Friday, June 10, 2011

Does new genetic study on autism disspell sacred cow beliefs?

Lately much has been made in the media about the new genetic findings that were published recently in the journal neuron, showing that there are many mutations on many different chromosomes that can cause autism. I will qualify this post acknowledging I have not read the actual study but only the media reports, I am not an expert on genetics, so if any of my detractors want to comment on errors of reasoning or to attack me personally or whatever I will begin the post with that caveat.

One of the significant things I have read about the study is that it seems to show that the vast majority of cases of autism come from spontaneous (denovo) mutations and are not inherited. This contradicts the tenets of Temple Grandin who has claimed that eradicating autism would be a disaster and that autism genes have stayed in the population because they provide some sort of adaptive or evolutionary advantage in the way that sickle cell anemia genes have stayed in the population to fight malaria or genes for hemachromatosis have stayed to combat iron deficiencies. She has claimed that autism is responsible for every invention from the spear to the computer to the cell phone. Simon Baron-Cohen has made a similar claim that autism genes provide some sort of evolutionary adaption and this is the reason autism has stayed in the population. He includes this in part of his arguments in stating that high functioning (though it is unclear where the demarcation between high and low functioning are from his writings) autism should not be considered a disability. There are some problems with these arguments I have written about them elsewhere. This study would seem to provide evidence against Grandin's and Baron-Cohen's arguments that autism genes are something good and have stayed in the general population due to adaptive status, but rather autism has stayed in the population because of denovo mutations.

What of the arguments of Mark Blaxill and others who support ageofautism website and philosophy who believe that the cause of most autisms were simply that something (such as vaccines) was introduced into the environment that did not exist previously (at least not in high numbers) and this has caused a huge spike in autism and if we could do research and isolate what this thing is, it would lead to solutions in the etiologies and treatments of this condition? It would seem this research might reduce the credibility of their beliefs, though certainly they will have an explanation and this study or any other won't dissuade them.

The neurodiversity movement has long espoused the dogma that genetic research into autism will result in prenatal testing and widespread abortions of autistic fetuses, possibly as soon as the next five years or less. Will this study, showing in fact how complex and diverse the genetics of autism really are, lead to less credibility of this dogma.

Ari Ne'eman who now has power to recommend policy or even vote on autism policy in two different government positions created at taxpayer expense has called for a ban on all research of this kind. Yet Michael Wigler, one of the principal authors of this study, has claimed that this research at some point may present treatment options for some kinds of autism or perhaps even a cure.

Gadfly wonders if more research along these lines are pursued and published, what will happen to all of these sacred cow beliefs?


Minority said...

1) De novo mutations can be caused by environmental toxins.
2) These mutations on their own might not result in full-blown autism, but in combination with a variety of insults could.

Consider that a difficult birth makes autism more likely, older parents make autism more likely, and so on.

I don't think that demonstrating that there is a wide range of things which can go wrong, which in some children result in autism, gets toxins off the hook.

jonathan said...

@Minority: You make some valid points. Of course there might be some causes of autism that have nothing to do with the research by Wigler and company.

I know that a relationship between paternal age has been suggested to make autism more likely, I am not aware of evidence of a relationship between maternal age and autism, though it might exist.

These things might not get toxins off the hook, the problem with toxins, so far as i know, is that there is no legitimate or well down research showing any relationship between toxins and autism. Until that time, there is no real evidence that toxins have anything to do with autism. Of course that might change at some point in time.

Anonymous said...

You'll have to check me on this, but I think at least one of the articles points out that de novo copy number variants account for less than 5% of all cases of autistic disorder.


Minority said...

Research looking for environmental factors in relation to ASD.

This search at PubMed brought up 28 candidates

a search on toxins autism brought up 58

chemicals autism 35

environment autism 867

Looks as though the door is wide open for environmental factors to play a role in ASD.

The Fauxtist said...

Maternal age progression has shown, pretty conclusively, that there is a higher risk of gene depletion or mutation. The risks skyrocket for Down Syndrome, as one example, from 30+ on.

