Imagining the effects of Glutamic Acid…

Thi sis how I picture the GABAergic and glutamergic cycles affecting Dup15q kids.  It’s highly hypothetical and I’m not a scientist. But this is a blog I’ve made with the intention of getting the goat of real scientists so they’ll prove or disprove me… 😀

(Edit, January 31, 2016.  I am not sure if having extra glutamine in the cells affects free glutamine outside the cell.  One of the parents commented on a different source that their kid had normal glutamine and it was confusing to them as glutamine overload was such an expectation of an autistic child.   If my understanding is correct, it’s only going to be higher because of GABA; and only in the cells where extra GABA has flooded through on those myriad extra GABA-A receptors our kids have.  The work of Yehezkiel Ben-Ari in France shows that kids who have intractible seizures extra chloride inside the cells- our kids definitely tend towards that kind of seizure, and chloride piggybacks into cells alongside the GABA-turned-Glutamic.   He sees improvements in tiny clinical trials of drugs that flush chloride out of the cells- and effectively, leaving less to transport GABA through the nerves, as well.  Makes an interesting theory, to me, of what goes on in our kids)

So, if this only goes on inside the nerve cells themselves, SOME of the metabolic changes of dup15q would only be visible in, say, a nerve cell biopsy.  Excitingly enough, this is the kind of biopsy that Dr. Reiter is working on, with nerve cells derived from lost baby teeth, at the Memphis clinic.  It wouldn’t be likely, in my mind, to show up in the blood, or even spinal fluid, because it would be specific to what is going on inside the nerve cells themselves– something we would rather hope we weren’t getting samples of in a spinal tap!!)

Imagine that a cell is a box and the gaba receptors are kids tossing legos into the box… they transport the legos into the box or wherever. And they do it a specific way. There are lots of legos, but every time a blue square lego is connected to a yellow square lego, that’s gaba. So they yank the yellow part off and toss in the blue. The blue by itself is glutamine. Then you have a bunch of kids in the box trying to put yellow blocks back on the blue blocks and tossing them back out. It only works if you have enough kids inside the block to make up for the kids tossing in blue blocks. Then imagine someone dumps a big bucket of blue blocks in– gluten, glutamine– and the kids in the box work even harder. And then you have a bunch of extra kids outside the box because of Dup- and so you get even more blue blocks. And then imagine that there’s someone running around inside the box taping together the hands of the kids inside the blocks becuase our detox enzymes that make it possible to move the glutamine back out is on the same part of 15q too. This makes it very hard for doctors to sort out where to start treating Dup. . BUt it makes NAC a great place to start. It takes the tape off the kids’ hands. Gluten free and low glutamine diets keep the dumping bucket away, and there are also ways to slow down GABA. But that’s only one component of Dup. It does make me very hopeful.

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NIPA2

This is one of those blog posts that probably won’t interest anyone else out there, especially not very many in the 11.2-13.1 duplication region.  I’m trying to figure out if there’s any link between the cause of my disorder (dopa-responsive dystonia) which is usually caused by a genetic mutation of the GCH1 gene, and the duplication that Anneliese has.  I have no guilt in this search, mind you.  But, if I turn out not to have the GCH1 gene mutation, I’m going to turn to looking into genes on 15q that are related to dopamine production.  So far tonight, I was most interested in NIPA2.

The Dup15q family does most of their research to try to reduce the severity and delay the onset of seizures, which are a dangerous factor and have lead to a slightly high rate of sudden death among our kids.  It’s a difficult topic to absorb, and the way that doctors advise us of this increased risk makes most of the group hyper aware that any night of our child’s life, they could go to sleep and never wake up.  Most of us will get to see our children age.  But the risk and history of alarming deaths in the Dup population seems most related to the kinds of seizures kids have, and the types of medications they are taking.  Benzodiazepines are riskiest.  For those parents with newly diagnosed, pre-seizure kids–sleep while you can.  It’s a risk at any time, but it’s not a huge risk right now and you’ll need so much more sleep later.

Dup comes with other unique features, though, like slowing of social and intellectual development– or at least, a lack of use of social and intellectual skills which may or may not be stored in the brain.  It’s painful to watch Anneliese’s discouragement when she tries new things.  Also, the kids’ skeletons develop differently– cartilage areas kind of seem to be smaller so that their chests can cave in/out and their noses are short and cute.   Oh, so cute!  Their ears are underdeveloped so that they are low on the head and rotated to the back.  Their eyes look like precious moments’ eyes, and their lips are precious little rosebud tents.  I love Dup kids.  They’re downright gorgeous.  They have features of Autism.  They love to be touched (most of them do….), and are commonly extra fond of books and music from a young age.  They have features in the way they use books that make them look like they would be early readers, but as of yet, that hasn’t been the case for most of the Dup kids.  It’s a goal I have for Anneliese, because she’s never very far from her bookshelf.  She will sit for hours with her books, looking at each page and turning them.  She will do the same with novels that have no pictures, even!

Anyway.   I have another disorder entirely that is also genetic, but sometimes has an unknown genetic cause.  So I’m tossing out a candidate gene for later if I need one to research.  NIPA2 interests me because having lots of little changes (calls SNPs) on this gene is  involved in Schizophrenia risk… and another gene that has increased risk with lots of SNPs is called COMT.  COMT eats dopamine.  Lots of COMT means your body is aching for more dopamine.  So I’m thinking the two may be related… maybe?  This is the joy of not finishing (erm, starting) grad school or med school.  I have to guess a lot.

Anyway, it’s time for bed so I needed a place to pin this down that wasn’t my Facebook group for Dup15q and chose you, dear reader, to bore in addition to the facebookers who may or may not have been interested in my post on dup15q.  So far I have saved myself some information that says there’s a zebrafish model of NIPA1 and NIPA2 gene expression that is used for Prader-Willi syndrome research (another disorder in the same area on this chromosome).  I also saw that NIPA2 is related in some way to diabetes and magnesium intake reduces the risk of diabetes when NIPA2 has this one particular format.  Since I haven’t got full-text access to studies, I haven’t yet gotten a good clue how they came to this conclusion.  However, it shows that the gene is related to magnesium metabolism, neurology, and the use of insulin in the body- which includes certain organs and certain points in the brain and certain nerves and certain parts of the blood.

I like looking at each gene in depth.  It gives little clues to what we’re dealing with.  My daughter’s previous neurologist was rather non-plussed about current studies of gene expression- it’s all interrelated and highly variable and not direct enough in its relationships to effects to interest him.  But I believe in learning, and I believe in helping.  This is a clue.  I love puzzles!  Let’s solve the puzzle! 😀

For reference reading:

Magnesium, diabetes, NIPA2:
http://www.ncbi.nlm.nih.gov/pubmed/25733456

Microdup11.2 Gene variance in PWS
http://www.ncbi.nlm.nih.gov/pubmed/16982806
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346944/#B6-ijms-16-04068

Zebrafish model team posted an explanation of their work here:
http://www.pwsausa.org/get-information/researcher/Articles%20and%20Abstracts/History%20of%20Conference%20Abstracts/History%20of%20Conference%20Abstracts%202012.pdf

Duplications, deletions, and mutations affecting Schizophrenia:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3456994/