There is such exciting news lately about the gains made in treatments for DMD. I attended the conference hosted by Action Duchenne in London a few weeks ago and heard representatives speak from AVI, Biomarin and Prosenza. What I find a little puzzling is why two trials are both testing deletion of exon 51. Is that deletion the most prevanlent form of mutation causing DMD? It seems they are going on next to a trial to treat patients with a deletion of exon 50. How do they make these decisions on which exon deletion to test next? Does anyone have any idea?

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What do you mean by "single point" deletion of 52? Does Trey have a deletion of exon 52 or point mutation in 52?

~ 13% of DMD boys need skipping 51
~ 4% of DMD boys need skipping 50

of which some might be candidates for the trials, some not, depending on trial inclusion criteria (age, ambulatory, other health conditions AND biopsy proving that the same mutation found at DNA level is found at mRNA level).


Cori said:
I am going to switch the topic a bit for a moment if anyone wants to participate...how many of your sons would become inframe by skipping exon 51? And how many of your boys would become inframe by skipping of exon 50?

Trey has a single point deletion of 52, therefore would become inframe by exon 51 skipping...I guess you could say we are one of the lucky ones if there is such a thing with this diagnosis.
My son, Sam, has a deletion of exon 50, so he is one of the ones who could be helped by skipping 51.

Cori said:
I am going to switch the topic a bit for a moment if anyone wants to participate...how many of your sons would become inframe by skipping exon 51? And how many of your boys would become inframe by skipping of exon 50?

Trey has a single point deletion of 52, therefore would become inframe by exon 51 skipping...I guess you could say we are one of the lucky ones if there is such a thing with this diagnosis.
Ofelia, sorry, Trey has a deletion of just exon 52.

Ofelia Marin said:
What do you mean by "single point" deletion of 52? Does Trey have a deletion of exon 52 or point mutation in 52?

~ 13% of DMD boys need skipping 51
~ 4% of DMD boys need skipping 50

of which some might be candidates for the trials, some not, depending on trial inclusion criteria (age, ambulatory, other health conditions AND biopsy proving that the same mutation found at DNA level is found at mRNA level).


Cori said:
I am going to switch the topic a bit for a moment if anyone wants to participate...how many of your sons would become inframe by skipping exon 51? And how many of your boys would become inframe by skipping of exon 50?

Trey has a single point deletion of 52, therefore would become inframe by exon 51 skipping...I guess you could say we are one of the lucky ones if there is such a thing with this diagnosis.
Good! Skipping 51 restores the reading frame.
I feel the same way, I just hope they hurry up already! Get it worked out for Trey and other kids it can help then move on to the others where really no research will need to be done since the process will already be in place... He is definitely one of the rare few who with just as the doctor referrs to it a 'single point deletion of exon 52', basically meaning he is only missing exon 52, yet I looked at his genetic results it says deletion 52, I don't know why they refer to it that way...anyhow either 51 or 53 skipping will work for him...see your son needs 50, here is to hoping and praying and wishing!

Ofelia Marin said:
Good! Skipping 51 restores the reading frame.
Cori, I do not know why the doctors call it that, but if the DNA test result says deletion of exon 52 it should be fine. They should also have the number of missing nucleotides in the report. My son has a deletion of 50, he also needs skipping of 51.

I forgot to mention in my pervious reply to Tina about some BMD cases not being diagnosed... I read a paper recently about a family with a 4 year old with a deletion of 50&51 having muscle cramps (as the only symptom). After the diagnosis, they tested 4 other men in the family (the oldest in his 60's), they all had the same mutation and were asymptomatic. This is one case where they would not have known they had BMD w/o the boy's diagnosis. I wonder how many other BMD cases are not diagnosed. That is one of the reasons why I am not positive if the mutations in the databases can predict exon skipping outcomes at this point.


Cori said:
I feel the same way, I just hope they hurry up already! Get it worked out for Trey and other kids it can help then move on to the others where really no research will need to be done since the process will already be in place... He is definitely one of the rare few who with just as the doctor referrs to it a 'single point deletion of exon 52', basically meaning he is only missing exon 52, yet I looked at his genetic results it says deletion 52, I don't know why they refer to it that way...anyhow either 51 or 53 skipping will work for him...see your son needs 50, here is to hoping and praying and wishing!

Ofelia Marin said:
Good! Skipping 51 restores the reading frame.
Just an add here: Exon skipping will help boys with point mutations and duplications and some exon skips ( i.e. 45 will have a better BMD outcome (85% after skipping 45) than other skips, including 51. 45 is the 2nd most popular skip needed.
Let's just get this stuff rolling into our boys ( it's too late to think where was advocacy during all of this) and hope/pray for a positive outcome for all 65% that would benefit from exon skipping. Utrophin is another promising drug coming down the pike for all boys with Duchenne.
Most point mutations (but not all) require multiple exon skipping and the duplications cannot be restored at this point (scientists are working hard trying to make it work for duplications). As for the "better" outcomes skipping one exon vs the other, different scientist have different opinions about this at this point. I know that MDEX scientists involved in the UK trial have a different opinion than what was published in Eric Hoffman's paper showing the prevalence and possible outcomes. In fact, one can read the disclaimer in Hoffman's paper after the graph is presented as well:

“Not enough is known about dystrophin
structure and function, and the relative importance
of the protein sequence within the rod domain
remains entirely a matter of speculation. Historically, lack
of dystrophin expression has been used as the key criterion
for DMD diagnosis. This together with the presence
of theDMD clinical picture with such in-frame mutations
argues that other confounding variables such as
imprecisely defined mutation or aberrant splicing may
explain these “exceptions to the reading frame rule.”
Thus,
it is anticipated that most or all patients with mutations
in the central rod domain would benefit from the production
of truncated dystrophin.”

