Acceptance and Genetics

There's a change going on for me at work that has come unexpectedly. It's one of those changes that is, I am quite sure, ultimately for the ultimate good, but---just as changes aren't so easy for Charlie---so this one is slowly settling in with me. Don't worry, I most assuredly still have my job; it's just that some things are shifting and in ways that are (again) ultimately for the better and not only for me, but for things in general at work.

Still, the sad feeling's there and, driving home with Charlie today---Jim had gotten him off the bus and met with Charlie's teacher for a home visit, and then they'd driven into Jersey City to my office---I realized that I'd had this feeling before. A feeling of a necessary change that portended a significant shift in the established order of things; a change that, I understood, must run its course, and it was up to me not to get stuck in wishing things could be the way they used to be, and direct my energies to moving forward.

You could say I've had a bit of practice managing these sorts of feelings in myself, from learning to accept that Charlie is autistic to reflecting on how autism in Charlie is connected to the various diagnoses, traits, conditions, what have you, of my own family and of Jim's. The cause of Charlie being on the autism spectrum that makes the most sense to us is genetics and yesterday three new studies on the genetics of autism were reported. As noted by NIH News, all were genome-wide studies, which involve the scanning of the genome (the entire set of DNA) to identify differences (potentially small) between those who have a condition and those who do not. The largest study involved more than 10,000 participants, including individuals on the spectrum as well as their family members and volunteers across the US (you can access a PDF file of the study, Common genetic variants on 5p14.1 associate with autism spectrum disorders). As noted on Science, the three studies focus on DNA that had been previously overlooked in research on the genetics of autism; the new research highlights cell adhesion molecules, which play a roll in the connectivity and "wiring" of the brain.

There's a rift (understatement) about what causes autism, with people tending to believe that autism is something one is born with (and genetic), or that autism is something one "gets" (from an external agent). Jim and I do think that Charlie was born with autism; certainly we see more and more about him that is like us, and that connects him to us, every day, and I guess there is some of the sadness I mentioned at the start of this post in this. A parent thinks, what did I "give" to my child?

Then I think, whatever happened, so it is, and sure there is sadness, but---for me now---fighting it off, in warrior mother mode is not an approach to truly helps Charlie. But finding out how he learns---and learning about why that is, by studying neuroscience and genetics---does.

NIH News summarizes the three new studies:

In [the first] study, Dr. [Hakon] Hakonarson [of the University of Pennsylvania School of Medicine] and his colleagues found several genetic variants that were commonly associated with ASD, all of them pointing to a spot between two genes on chromosome 5, called CDH9 and CDH10. Both genes encode cadherins – cell surface proteins that enable cells to adhere to each other. The researchers also found that a group of about 30 genes that encode cell adhesion proteins (including cadherins and neurexins) were more strongly associated with ASD than all other genes in their data set. In the developing brain, cell adhesion proteins enable neurons to migrate to the correct places and to connect with other neurons.

In a second study, Dr. [Margaret A.] Pericak-Vance completed an independent search for small genetic variants associated with ASD, in collaboration with Jonathan Haines, Ph.D., of Vanderbilt University Medical Center in Nashville. Published in the Annals of Human Genetics, the study provides a striking confirmation that ASD is associated with variation near CDH9 and CDH10.

"We are starting to see genetic pathways in ASD that make sense," says Dr. Pericak-Vance.

Finally, in a third study, reported in Nature, Drs. Hakonarson and Schellenberg led a search for genes that were duplicated or deleted in individuals with ASD. In the rare cases where those variations occurred, many tended to affect genes involved in cell adhesion. Others tended to affect genes involved in the ubiquitin-proteasome system, a cellular waste disposal system that probably affects the turnover of adhesion proteins at the cell surface.

Previous, smaller genetic studies reported a connection between male-only autism and CNTNAP2, a type of neurexin. Together, the three new studies suggest that genetic differences in cell-to-cell adhesion could influence susceptibility to ASD on a large scale. Dr. Hakonarson and his colleagues are planning an even more extensive genome-wide association study to gain a more complete picture of the genes and gene interactions involved in ASD.

(Also see Not Rocket Science.)

What stands out to me about these studies is the findings about genetics and the brain, about the role of cell adhesion proteins in the functioning of neurons and in connecting neurons to other neurons. Whatever is said or observed about Charlie's cognitive abilities, if you spend time teaching him, communicating with him, playing the piano, you can see that he's absorbing everything around him. But making the connections about all of that and then making still more connections to communicate what he's observed, what he thinks about it, what he wants to tell us: At each of these junctures, it seems like something gets (if I may lapse into an electronics metaphor) short-circuited. "'We are starting to get convergence around genes that affect how synapses and connections in the brain are made and maintained ...,'" as Geraldine Dawson, chief science officer for Autism Speaks, is quoted in Time. Is autism's cause at the synapse, as a July 13th Science Magazine article asked? From the discussion section of the Nature study:

The genetic findings, when coupled with anatomical and functional imaging studies, convergently indicate that ASDs may result from structural and functional disconnection of brain regions that are involved in higher-order associations, suggesting that ASDs may represent a neuronal disconnection syndrome.

However large these new studies are, "'they're still too small to nail down the major genes behind autism'" as Joachim Hallmayer, an autism genetics researcher at Stanford University School of Medicine says in Science. Various reports about the new studies such as one in the Telegraph and one in The West Australian already mention that new treatments (such as drugs) and tests might be developed from these findings.

For me, knowing just a little more of how Charlie is Charlie helps; helps in moving forward.

Wang K et al. "Common Genetic Variants on 5p14.1 Associate with Autism Spectrum Disorder." Nature, published online April 28, 2009.

Glessner JT et al. "Autism Genome-Wide Copy Number Variation Reveals Ubiquitin and Neuronal Genes." Nature, published online April 28, 2009.

Ma D et al. "A Genome-Wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1." Annals of Human Genetics, published online April 28, 2009.