Saturday, February 14, 2015

Guanidinoacetate Methyltransferase Deficiency

I love to research and to create theories from that research. I'm not talking about theories of aliens that have been supposedly visiting our planet for centuries or conspiracy theories regrading fake moon landings, as humorous as they may be. I do however, enjoy reading scientific based theories that have been studied, documented, and published, in an effort to educate.

I have read literally thousands of abstracts and articles on epilepsy. Obviously, I do this in an effort to see if there is anything that might be applicable to Mira, in the absence of a definitive diagnosis. Most are irrelevant or things we have already tried. Many are so technical in nature that as a lowly architect, I can't begin to understand the complexity of the study at hand. Mira's neurologists have speculated that she has a genetic mutation of some sort, but have failed to pinpoint a specific relevant mutation, mosaicism, or deletion in any of her genetic screens thus far. So, I continue to read.

A few weeks ago, I stumbled on a very unassuming interactive website that investigates (granted on a very limited basis) the scientific research behind the supposed health benefits of  some common vitamins and supplements. Frankly, I didn't think much of it, since I have read quite a bit on a majority of the vitamins, herbs, and amino acids they had listed in the chart. There is no shortage of opinion-based supplement literature floating around in cyberspace.

On the website, you can hover your mouse over the chosen supplement selection and it will provide an external link to the research behind the claim. Most, if not all of the supplements on the chart only provide a single source of data and/or study, thus provides an extremely narrow perspective on the research behind the claim. The top of the chart provides links to supplements with the strongest supportive evidence, again, based on a single linked source. As you work your way down the chart, the evidence diminishes in regards to the specific claim, yet many supplements are represented multiple times in the chart, as they have multiple claims of health benefits associated with them.

To be honest, I was most intrigued by the interactive nature of the chart and at first, paying little attention to the actual supplements being investigated. I then pursued some of the links that I have read extensively about, including vitamins D, E, and B12, glancing over some of the data provided. As I returned to the top of the page, I was most interested in reading something new and trying to find something I new nothing about, which happened to be creatine and its claim of having cognitive benefits.

Creatine was one an amino acid which I had only briefly scanned in all of my readings and to see it not only listed in the top of the chart in the strong evidence category but also having an association with cognition, I was hooked on finding out more. I was prepared to be redirected to a site along the lines of or a random advertisement, so I was pleasantly surprised to end up on a Pubmed server for its link. The abstract regarding the connection between creatine and cognition was very brief, but cited a host of references for further reading, as most Pubmed articles do.

Until now, I had only a limited association of creatine with muscle performance, but nothing beyond that. So, I started digging. I found creatine had some broad reaching effects on not only athletic performance, but ironically, on seizure activity. I discovered, through a rabbit hole of references, that creatine was actually implicated in a few rare, but debilitating epileptic syndromes, including guanidinoacetate methytransferase deficiency (GAMT), arginine-glycine amdinotransferase deficiency (AGAT), and creatine transporter deficiency (CT-1). I happen to find a dozen or so articles on these three creatine transport defects and focused my attention on this article and also this one, regarding GMAT.

All three of these syndromes are connected through a defect involving the transport and metabolism of creatine in the brain. I won't go into the specifics on each, but GAMT seemed most applicable to Mira's situation. It basically involves the build-up of guanidinoacetic acid in the body, which happens because of a defect in a gene (SLC6A8 and similar functioning genes) involved in the transport of creatine. This failure of the brain to properly process and transport creatine, causes encephalopathy, seizures, hypotonia, developmental delay, and autistic-like features.

There is no denying that epilepsy is complicated and the brain is equally complicated. There are a myriad of issues that can cause a seizure, from metabolic disturbances, to genetic defects, to structural problems, to everything in between. Trying to pinpoint a single root cause of why Mira has been having daily seizures for the past 9 1/2 years has been elusive and will most likely, continue to be so. For now, I am very intrigued by the notion that creatine, GAMT in particular, is somehow involved.

When Mira was about a year old, she had already been through a battery of genetic testing, MRIs, and EEGs, with no conclusive reason why she was having seizures. Her neurologist at the time mentioned possibly doing a creatine study on her, but the chance of it yielding anything were slim to none. Mira ended up having a MRI with spectroscopy, but it didn't reveal anything. What I had read through these articles is that sometimes, a MRI-S can help in the diagnosis of GAMT, AGAT, and/or CT-1. Her neurologist at the time mentioned this in his notes, which we have a copy of.

My theory for now is, that some sort of creatine transport issue is something to pursue with Mira. After reading the studies and their therapeutic approaches to managing a creatine deficiency, it basically comes down to a trial of creatine monohydrate. Since there is no risk of toxicity or side effects (even at very high dosages), we are supplementing Mira's diet with a ratio of it. I figure one of three things can happen: 1. she gets an energy boost from it, helping to also possibly support muscle stamina or 2. it does nothing for her or 3. she truly does have a creatine transport issue and it will help restore her creatine levels and ideally, help with her seizures and/or development.

I'm certainly not banking on scenario number 3, but am staying optimistic. Mira has been trying the creatine for the past 4-5 days, without a whole lot of change, until today. In terms of seizures, nothing has really changed, as she had another big tonic-clonic this morning and continued to have a ton of myoclonics this afternoon. No surprises in that department. Interestingly though, Mira did not fuss a single time the entire day today. Not when she woke up, not when we gave her a bath, not when she wanted a nap, and not even during the notorious Unhappy Hour, from 3:00-5:00pm. It was really strange to not hear her complain, cry, or become irritable, not even once.

It could be total coincidence, a really lucky day, or it could be something more, but whatever it was for her today, I don't care. Mira was happy. She was even smiling and giggling at a few times during the day. I would love for the creatine theory to be proven, but it is way to early for that to happen, as it takes months to restore and maintain creatine levels sometimes.

Seizures aside, I'll take Mira having a really positive day for now.

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