An Evolving Understanding: New Study About Autism Genes
July 10, 2008 by Kristina Chew, PhD
Filed under Health
By analyzing the genes of 88 families from the Middle East, Turkey and Pakistan in which cousins married and had autistic children, researchers have found clues to the neural impairments associated with autism. While researchers found multiple genetic causes for autism in different individuals, a few inherited deletions that have been linked to autism stood out. That is, while there may be different (and many different) genetic mutations that lead to autism in different individuals, some common mechanisms in the brain are affected.
The study, Identifying autism loci and genes by tracing recent shared ancestry, was led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University and is published in the July issue of Science. Here’s the abstract:
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations [my emphasis].
Left Brain/Right Brain nicely refers to the “ever-shifting Aurora of autism” regarding the constantly evolving cosmos (to extend the astronomical metaphor) of findings about autism’s causes; about what autism is, and other neurological differences are. Here’s further commentary from today’s Science Daily:
The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive diseases. Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.
The ratio of females to males with autism — normally one female to four males — was less lopsided in such families in which parents share a common recent ancestor. This ratio equalized even more in a subset of these families with more than one affected member, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked chromosomes. Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.
The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry. Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out. The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.
“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” explained Walsh. “Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations.
Science Daily also notes that the study supports the use of behavioral therapy in teaching autistic children, as it exposes them “to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections.”
Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene — in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches. This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD. “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.
An July2007 study indeed suggested that autism’s cause may reside in abnormalities at the synapse—-in the places where connections happen in the brain. More later—-Charlie’s calling me to practice piano (which he learned to do through carefully structured ABA teaching, enhanced with his own natural liking for music).
What a great idea to study cousins that marry in the middle east to see what causes autism. Oh but wait, we are not in the middle east. Oh, and we do not typically marry our cousins in the US.
They explain why they chose this particular group to study these genes,
Middle Eastern Families Help Scientists Pinpoint Autism Genes, HHMI
It is good to see a serious study being published. More information brings us closer to managing and improving upon some of the debilitating aspects of autism.
Today’s Washington Post quotes Dr. Morrow, who says that “‘autism is a disorder of social learning for sure.’” And about the developing brain:
This explains why early intervention and behavioral therapies work well with many autistic kids. This also suggests that more money should be spent on special classes or programs (pre K) to give kids recently diagnosed with autism to get the type of extensive therapy needed to help them make these gene connections whole.
I doubt they’ll ever link these gene problems to chemicals or toxins (www.bodyburden.org) but I suspect that’s the case. It would be interesting to see how many 50 somethings have this gene problem or is this just a recent phenomena. That would settle once and for all “why aren’t there any old people with autism”
No one underestimates the importance of quality early intervention services for young autistic children. As autism is a lifelong condition—-and as autistic individuals continue to grow and develop and learn over their lives—the same quality of educational services and trained staff and teachers needs to be in place throughout their lifespan, if such services are called for.
“No one underestimates the importance of quality early intervention services for young autistic children…”
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Kristina, with all due respect, based on a study coming out of a committee in my state, and the current various state legislative battles which often involve coverage of quality intervention services and identification of best practices, I might venture that there are quite a few that underestimate this importance, and even for early intervention. Now what is commonly said is another matter.
I think the point is whether the front-loading helps to mitigate future projections or put them into a different area of future supports.
Anyway, it’ll be interesting to see if there is further research from a neuronal/genetic point of view and tie that into the education function, both to counter a somewhat dismissive attitude on habilitative services as medical necessity, and some classification of autism as a mental illness.
I’m not surprised to hear that—-I meant to refer more to the lip service (”what is commonly said”) given to EI, and the tendency not always to acknowledge the needs of older children and adults—-yes, there needs to be more “quality intervention services and identification of best practices.” And recruiting of really good staff.
Some of the children that we are bowling with attend an out-of-district but public autism school that we could have easily and automatically have gotten Charlie into, without moving, or a lawyer, or anything. Everyone seems to be doing fine but—at the risk of offending someone about what’s “quality” and what’s not—-there are some things about the program that Charlie is in that make it really “quality.” Sorry to be elusive; I don’t like judging or comparing anyone, but I knew there was a reason I did not want Charlie to be in that particular program.
I was really interested in the mention of education in relation to this study (and the Time article refers to autism as a “mental disorder”).
There are plenty of ‘old people’ with autism, some of them respond here. Including myself, oh underinformed one.
Here’s what the study showed:
“Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism”
Here again a handful of cases beinbg presented as ‘new autism genes discovered’. Inbreeding has long been known to cause mental retardation. This study does not report on the phenotype being discusssed. Is it ‘autism’ or mental retardation with some ‘autistic-type’ features.
Our issue of Science is floating around here somewhere, but would you say that the point of this was to find “THE” autism genes or to use this somewhat restricted group to study recessive transmission of a controlling region that could be potentially mediated or externally activated by changes in environmental conditions, in this case method of training and environmental enrichment?
Given that there is probably not ONE autism, it doesn’t make me too crazy that multiple sources are being investigated, and I understand why they might pick a particular cohort to amplify the regions that they wish to study.
The point about the phenotype is taken. My understanding is that there was some work preliminary to this study–what was the phenotype there?
Sorry…got kind of interested in this. Probably should just find the article.
David Brown, Washington Post
“…Marriage between first cousins doubles the risk of neurological birth defects. The researchers said they think that shared ancestry would increase the risk of autism caused by recessive mutations that cause problems only when a child inherits the defective gene from both parents. By studying cases caused by such rare events, researchers can often learn about the biochemical and genetic underpinnings of the far more common cases in which there is no inbreeding. ”
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As RAJ noted about what else might be going on/phenotype
“…The researchers looked for one of the gene defects in autistic children whose parents were not related and found it, but it remains unclear how applicable this study is to garden-variety autism.”
(too bad the reporter could not be more specific about what is “garden-variety autism”; kind of curious about what is meant there.)
Many of the Middle Eastern children had other neurological problems, such as epilepsy. Whether the activity-driven gene defects are also present when autism occurs by itself is unknown. “
And how is autism identified and diagnosed in a Middle Eastern culture?
Scientific American highlights the early learning angle and especially how synapses are created and strengthened:
I was kind of trying to say this in my comment above—–Charlie got the kind of early intervention that the researchers refer to and it laid a solid foundation for the learning he has continued to do (and still continues too—-and still needs). The notion of genes that need to be “switched on,” by whatever way (a drug; behavioral therapy) seems to underscore the need, again, for education at any early stage.
i totally agree. my daughter has been in school since the age of three, she is twelve now. they told me she would never be able to read, write, or do math. shes doing all of that on a lower level but shes doing it. i beleive early intervention is very important i have all the proof. thanks for your time.