Ari Ne'eman doesn't believe this research should occur because Ari Ne'eman doesn't know anyone with LFA and very few with actual AS. If your world view is as narrow as his, its logical to believe everyone must have the same opportunities as he does.

He's a waste of time and I can't really point to anything of substance he has done since his appointment to better the lives of people with autism.

jonathan said...

Morgan: No i seem to remember they said de novo accounted for the majority.

Minority: A wide open door gathers no moss. These are just search words, I am still waiting for real substantive science to show a link between chemicals and autism, to the best of my knowledge there is none.

Minority said...

Okay, lets take it from another direction.

Can toxins cause mutations?


Can toxins cause neuro-developmental delays and problems? Absolutely. One clear example is exposure to alcohol in the womb.

Are autism spectrum disorders a form of developmental delay or blockage? Yes, they do fall into that area.

Are autism spectrum disorders considered to have something to do with the brain and neurological system? Yes, they do.

However, until we've got a smoking gun, you are willing to assume that toxins which are documented to cause neurological problems, brain damage, developmental delays and mutations could not possibly be connected to autism which is neurological, includes signs of brain injury, involves developmental problems and now looks to be connected to mutations are not connected to autism.

Well, okay...

Anonymous said...

My recollection was indeed faulty.

From Levy et al: “We find de novo events in 8% of children with ASDs and only in 2% of their unaffected siblings, in keeping with other reports.”

There is no breakdown for the Autistic Disorder component of 'children with ASDs.'

link here:

From Sanders et al: “Overall, 5.8% of probands (n = 51 of 872) had at least one rare de novo CNV compared with 1.7% of their unaffected siblings (n = 15 of 872), yielding an odds ratio (OR) of 3.5 (CI = 2.2–7.5, p = 6.9 3 10_6, Fisher’s exact test) (Table 1 and Figure 2).”

The breakdown of the sample group is as follows: “All had confirmed ASD diagnoses based on well-accepted research criteria (Risi et al., 2006), including autism, 1006 (89.5%), pervasive developmental disorder-not otherwise specified, 96 (8.5%), and Asperger syndrome, 22 (2%).”

link here:

Gilman et al used data from the same sample group as Levy et al

link here:


farmwifetwo said...

Saw it on the news last night.

Thanks for posting about it.

Minority said...

Article on brain inflammation. Aberrant NF-kappaB expression in autism spectrum condition:
a mechanism for neuroinflammation
Adam M. H. Young1,2, Elaine Campbell1, Sarah Lynch1, John Suckling3* and Simon J. Powis1
1 Bute Medical School, University of St. Andrews, Fife, Scotland, UK
2 Autism Research Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK
3 Department of Psychiatry, University of Cambridge, Cambridge, UK
Autism spectrum condition (ASC) is recognized as having an inflammatory component. Postmortem
brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebrospinal fluid, although little is known about the underlying molecular
mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein
found in almost all cell types and mediates regulation of immune response by inducing the
expression of inflammatory cytokines and chemokines, establishing a feedback mechanism
that can produce chronic or excessive inflammation. This article describes immunodetection and
immunofluorescence measurements of NF-κB in human post-mortem samples of orbitofrontal
cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK
(ASC: n = 3, controls: n = 4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6,
controls: n = 5). The hypothesis was that concentrations of NF-κB would be elevated, especially in
activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification). Neurons,
astrocytes, and microglia all demonstrated increased extranuclear and nuclear translocated
NF-κB p65 expression in brain tissue from ASC donors relative to samples from matched
controls. These between-groups differences were increased in astrocytes and microglia relative
to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in
homogenized samples demonstrated a 0.98-unit difference in means and a strong (F = 98.3;
p = 0.00018) linear relationship to the expression of nuclear translocated NF-κB in mature
microglia. Acridine orange staining localized pH reductions to lysosomal compartments. In
summary, NF-κB is aberrantly expressed in orbitofrontal cortex in patients with ASC, as part of
a putative molecular cascade leading to inflammation, especially of resident immune cells in brain regions associated with the behavioral and clinical symptoms of ASC

SM69 said...

The Levy Neuron paper is really difficult to read because all important information is either buried in the methodology and results, or plainly missing. Indeed there is no information what so ever on the participating families.

