So our little Trey has been diagnosed with a single deletion of exon 52. With that and all the research I have done I understand that he needs to skip exon 51 or 53 to become 'inframe'...and I also understand that research is currently being done for boys with this deletion.

A huge question I do have is I was told that if a child is missing exon 52 or any higher then that then they are missing isomers in their brain of DP140 and DP260. Little Treyman is very bright but it does seem to take him longer to 'get it' then what I feel is normal...although he does go to school and is doing amazing. Just wondering if anyone knows what in the world these isomers do, and I guess what missing them can cause...

If anyone can help that would be great, although I feel like I am 'researched up' since the 2 months we have known of this, I still feel very confused at times...

Thanks so much! Cori

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Comment by Ofelia Marin on November 6, 2009 at 4:38pm
This is a very interesting topic. What happens if the mutations around hinge 3 are in-frame? Has anyone studied this? Probably not.
Comment by Julie Gilmore on November 6, 2009 at 2:36pm
Hi (again)

I think this paper:
http://www.parentprojectmd.org/site/DocServer/PPMD2007Poysky.pdf?do...
may be more what you are looking for......as it explains what cognitive issues have been observed in boys with Duchenne (rather than trying to explain why)

Hope that helps,

Jules :)
Comment by Julie Gilmore on November 6, 2009 at 2:13pm
Hi Cori,

Well papers not finished *sigh* but I needed a break so here I am!

Where to begin? With a quick 101 in genetics I think. While some genes produce only 1 protein, others are able to produce multiple proteins, either through alternative splicing of exons, or the presence of additional promoter sites within the gene. These proteins share structural similarities and are called isoforms.

The DMD gene produces at least 9 isoforms of dystrophin - 8 through unique promoter sites, and 1 by alternative splicing. Mutations within the gene resulting in a loss of reading frame can affect the expression of a single isoform, multiple isoforms, or (in rare instances) all isoforms depending on the location of the mutation.
Therefore if the location of the mutation is known, you are able to predict which isoforms will be affected.

(Now this is where things start to get interesting).

I am sure you have noticed by now that boys with mutations in the same exon do not necessarily progress at the same rate. This is because there are many factors affecting how the muscle responds to physiological stresses when dystropin is not produced. Likewise, the symptoms associated with loss of dystrophin in neural tissue varies between individuals - even if they have a similar mutation.

Even with the knowledge that has been gained into the role of dystrophin in the brain the exact clinical symptoms for each individual can not be determined by mutation location alone. This is because we are very cleverly designed, and organs that are vital to our survival often have "substitute" proteins that can be perform a similar function if a core protein is lost due to genetic mutations. (You would all be familiar with utrophin - this is one of the proteins that is very structurally similar to dystrophin, and has been proven to function in a similar manner.)

Even though the roles of the isoforms are slowly being discovered, researchers are still a long way off understanding all the compensatory mechanisms that "kick in" when dystrophin is not produced. Therefore (like in muscle) the neurological symptoms observed in each child are unique.

So what does that all really mean? As Pat mentioned your sons mutation has not been show to result in severe intellectual problems, but given that you have note how bright he is, I am guessing you are more concerned about the comprehension issues.

Loss of the longer isoforms of dystrophin can result in a whole range of clinical conditions that are quite often able to be overcome by things such as a change in teaching technique, or with the help of an occupational therapist. Therefore if you feel that your son is having a problem grasping concepts as quickly as the other children, and this will be detrimental to his learning, I would speak to your doctor about having an assessment done, so you can implement an IEP (individual education plan) if required.

Now this may seem like a cop out answer, as I have not gone into the nitty gritty of the function of each isoform. But the reality is these protein interactions are so complex, to try and fit the information into a short and easy to read post is near on impossible, and may create more confusion and stress than putting nothing at all. I guess the best way I can sum up the neurological symptoms in each child is with what I have learned throughout our journey with Duchenne:

The hardest lesson I have had to learn while watching our son battle Duchenne, is that sometimes knowing the reason WHY something has happened, does not change the outcome. Knowing which cells and signalling pathways may be affected in our sons brain does not change how he will go at school tomorrow if we don't ensure his learning difficulties are addressed today.