In all fairness, only the clinical trials will prove what works and what doesn't.


Tina said:
Just an add here: Exon skipping will help boys with point mutations and duplications and some exon skips ( i.e. 45 will have a better BMD outcome (85% after skipping 45) than other skips, including 51. 45 is the 2nd most popular skip needed.
Let's just get this stuff rolling into our boys ( it's too late to think where was advocacy during all of this) and hope/pray for a positive outcome for all 65% that would benefit from exon skipping. Utrophin is another promising drug coming down the pike for all boys with Duchenne.
Our son has a deletion of exons 22-34....
Deletion of 45-50
Speaking about possible outcomes of exon skipping 51, if anyone is interested, I recently found this article presenting a family with in-frame deletion of exons 50-51. Four healthy adult males aged 28-69 found asymptomatic.

http://www.ncbi.nlm.nih.gov/pubmed/17258443

The paper below states: "we provide immunohistochemical and clinical evidence that in-frame deletion of the hinge III region in the distal rod domain results in a milder phenotype as compared with shorter deletions that do not include the hinge III region".

http://www.ncbi.nlm.nih.gov/pubmed/15845029

It will be interesting to see what happens in the clinical trials.


Ofelia Marin said:
Most point mutations (but not all) require multiple exon skipping and the duplications cannot be restored at this point (scientists are working hard trying to make it work for duplications). As for the "better" outcomes skipping one exon vs the other, different scientist have different opinions about this at this point. I know that MDEX scientists involved in the UK trial have a different opinion than what was published in Eric Hoffman's paper showing the prevalence and possible outcomes. In fact, one can read the disclaimer in Hoffman's paper after the graph is presented as well:

“Not enough is known about dystrophin
structure and function, and the relative importance
of the protein sequence within the rod domain
remains entirely a matter of speculation. Historically, lack
of dystrophin expression has been used as the key criterion
for DMD diagnosis. This together with the presence
of theDMD clinical picture with such in-frame mutations
argues that other confounding variables such as
imprecisely defined mutation or aberrant splicing may
explain these “exceptions to the reading frame rule.”
Thus,
it is anticipated that most or all patients with mutations
in the central rod domain would benefit from the production
of truncated dystrophin.”

In all fairness, only the clinical trials will prove what works and what doesn't.


Tina said:
Just an add here: Exon skipping will help boys with point mutations and duplications and some exon skips ( i.e. 45 will have a better BMD outcome (85% after skipping 45) than other skips, including 51. 45 is the 2nd most popular skip needed.
Let's just get this stuff rolling into our boys ( it's too late to think where was advocacy during all of this) and hope/pray for a positive outcome for all 65% that would benefit from exon skipping. Utrophin is another promising drug coming down the pike for all boys with Duchenne.
Yes, according to Steve Wilton, if the mutation is ouf-of-frame at mRNA level, exon skipping works. This is his explanation of the reading frame:

"The reading frame rule holds true in about 90% of cases when the DNA is studied. When the RNA is studied, I think the reading frame holds true for 99% of cases.

There are a number of mistakes / changes in the DNA that affect the processing of the gene message. That is what may look like an in-frame deletion at the DNA level is manifested as an out-of-frame mutation at the mRNA level.

A good example of this is the deletion of exon 5, as detected by routine DNA testing. Loss of this exon does not disrupt the reading frame and would be expected to be BMD. However, two independent cases of an exon 5 deletion were found to lead to DMD. When further testing was done at the mRNA level, the gene transcript was missing exons 5 and 6 (out-of-frame) and this is consistent with DMD.

There are still other reasons for an in-frame deletion giving rise to a severe DMD phenotype.
1. the deletion is so big that crucial domains are lost and the encoded protein is too small to work. I understand that deletions of 34 (or 36 ?) or more exons are always associated with a severe prognosis.
2. the deletion has taken out a crucial binding domain. An in-frame deletion of exons 66-70 removes the b-dystroglycan binding domain. The protein would be non-functional
3. there is another mutation in the dystrophin gene. There are now several cases where multiple mutations in the one gene have been reported. Hence during routine screening a deletion may be found but there is still the possibility of subtle spelling errors (AND >END) in other parts of the gene.

I hope this helps. DNA diagnosis is a good start but it can miss the processing errors that may lead to deletions form the mRNA."



Rhiannon Hubbard said:
Ofelia, do you have a link for these expamples? I'm interested in seeing them as Carter is one with an in-frame deletion that is progressing as DMD. He is missing exons 45-48. We were told that exon skipping wouldn't be of any benefit to him since he's already in-frame. Do you know if exon skipping would have the ability to help boys who are only out-of-frame at mRNA level?

Ofelia Marin said:
Tina,

2. Some BMD cases progressing like DMD might have other mutations in the gene (Steve Wilton has a number of examples of in-frame mutations at DNA level progressing like DMD, proven later to actually be out-of-frame at mRNA level)

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