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#apaperaday: DMD deletions underlining mild dystrophinopathies: literature review highlights phenotype-related mutation clusters and provides insights about genetic mechanisms and prognosis

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: DMD deletions underlining mild dystrophinopathies: literature review highlights phenotype-related mutation clusters and provides insights about genetic mechanisms and prognosis

Today a paper from @FrontiersIn neurology by Fortunato et al on deletions in the dystrophin gene that are associated with no or very mild muscle disease and thus allow production of very functional dystrophins. DOI: 10.3389/fneur.2023.1288721

Deletions in the dystrophin gene can cause Duchenne, when no functional muscle dystrophin can be produced, or Becker, when internally deleted partially functional dystrophins can be produced. However, some deletions allow production of very functional dystrophins.

Here authors did a horizon scan to find these atypical variants that cause only very mild or no pathology. The definition for mild was no symptoms by age 43 years, or only mild elevations of CK or mild weakness. They found 81 patients reported in 11 papers and 16 reports.

The deletions reported were all in-frame and located between exon 2 and 55, except for 1 exception: a deletion of exon 78 that is out of frame, but exon 78 is alternatively spliced and therefore it makes sense that the resulting dystrophin is functional.

Deletions clustered between exon 45-55, where a deletion of exon 50-51 and 51-52 were found in asymptomatic individuals, while a deletion of exon 45-55 was found in asymptomatic and mildly symptomatic individuals, but also in Becker patients.

The same is true for the other deletions but reports of BMD patients are very rare for those, e.g. only 1 report of a Becker patient with a deletion of exon 51-52 was found by the authors.

A deletion of exon 2 is out of frame as well, but ‘not really’ as it allows production of a dystrophin starting in exon 6. Note that many out-of-frame variants before exon 8 are milder than ‘typical Duchenne’ because of start sites in exon 6 and 8 that are used at various levels.

The deletion of exon 2 allows good production of dystrophin, while this is less for e.g. a deletion of exon 3-7. This deletion has been found in both mild Duchenne and severe Becker. As mentioned before, these cases underline why it may be better to talk about dystrophinopathy.

Back to the paper: authors stress that while these individuals have mild or no muscle pathology, they may be at risk for developing cardiomyopathy. They also discuss that the fact that asymptomatic in-frame deletions do not occur beyond exon 55 has implications: This suggests that the region coded by exon 56-77 is apparently more important for dystrophin function.

For the cysteine rich domain that was already clear and this region (exon 64-70) is part of all micro-dystrophins. However, the region from exon 71-77 is not. The micro-dystrophin from regenxbio does have this region however.

Authors do discuss that for deletions you rely on however the spectrin repeats are put together based on the amino acids missing, while for a micro-dystrophin this is engineered much better.

As such, micro-dystrophins may be more functional than expected from patients with deletions. Authors outline more work is needed to see if the location of intronic breakpoints has an impact on why some individuals with the same deletions have no symptoms while others have Becker.

My own extra addition: some of these deletions affect the production of Dp140, which is known to increase the risk of learning difficulties and behavior problems. I would be interested to know whether the individuals without muscle problems did have cognitive problems.

This is something that only now is getting more attention, so it was probably not reported in the papers that the authors analyzed. Still it is something that we should focus on more in the future as dystrophinopathy can cause muscle heart and cognitive pathology.