A SINGLE gene that appears to increase the risk of a person developing autism when mutated has been identified by scientists, suggesting new approaches to diagnosing and treating the condition.
Research in the United States has revealed that many cases of autism may be triggered in similar fashion to diseases such as cystic fibrosis — in which one gene goes wrong, but in a multitude of different ways. The work at Vanderbilt University in Tennessee suggests that it may be possible to develop a blood test that can pinpoint the probable cause, which could have important implications for treatment.
It is known that some children and adults with autism respond positively to a class of antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs), which includes Prozac and Seroxat.
James Sutcliffe, a research leader, said: “You might be able to predict which kids would respond positively to particular SSRI medications.” The gene that has been implicated in autism is the serotonin transporter gene, known as SERT. This plays a key role in regulating the brain’s levels of serotonin, a signalling chemical involved in mood, impulsive behaviour and sleep.
Scientists have known for some time that about 25 per cent of people with autism have elevated levels of serotonin in their blood, suggesting a possible link to the disorder.
Two new studies by the Vanderbilt team have shed light on how the SERT gene might influence autism. The first, published in the American Journal of Human Genetics, shows that several mutations in SERT may be risk factors in autism. The second, published in Proceedings of the National Academy of Sciences, suggests a possible mechanism by which these mutations may have adverse effects.
Randy Blakely, who led the studies with Dr Sutcliffe, said: “Autism has such a high genetic risk, but these new findings suggest that there may be many variants of individual genes at work. We now have concrete evidence that the SERT gene is a risk factor in autism. Perhaps more importantly, we also have new pathways that could have some therapeutic end points.”
The protein produced by the SERT gene normally has the job of mopping up excess serotonin in the brain. The Vanderbilt team, however, has shown that several of the proteins produced by mutant versions of the gene cannot be properly “read” by cells, and this may play a part in autism.
“We were stunned because the cell just can’t talk to these SERT proteins in a normal way,” Dr Blakely said. “Although it’s impossible to extrapolate from a molecule to a person, it is striking that these mutations, which do not allow proper communication with SERT, show up in a disorder fraught with communication problems.”
Another promising finding is that certain key signalling pathways go wrong with mutated SERT genes. As drugs that target these pathways are being investigated to treat cancer and inflammation, these might have potential for autism. “This is a potential therapeutic area we hadn’t envisioned before,” Dr Blakely said.
http://www.timesonline.co.uk/article/0,,...98,00.html
That's an interesting article.
Gene theraphy is likely to be able to repair the cell components that create the SERT proteins. Or for that matter SERT drugs like Prozac in this case could help too, but I've always wondered one thing on "cures".
In changing how the brain functions and clearing the "problems", would you lose the characteristics that also give Asperger's their unique advantages (Intense focus and interest and the like), or have those changes since become an engrained part of their nature through repeat use of those skills, in which case would repairing the SERT proteins/aiding them actually have any real effect besides uplifting their mood - in adults at least.
In changing how the brain functions and clearing the "problems", would you lose the characteristics that also give Asperger's their unique advantages (Intense focus and interest and the like), or have those changes since become an engrained part of their nature through repeat use of those skills, in which case would repairing the SERT proteins/aiding them actually have any real effect besides uplifting their mood - in adults at least.
Really good points. I certainly wouldn't want the way I think to be changed -- but I could do with less anxiety! I can't recall where, but I read somewhere (New York Times article?) about a guy with Tourette's syndrome who was an amateur jazz musician (drummer) -- played usually only on the weekends -- and did something else during the week to make a living.... In any case, he started taking medication to stop his tics -- and while things improved at work -- he felt he lost to a certain degree his ability to improvise during his jazz sessions. He ultimately opted for meds during the week, but not on the weekend so he could play and improvise.
I know I wouldn't want to take medications that would alter my thinking or my personality.
Here weve got yet another so-called Autism Gene. Ignore it. The last 100 or so 'autism genes' didnt bring prenatal testing, the odds against the latest find being The One are long and getting longer.
Its not humanly calculable to state that the odds are getting longer, as its a completely unknown quantity.
From what I have studied, there certainly have not been 100 identified 'autism genes' so far.
You are also assuming that a prenatal test will have to come from genes, false presumption.
Baron-Cohens findings on testosterone could produce a prenatal test in a much quicker and simpler fashion.
If women who already had a child with autism were tested in the next pregnancy, and higher levels of testosterone were found, they could be informed and may consider abortion.
That could be the start of it.
What I mean by the odds getting longer is that the more genes are discovered and not do not result in prenatal tests, the more thoroughly the unlikelyhood of a given gene resulting in a test is confirmed.
Example:
if 1 gene has been discovered, and does not lead to a test, this doesn't say much about the likelyhood of the next gene linked to autism resulting in a test.
after 10 genes have been found, and none shows any indication of resulting in a prenatal test for autism, then we can make a more accurate estimation of the likelyhood that a given linkage will result in a prenatal test.
and so on...
of course it is always possible that the next one will be The One, but the more genes come and go the less credit I give to each individual finding.
