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 Julie Gilmore on November 17, 2009 at 6:08pm
Hi Cori, sorry for the delay - few issues this end that had to be sorted out :(

OK..... Retina - the main problem we found in several research papers was color blindness....however once again this doesn't affect all boys. I have checked with a few mums whose sons have mutations in this region, and very few are color blind.....

Kidney - there is very little information on the kidney, however as dystrophin isoforms have been found to be aquaporin anchors in other organs, it is fair to assume they have a similar role in the kidney. Very few boys have kidney issues as a result - however consideration must be given as to how much load is placed on them, above and beyond normal physiological limits.

This makes it really important to check with your Drs before starting any over the counter supplements that may put undue stress on the kidneys and/or liver, and keeping fluid intake up, but not to the point where it is excessive.

Incomplete bladder clearance is the main cause of UTIs and the boys are at no more risk that the general population. There are some that experience incontinence, however this is largely due to loss of muscle tone in the sphincter, rather than a problem with the bladder.

All in all the secondary problems associated with Duchenne are largely undefined, for 2 reasons :
1) for a symptom to be recognised as being a secondary complication to a condition there must be an increased percentage of patients that exhibit the problem. Problems associated with the loss of isoforms do not present in great enough numbers to be recognised at this time
2) even with the change in function in some organs, their influence over the progression of DMD is minimal - therefore maintaining muscle mass still remains a priority. (as it should)

So I guess the best advise I could give you right now is to be remain aware of the changes that may result when other isoforms are lost, but don't panic. The risks of complications are very low. The blessing in all of this is that our boys are all closely monitored, so if any other problems develop, the Drs will pick it up a lot earlier than a child without a chronic health condition.

Hope that helps,

Jules :)
Comment by Cori on November 7, 2009 at 9:09pm
Okay Miss Julie =), thank you for taking the time to reply, I am still so lost LOL...here I am a Physical Therapist and can't even quite come to understanding this, I feel like a dummy =)!

I am not so concerned with Trey's comprehension issues, he is getting all the help he can possibly get, and really the problem is not that big of a problem...Thankfully at this point Trey is a completely normal 5 year old without any huge signs physically, and just some minor problems regarding the learning...

What I am trying to understand is that okay I understand that he is missing DP260 which effects the retina...how exactly does it affect the retina, does it make his eyes more sensitive, should we be prepared for visual problems, etc?

And then DP140 effects the kidneys and cerebellum, which may account for his needing of being taught in a repetitive nature to 'get things', but does it signal that he potentially will have kidney problems in the future and should we be cautious of those types of things like bladder infections, making sure he drinks enough water (always do anyways)?

If you have the time I would love to hear back from you!

Cori
Comment by Ofelia Marin on November 7, 2009 at 10:40am
Thanks Julie...so this isoform does not work as the large one for muscles where in-frame mutations in the central rod domain can still produce DMD like phenotype (protein is not functional).
Comment by Julie Gilmore on November 7, 2009 at 4:49am
There should be no change to the function of this isoform.

A deletion of exons 52-53 will result in a mutation in the central rod domain (around SLR20). As this SLR is not required for protein binding the truncated isoform should still be functional.

:)
Comment by Ofelia Marin on November 7, 2009 at 4:18am
Thanks Julie. You are correct about the neural tissue response to mutations. I do know 2 boys with those mutations not having any learning problems at all.

So my question should have been: in the case of of an in-frame 52-53 deletion, Dp140 is expressed but shortened, will that still produce the same "problems" as missing Dp140?
Comment by Julie Gilmore on November 6, 2009 at 11:38pm
Ofelia the promoter is in intron 44, and the initiating codon in indeed in exon 51. Therefore the mutations you described should result in the loss of Dp140 expression. However, as mentioned earlier the neural tissue response to mutations in the DMD gene is vastly different to that of skeletal muscle.

These papers (although old) may shed some light on the situation:

Wilson J, Putt W, Jimenez C, Edwards YH. Up71 and up140, two novel transcripts of utrophin that are homologues of short forms of dystrophin. Hum Mol Genet, 8, 1271 - 1278 (1999).

Mehler MF. Brain dystrophin, neurogenetics and mental retardation. Brain Research Reviews, 32(1), 277-307 (2000).
Comment by Ofelia Marin on November 6, 2009 at 11:20pm
Is the intiating codon for Dp140 in exon 51? So even with an in-frame mutation of 50-51 or 49-51 the initiating codon will be missing.
Comment by Ofelia Marin on November 6, 2009 at 11:11pm
If the promoter is still present (is this in intron 44?) but we have an in-frame mutation on hinge 3 for example (let's say deletion 50-51 or 49-51)? So Dp140 is produced but those exons are missing. What is the impact on the brain?
Comment by jenn on November 6, 2009 at 9:39pm
cory, yes, my boys have a single exon mutation of 52
Comment by Julie Gilmore on November 6, 2009 at 7:27pm
In what regard Ofelia? The possible loss of the hinge function, or the possible loss of the initiating codon for Dp140 (the only isoform predicted to be affected by inframe mutations in this region)?

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