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#apaperaday: Treatment with ataluren in four symptomatic Duchenne carriers. A pilot study

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Treatment with ataluren in four symptomatic Duchenne carriers. A pilot study

#apaperaday brought to you again from #myologie2024 meeting in Paris. Today’s pick is from Acta Myology by Dori et al describing the experience with treating 4 female dystrophinopathy patients with ataluren (stop codon read through) DOI: 10.36185/2532-1900-398

Duchenne is caused by lack of dystrophin. In ~10% of patients this is due to a nonsense variant, where the code for one amino acid is changed into a stop code. Stop codon read through compounds can suppress these nonsense variants, allowing expression of dystrophin at low levels

As the dystrophin gene is located on the X-chromosome, primarily males are affected by pathogenic variants, as females have a back up copy. However, females with symptoms are present, this is called female dystrophinopathy. Symptoms are generally milder than for Duchenne, but female dystrophinopathy can still be debilitating involving weakness, cramps and loss of muscle function. In a subset of females also cardiomyopathy occurs (with or without muscle pathology). Authors suggest that female dystrophinopathy can be due to skewed X-inactivatio

However, this is not always the case (see also the video from @DuchenneDay #WDAD2022 videos on females and Duchenne). Authors here prescribed ataluren to 4 female dystrophinopathy patients with a nonsense variants, 1 from Israel and 3 from Italy with up to 4 year follow up

The first patient was diagnosed at age 40 after 10 years of progressive muscle weakness, with falling and difficulties climbing chairs. After treatment initiation the woman reported improved balance and less falls. Also her strength increased.

Later however her disease progressed and she lost ambulation at age 49. The second patient was diagnosed at age 33, but already had symptoms since she was 12 with delayed milestones and elevated CK. Ataluren treatment was started, but then stopped after a fracture.

Then treatment was reinitiated and ambulation was regained (lost with the fracture). The 6 minute walk distance was 52 meters, which showcases that female dystrophinopathy can be debilitating. Heart and respiratory parameters remained stable over time.

The 3rd patient was 33 years old and had symptoms since she was 17. Treated started when she was 29 years old and parameters stabilized at first, but then declined both for walking, respiratory and heart function.

The 4th patient was 45 years old, with symptoms starting at 35. Treatment started when the woman was 43 and the woman chose to stop the treatment after 21 months. She was stable while on treatment. Authors discuss that the age on onset and time of treatment after onset varied.

Biopsies were done for each patient showing mosaic patterns of dystrophin staining. For 2 patients the treatment was stopped, for patient 1 after she lost ambulation and for patient 4 on a voluntary basis. Treatment was tolerated well.

Authors discuss that the treatment effects were limited and also difficult to pick up due to the small number of patients and different levels of involvement. Authors outline that female dystrophinopathy patients (manifesting carriers before) are often overlooked.

This is also clear from each of these cases: there was a delay in diagnosis. Authors outline recognizing symptoms in females who carry a dystrophin mutation is important, because one it is recognized, the symptoms can be managed.

Here women were often diagnosed late and time of intervention might not have been optimal – authors expect earlier treatment might have resulted in better therapeutic effects. However, they stress that the small number makes it challenging to draw robust conclusions