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 :-).