

Heart function was normal until age 12 for most patients but then started to decline with 50% of patients having heart failure at age 13 and over 75% at age 15. The first case of cardiomyopathy was seen at age 8 (note that these are patients mostly not on steroids!)

Authors looked at whether the exon skipping groups differed but they did not find difference in CK or function. Note in other cohorts exon 44 skippable patients had a slower trajectory. However, this difference was mainly found with milestones and 6 minute walk test and NSAA

So it is possible the exon 44 skippable patients from Japan also have a slower trajectory but this was not detectable with the tools used here. Authors discuss the limitations of the study: due to the retrospective nature the outcome measures were based on what was available.

Authors also discuss that ACE inhibitors in Japanese patients were generally not given prophylactically but only when heart failure developed between age 13 and 15, while the guidelines suggest starting at age 10.

Authors also discuss the cause for the low percentage of patients on steroids: oral steroids were only approved in Japan in 2013. This means that most likely more patients will be on steroids in the future and the natural history for Japanese patients will change.

So more data will need to be collected. Furthermore, for using the data instead of a placebo group or to design trials, ideally the outcome measures used in the trials would have to be part of the dataset.