Friday, September 11, 2009

Becca's Story

Since we want this blog to be a record of our journey with Rett Syndrome, I thought it would be a good idea to record a little bit about Becca's life so far.

March 20, 2007. Rebecca Jane Whitmer joined our family. The second I laid eyes on her I knew she was special. I can't really describe it in words. It was just a strong feeling that I was extremely blessed to have such an amazingly strong and special girl as a part of our family. The first part of her life was quite uneventful. She was a healthy, happy baby and very content most of the time. Her only problem was that she didn't know how to suck when she was born. It took her until she was two months to learn to nurse. Looking back on it we now realize that she was a floppy baby. She learned to lift her head a little bit later than other babies and it sure seemed a lot harder for her.

By five months Becca was really good at rolling from her tummy to her back and she wasn't consistant at rolling from her back to her tummy until she was seven months. But she was quite the roller.

The first time we really started to worry about Becca was at around 9 months. We would try to get her to sit and after a few seconds she would fold in half and then she couldn't get back to sitting. At around 11 months she wasn't really any better so we signed her up with the early intervention program. She started up with physical therapy right away and within a month we saw a big difference. She could get herself back up to sitting if she folded in half. Also around this time we noticed that when Becca would get startled awake she would shake really bad (looked like arm and leg convulsions). We didn't think it was a seizure because she would look us in the eye when it happened, but other than that, it looked like it could be a seizure.

Around this same time Becca had her first of many tests. She didn't like (and still doesn't like) to put weight on her right leg. She had an ultrasound of her hips and everything looked great and normal! Her second test came when she was about 14 months. The doctor referred her to a neurologist (Dr. Benedict) at this time and she recommended that we get an MRI to make sure nothing was wrong with Becca's brain. Once again, completely normal!

Next on the neurologist's list of things to try was an EEG. This test would be done when Becca was asleep and would show us if she was having seizures (at least during the test anyway). This test came back abnormal, but there was no actual seizure activity. So, once again, no answer. It only could tell us that Becca may be prone to have seizures. At this point, Dr. Benedict was almost positive that Becca had Angelman Syndrome. We definitely didn't agree. But, Dr. Benedict referred her to a geneticist (Dr. Rope) which we thought was a good idea.

Around 18 months Becca started figuring out how to get up to sitting all by herself! We were so thrilled! She would get up on all fours and then push up to sitting from there. This was a huge improvement. I remember that one of the most exciting things for me was to see Becca sitting up when I went to get her from her crib. But it was sort of bittersweet, because her shaking was getting worse. She would shake whenever she felt unsteady or got scared.

At 22 months we took Becca to see Dr. Rope. He was almost 100% sure that it wasn't Angelman Syndrome. Yay. But, he was also not convinced that it was anything genetic. He told us of a few tests he would do if he were to do testing. But, he didn't want to right away partly because it's harder to get insurance to cover at that young age and partly because it's easier to diagnose when they're a bit older. Besides, he thought it was neurological. So, we were sent back to Dr. Benedict with the idea that we would come back to see him in a year and at that point do testing if things hadn't improved. Dr. Rope also told us to contact him if Becca were to ever be admitted to the hospital. Apprantly, insurance will pay for some genetic testing if she were in the hospital. So silly.

At about 24 months Becca started crawling! Not like crawling all over or anything. It took her a ton of motivation and prompting to get her to crawl to a toy. But, she was moving a little more and playing in kneeling position. We were so excited to see these little improvements.

Things were moving along with not much improvement. We had noticed that Becca had started doing this patting motion with her hands basically all the time. She wasn't able to use her hands to pick up small things anymore (no more self feeding). Also, her shakiness had gotten quite a bit worse to the point that it was hard for her to get to her toys and play with them without falling over. She was still putting everything in her mouth and biting everything she could get her hands on. We attributed this to teething (2 year molars are brutal). But it's not like this was a sudden change. It had been quite gradual, so we didn't notice it right away.
Then one morning (about 26 months) Becca had slept in quite a bit later than she usual does. Then I heard her crying in a different way than I had ever heard her cry. It wasn't really loud, just a soft really sad cry. I went to get her and when I picked her up I noticed she was really floppy. But, I had to nurse our other child so I placed her on the floor in front of me and figured she just had to wake up. When Brian came out and picked her up she was like a wet noodle. He could hardly hold her because she was just slipping through his hands. Needless to say, we were really scared. She was just laying there not moving and when we would try to get her to sit up she would just moan. I gave her a drink and just let her lay there while we tried to figure out what we would do. And then, about a half hour later, she was fine. Not 100% back to normal, but she was moving around and acting pretty much like she normally does.

We luckily got an appointment with Dr. Benedict that afternoon. She told us that it sounded like she may have had a seizure before I went in to get her. But what she was most concerned about was that Becca seemed to be doing worse. So she had us schedue her to have another MRI and EEG the following week. And the results from those tests came back exactly the same...normal MRI, and abnormal EEG with no actual seizure activity.

With those results, Dr. Benedict decided it was time to come up with a reason for Becca to be admitted to the hospital so that she could be tested for a couple genetic disorders. Dr. Benedict had her admitted for a 48-hour EEG. While she was there she had a couple genetic tests one being the test on the MeCP2 gene (Rett Syndrome). She also had an eye exam and a swallow study. Both were normal. Of course.
That brings us to August 25, when we received the results telling us that Becca has Rett Syndrome. I'm sure I will never forget what it was like to receive that news. It was such a strange mix of relief and complete devastation. We had been wanting to know what was wrong with Becca for all this time and yet, I couldn't help but have a small part of me feel like I didn't want to know after all. But, we take it one day at a time. We have our hard days and our easier days, and I suppose that's how it will always be.
I had a lot of fun putting together a slideshow of Becca's life so far. Becca has always been such a beautiful, happy girl. I sure love her.