As for the 100 genes, That is not a serious figure, but there have probably been more than you know. For every one you hear about on the news, several probably go unreported. (the news media have only so much capacity for rehashing old topics)
As for hormonal tests, those are certainly a possibility, but saying that such tests are quicker and simpler is not necessarily correct. A hormonal assay would require sampling directly from the fetus' blood supply (I am not certain about that, but do keep in mind that the fetus' blood supply is separate from the mother's) whereas a genetic assay be done using amniotic fluid if I recall correctly, or even before conception.
Im not saying its impossible, just that its not quite so easy, and unless doctor Baren-Cohen's findings have been reproduced in other labs they cannot be considered definitive.
On that subject, please do post more about this testosterone theory. It sounds interesting.
As far as I know, they ascertained the testosterone level through amniocentesis samples, which a lot of women already have taken anyway.
They were asking for the amniocentesis results of autistic pregnant women at one point.
I found the abstract of this research, which doesn't have any specific references to autism in it at all. The words in bold are my emphases.
I don't understand what it all means, but here it is anyway:
Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11545-50. Epub 2005 Jul 29. Related Articles, Links
Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase.Prasad HC, Zhu CB, McCauley JL, Samuvel DJ, Ramamoorthy S, Shelton RC, Hewlett WA, Sutcliffe JS, Blakely RD.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, USA.
Human serotonin [5-hydroxytryptamine (5-HT)] transporters (hSERT, 5HTT, and SLC6A4) inactivate 5-HT after release and are prominent targets for therapeutic intervention in mood, anxiety, and obsessive-compulsive disorders. Multiple hSERT coding variants have been identified, although to date no comprehensive functional analysis of these variants has been reported. We transfected hSERT or 10 hSERT coding variants and examined total and surface protein expression, antagonist recognition, and transporter modulation by posttranslational, regulatory pathways. Two variants, Pro339Leu and Ile425Val, demonstrated significant changes in surface expression supporting alterations in 5-HT transport capacity (V(max)). Regardless of basal transport activity, all SERT variants displayed a capacity for rapid, phorbol ester-triggered down-regulation. Remarkably, five variants (Thr4Ala, Gly56Ala, Glu215Lys, Lys605Asn, and Pro612Ser) demonstrated no capacity for 5-HT uptake stimulation after acute protein kinase G (PKG)/p38 mitogen-activated protein kinase (MAPK) activation. Epstein-Barr virus (EBV)-transformed lymphocytes natively expressing the most common of these variants (Gly56Ala) exhibited a similar loss of 5-HT uptake stimulation by PKG/p38 MAPK activators. HeLa cells transfected with the Gly56Ala variant demonstrated elevated basal phosphorylation and, unlike hSERT, could not be further phosphorylated after 8-bromo cGMP (8BrcGMP) treatments. These studies reveal cellular phenotypes associated with naturally occurring human SERT coding variants and suggest that altered transporter regulation by means of PKG/p38 MAPK-linked pathways may influence risk for disorders attributed to compromised 5-HT signaling.
Grant Support:
DA07390/DA/NIDA
MH55135/MH/NIMH
MH61009/MH/NIMH
MH62612/MH/NIMH
I am nto certain if I have this right, but this appears to say that certain versions of the gene in question are less likely than others to reabsorb seratonin from the synapse once signaled to do so. That means certain variants will allow more seratonin to remain in the synapse longer. Seratonin is extremely multipurpose, and serves different purposes in different places, so I cant get any more specific information.
Amy, I am of course not certain, but I dont see how they could get testosterone levels through amniocentesis. Testosterone I would expect to be confined to the blood supply, Im not sure if it can leech to the amnion or not. Something to look up, I guess.
This is interesting, because I acted much more Aspie before I started taking Zoloft.
I tried an SSRI (and dopamine transporter reuptake inhibitor) kaugoued, or kanna.
Hated every second of it, now its relegated alongside my ergot, as part of a collection
Familiarity with the history of Alzheimer's disease (AD) research tells us that this SERT breakthrough might not be all that big a deal. Decades ago, a few specific variants of the amyloid precursor protein (APP) gene coding sequence were shown to pretty much guarantee that the person with these variants would develop early-onset familial AD (FAD). Case closed, problem solved, a little gene therapy, disease eradicated, right?
Wrong. FAD accounts for no more than 5% of all cases of AD. The other 95% have no causative relationship to any specific gene variation, although there are risk factor polymorphisms, but these risk factors do not guarantee the disease.
I'd say that SERT is likely to fall into a bucket similar to the FAD variants of APP. Interesting model system, little to say about autism spectrum in general.
I found the SSRI medication useless but am now taking a SNRI which is a newer generation medication and it is helping with anxiety. I very rarely get panic attacks now.
Given the spectrum nature of autism, I would suspect that several genes interact to cause the symptoms and there could be many different permutations ie. "mild autism" might be caused by the interaction of 5 different genes but classical autism by maybe just 2.