Outliers - Intermediate between Duchenne & Becker MD

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Outliers - Intermediate between Duchenne & Becker MD

The reading frame rule holds true 90% of the time. There remains those 10% that does not fit dmd/bmd phenotype. There is a 3rd form that may be considered as an intermediate between Duchenne and Becker MD(mild DMD or severe BMD.

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Outliers?

Started by Simone & Elias. Last reply by KarstensMom Dec 31, 2017. 16 Replies

Utrophin

Started by Eliane Khoury. Last reply by Keith Van Houten Mar 25, 2009. 1 Reply

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Comment by Ofelia Marin on March 18, 2009 at 9:03am
Hi Keith,

No, my son is out-of-frame. I was just interested about this thinking at possible exon skipping results. That was Steve Wilton's answer to the question, it is posted on http://www.actionduchenne.org/ also. I don't think he commented more but feel free to email him about this.

You can also ask Dr. Wong about doing a skin biopsy, they can send it to Steve I guess and he can look at your son's mRNA to see if anything else is missing there. I wanted to do one for my son in order to see if he would be a candidate for exon skipping, if only exon 50 is missing in his mRNA then he would qualify for skipping 51, but decided to wait since exon skipping is still years away...

Ofelia
Comment by Keith Van Houten on March 17, 2009 at 7:11pm
Cheri - so, how do you get an in-frame deletion with a stop codon? The period's at the end of the reading frame?
Comment by Keith Van Houten on March 17, 2009 at 7:10pm
Very, very interesting, Ofelia. I had emailed Steve Wilton a while back and asked him asked him that exact question about skipping to create a larger in-frame deletion around exon 5. I never got a reply - but, boy, there's the answer.

Did you take the message below from some larger document? I'd really like to look at it. He mentions exon 5 - which is my son's - and there's only 40 cases in the Leiden database, so I'm interested to read anything else he's written about this specific mutation.

The RNA discussion is fascinating, but a bit over my head. I bought "Genetics for Dummies", I need to crack that thing open....

Is your son in-frame also?
Comment by Ofelia Marin on March 17, 2009 at 1:43pm
This is Steve Wilton's explanation about the DMD phenotype of some in-frame mutations. He is one of the exon skipping pioneers.

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.'
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

I asked then if exon skipping would be viable when an in frame DNA deletion resulted in an out of frame mRNA code. Professor Wilton went over this as an example again :
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

'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.'
Will have to look into this but there may be 2 options.
1. take out exons 7 and 8 and restore the reading frame
2. 2. see if it is possible to re-inforce exon 6 inclusion (exon insertion rather than skipping.. we are looking into that for another disease now)'
Comment by Cheri Gunvalson on March 16, 2009 at 9:50pm
Keith, A premature stop codon is like the period in the wrong spot ie the message to the RNA stops prematurly and produces no dystrophin or a truckated or non function dystropin. This is the mutation that PTC 124 can hopefully cure, unfortunately the drug company is not willing to consider compassionate use even though the head of the neuropharm div of the FDA has recommended it in writing. If you'd like to read more you may want to look at Jacob's journey on facebook. Cheri
Comment by Keith Van Houten on March 16, 2009 at 9:22pm
Cheri - my son has a deletion of exon 5. I'm not up to speed on stop codons - what's that mean? It's not a deletion of the exon, correct?

My son does not have any cognitive issues.
Comment by Cheri Gunvalson on March 16, 2009 at 8:23pm
Our son jacob has a premature stop on exon 5 and thus a inframe mutation. His first dx 10 years ago was BMD. He did how dystrophin on the western blot, however it looks like there was problems with the staining. There was not much known back then and very little research. Unfortunately as time went on he has a DMD phenotype. Jacob stopped walking at 15 1/2. he has been on steroids for 9 yrs. The boys I know with an inframe mutation do not have the congnative issues other DMD boys have I wonder if that is consitant.
Good Luck! Cheri
Comment by Char Burke on March 14, 2009 at 7:29pm
Thanks Keith. You didn't meet me in D.C. last month. We made our trip to see Dr. Wong in early Feb. and that was about it. I would like to go to that event some day. I have been to one PPMD conference and really enjoyed it albeit it was very intense with knowledge. Thanks again for your insight. Char Burke
Comment by Keith Van Houten on March 14, 2009 at 6:38pm
Char, when the deletion is out of frame - that's when exon skipping would apply. The skipping restores the reading frame - making the deletion now larger, but in-frame. Honestly, I'm not sure how duplications effect the reading frame, and how exon skipping would work. If you have an in-frame deletion, exon skipping would theoretically not help. Something different than expected is happening with boys with in-frame deletions and DMD like symptoms, though, so perhaps someday they'll look at this as an option.

Did your son's DNA test work indicate a phenotype? If I follow your posts correctly, it sounds like it said BMD.

On the DMD/BMD diagnosis thing - I don't think it has anything to do with funds. Projected phenotypes come from the reading frame rule. One study showed that when you compare that rule to the registries of how patients actually progressed - it held in 93% of the cases. The 7% that didn't conform to the rule are the so-called "anomolies". Some of these anomolies are grouped up around particular mutations.

Based on the 3 clinics we visited, most doctors choose an initial course of treatment based on the reading frame rule, and don't consider the patient might be in the other 7%. This was the case with us, even when I pointed out to one doctor the anomolies, and that my son's mutation was specifically written about in the literature as an anomoly and had a DMD phenotype in the registries. Dr. Wong recognized all of this on visit number 1 and put him on steroids and night splints immediately.

On the range of BMD thing - I suspect the geneticist meant it was "in the range" of BMD because it's an in-frame mutation. Not particularly well worded. You can definitely have BMD with a mutation anywhere in the gene. There may be places it's more common - just like there's a common area for DMD, but can occur anywhere in the gene. Similarly, there's probably regions that are more common for duplications, as you mentioned.

Did I meet you in DC last month?
Comment by Char Burke on March 14, 2009 at 11:38am
So - Keith - when the reading frame is in frame, I know that exon skipping would restore the error....but does it also mean that it is less severe than the out of frame error from a disease standpoint. Char
 

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