Sunday, September 6, 2009

Official Genetic Results

Well that was an interesting experience. We got a phone call last week with the official results of Becca's MECP2 tests. If you recall, before they told us they found something abnormal on Becca's test, but weren't sure what it was and they wanted us to get tested to confirm. When we finally got the call about Becca's test, Dr. Benedict (the neurologist) just said the test came back positive for Rett. She didn't say anything about the questionable-ness of the test, and we weren't entirely sure she got the final results instead of the intermediate results. Dr. Rope, the geneticist, called a few days later to set up an appointment to talk in more detail, and when we met with him we asked for clarification on our test results. What he said is that they asked for our tests for an independent study they were doing to double-check that there wasn't a correlation between parent and child in Rett cases or something like that. He said it was kind of inappropriate for them to not tell us that up-front, but at least we got tested for free and now know that Paula isn't a carrier.

Dr. Rope talked about a lot of stuff that I found interesting, and I thought I'd share. Keep in mind this is what I understood, so it's not necessarily 100% accurate, but it's probably more than you ever wanted to know anyway, so whatever :-).

The MECP2 gene, which is linked to Rett Syndrome (and some other issues, like autism and lupus), has four transcribed regions (exons), with exon 4 being the largest, which are involved in the process of generating the MECP2 protein. Mutations in one or more of the MECP2 exons can result in a malformed MECP2 protein and a common set of side effects known as Rett Syndrome.

In Becca's case, the mutation is on position 403, where she has a G nucleotide instead of an A in one of her X chromosomes (c.403A>G). Position 403 is part of the methyl-citosine-binding domain (MBD), and is on exon 4 which starts somewhere around nucleotide position 390 or amino acid position 130. This mutation is on the rarer side, 2 cases in 424 for the study I saw.

As a result of the mutation, the structure of the protein is altered because an amino acid is changed from lysine (AAA or AAG) to glutamine (CAA or CAG) (p.Lys135Glu or K135E, although if you search for K135E you run into a bunch of articles on Werner's Syndrome, which is this weird disorder where you age faster than normal). Lysine is a small, neutrally-charged amino acid, while glutamine is much bigger and negatively charged. As a result of the change, the protein can't 'fit' where it would have before, which causes problems. Dr. Rope said a few times that while the MECP2 mutation is a cause of Rett Syndrome, he thinks it's not the only cause, and that it's actually something that happens farther 'downstream', which is why some people test negative for Rett genetically with a positive clinical diagnosis.

Anyway, because all of this happens on the X-chromosome, it's not active in all cells. On a guy the X-chromosome is always activated, so an MECP2 mutation would affect every cell, which is why the only real male Rett cases have other problems (like Klinefelter's, where they have an extra chromosome, XXY). Since each cell only activates one chromosome, not all cells will have an active MECP2 mutation, and the ratio of mutations apparently relates to the severity of the disorder. X-inactivation is supposed to be random, which would put it at 50-50, but there can be reasons for it to not be completely random. Because Becca's case is somewhat abnormal and on the milder side, the assumption is that she doesn't have as many mutated cells as the common Rett case.

Oh! I just figure out what this lab report was talking about! The report said, "K135E was previously reported in several patients with classic Rett Syndrome; however, parental studies were not performed to confirm de novo occurrence. Another study found that K135E imparied the function of the MeCP2 protein." I didn't figure out until a minute ago that K135E and the Lysine-Glutemine problem were the same thing (although I'm still not sure what the 135 means in that... lemme know if you do!). So from that and Dr. Rope's comment, it sounds like the folks at ARUP are trying to show that the K135E mutation is not inherited ("de novo" mutations are new mutations, not inherited).

I actually thought all of that was really interesting. Maybe just because it's my daughter, I don't know. But none of it really helps in knowing what to expect for Becca's future. We did ask those questions of Dr. Rope as well, although he didn't have as good of answers. It's not his fault or anything, there's just not as good of answers to give. Andreas Rett first describe the syndrome in 1966, and since then there's been studies and things, but mostly on a clinical level. The genetic link wasn't discovered until 1999, so there's not really a lot to go off of. The cases that have been studied are those that matched the common case (which Becca's doesn't), and were diagnosed without genetic testing (which Becca wouldn't have been), so it's hard to say.

I'm still doing a lot of reading and studying on typical Rett (they call it RTT, I guess because that extra "e" in there was just too much to handle), and I don't know a whole ton more than I did before. I've been doing most of my looking on a technical level, though (interestingly enough, the report we got back from ARUP on Becca's lab results cross-referenced a couple papers on Rett, and they were the exact same ones I kept finding in my searches... I couldn't read them because I haven't paid for the journals, but maybe I can get to them on campus or something...). I'll start looking more normal places now for more general information.

Anyway, this post is totally just for the curious -- and in reality, probably just for my own benefit in the future. I assume this blog will change somewhat since we now have a diagnosis. Paula and I both agree that we'd still like to keep this blog going, in case it can be of use to someone else trying to figure out their own diagnosis or whatever (plus there's plenty more we'd like to share about Becca than we feel we can do without overloading the family blog), so stay tuned :-).