I really hope that helps you out Cori, and forgive me if it is a bit jumbled - it's 3am here!

Staff
Comment by Pat Furlong on November 6, 2009 at 1:05pm
Hello Everyone,
First, I apologize, was in a rush this moring with some family issues. Thankfully Julie Gilmore connected with me and I am here to re-trace my steps. I was trying to explain as well as provide some bit of reassurance about intellectual issues.
I posted the Leiden link for you to see the location of different promoters.
Your son (exon 52) has an out-of-frame mutation, which means that while the promoter is present for brain dystrophin, the fact that the mutation is out-of-frame, means that the isoform would be lost.
But in the databases/registries, we typically do not see severe intellectual problem with this deletion.
Sometimes all this is clear as mud!
Warm regards,

Staff
Comment by Pat Furlong on November 6, 2009 at 8:33am
Hi,
Dystrophin isoforms refer to the various transcripts of Dystrophin found it other tissues- basically shorter versions of dystrophin that are initiated in different regions of the gene. There is a very good explaination on the Leiden
http://www.dmd.nl/isoforms.html You will see the promoter for brain dystrophin is early in the gene and we would not expect to find the absence of brain dystrophin with mutations in the region of your son's mutation (52).
Warm regards,
Pat
Comment by Cori on November 6, 2009 at 2:23am
Julie... I ABSOULUTELY CAN NOT WAIT TO HEAR ABOUT YOUR RESEARCH!!! SO excited...this is definitely one thing about DMD that I absolutely feel completely idiotic about and can't find any information anywhere...

Jenn, you totally described Trey to the T...amazing vocab, and his event memory, yeah, WOW! He remembers stuff that I have long since forgotten and he remember it always once he learns it, just sometimes it seems to take him a little longer to get it then most other children, but once he gets it he gets almost 'stuck' on it... It definitely helps, do your boys have the single point deletion of 52 as well or does their deletion include 52 and other exons, I haven't had the opportunity to find anyone with the single point deletion as Trey has.

Darcy, Trey's short term memory is bizarre, I don't think he has short term memory problems, but linking stuff together like numbers, abc's he often needs cued to get him going again...I have been told that it is probably an auditory processing problem, but he is too young to know for sure...and I was looking at your page, and about the handwriting, why don't you have an IEP if you don't mind me asking? Trey didn't really need one, but we got one for him so that the teachers would have a little bit of awareness as to what was going on with him and it has helped tremendously since on the outside when you look at our little Trey you wouldn't have a clue...I just saw your handwriting issue and I thought that maybe his teachers are a little oblivious to the situation and need to be educated, which is what the IEP is all about, teaching the teachers how to understand your child a bit more. I didn't initially want it to be honest, because I didn't want to admit to myself that he needed it or have him 'labeled', but it has been a blessing for us...
Comment by Darcy Tumminello on November 5, 2009 at 8:02pm
Hmmm, interested in learning more. My son has deltions 51-55. Very intelligent and has excellent long term memory. I do catch him questioning the short term memory loss and if I drop hints, he eventually remembers. He had a little trouble between K and 1st grade reading but took off in 2nd grade. Overall, doing well in school. No IEP or aid at this time.
Comment by Julie Gilmore on November 5, 2009 at 7:39pm
Cori I am literally finishing a paper off on the isoforms of dystrophin as we speak (should be working, but find myself distracted once again). I will post a reply to you as soon as we are finished, as I have all the papers regarding Dp260 and Dp140 sitting here...... (in a huge cluster of "mountains" around me!) I did do a reply for you, but there was a huge typo, and the system would not let me edit my reply - only delete it :(
Comment by jenn on November 5, 2009 at 7:18pm
while im not sure i can explain isomers, i can tell you that i have 2 sons with a deletion of exon 52. the boys are 7 and 10, and both have normal or above average intelligence but have learning difficulties that look a lot like dislexia. they both have a hard time reading and understanding math but have an amazing vocabulary and an event memory that far surpases mine! i think every boy is different im not sure there is a simple answer to your question but, i do find that there is a similarity at least in the way my boys function. hope it helps!

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