“An ongoing study of the correlations between our genetic findings and the phenotypic data is not included in the present study”.

“Families with single high-functioning probands, usually with unaffected siblings, are preferentially recruited, and families with two probands are specifically excluded”.

No mention of how they define High functioning proband.

Blood DNAs (and a few rare cases, EBV-immortalized DNAs) from nearly 1000 families (of the 3000 planned) were sent to our group for processing and analysis.

So a selection of 1000 out of 3000- That would suggested 1000 with HFA (?), single child affected in the family. Is there any other exclusion criteria? Not specified.

“We define a trio as consisting of a mother, a father, and a child, either affected or unaffected.”

If each member of a trio has a hybridization that passes minimum quality thresholds (see Experimental Procedures), that trio and its associated hybridizations are called “high quality” (or “HQ”). Out of 1721 valid trios from 887 families, 1475 (86%) are HQ.

So that is all we know- picked 887 families HQ hybridization that form 1475 trios- throughout this report we refer to the children with diagnosed ASDs as “probands” and to the children who do not have ASDs as “sibs.”

We learned earlier this is High functioning proband.

Autism Male HQ:443
Autism Female HQ:93
Sib Male HQ: 343
Sib F QH: 398

Now what are the actual results?

Count children with de Novo event
Autism M: 55- frequency 7.4%
Autism F: 13 frequency: 11.7%
Sib M: 9 Frequency: 2.2%
Sib F: 8 Frequency: 1.8%

These results are totally consistent with earlier Genome wide analysis, Pinto et al. etc. I have previously commented in details about the Pinto study.
I will continue the development on a second post.

SM69 said...

I would concur with Minority and Anonymous here and I would reiterate:

1- A de novo genetic change does not imply a change of phenotype. A de novo genetic change can instead been seen as a surrogate markers of an environmental deterioration. Because these changes tend to be unique to affected individuals, the most logical explanation is that these are NOT involving any autism genes or regulatory domains of autism genes, even using a molecular pathway argument (that is flawed in my opinion).

2- De novo genetic changes imply environmental insults, to the parent germline cells. It is not clear if affected individuals are chimeric in their presentation- this means cells of related embryonic origin are different (in their de novo profile) to that of another embryonic linage. The GWA work is usually done on blood, this is one tissue only. If there is a degree of chimerism, then the de novo mutations occur also after fertilisation. There is mention above that age of mother is a pretty well proven risk factor for autism. I am aware of only 1 study, if there is more let me know. I don’t think this is conclusive at all. Our families of 400+ kids with autism only have a very small minority of parents who conceived after age 38- age of the mother. Late pregnancy does not explain the rise in autism prevalence.

3- When have these de novo mutations started to occur in human history? We do not know. It is important to flag that a comparable Pinto et al study used a control with a mean age of 37, a lot older than the autism group- and found fewer de novo mutations. What is an age factor? Possibly- just unknown at this stage.

Anyone can speculate on what causes autism and what will cure it- whether it uses a genetic, environmental, evolutionary or molecular argument. What is certain is that at the moment, we cannot correct multiples de novo mutations other than through ES therapy. And who would do this anyhow as these do novo mutations are not proven in any way to cause autism. (ES therapy might still work, but for very different reason- that is to give the organism a chance to recover after the insult created).

In my opinion these GWA studies if anything flay a problem with our environment. What we can do is to look a lot more closely at it and address the issues. Without taking any religious stand, I am certain that we have violated fundamental equilibriums at many levels. This is what we see. We either continue to burry our head in the sand and come up with irrelevant and expensive research to protect our industries, or we deal with it.

It’s about our children, it’s about our grand-children, and great-grand-children. I think these are way higher values.

Minority said...

Very well said, SM69! Thank you for pulling the pieces together so well.

Minority said...

How about this study?

SM69 said...

I presume you have read yesterday’s post on AoA on a genetic screen for autism based on the CNV variations- At the moment proposed to children at pre-diagnosis stages.

See the comment section too.

Lienagen company offering the test:

“CMA testing for copy number variation (CNV) is recommended as a first-line test in the initial postnatal evaluation of individuals with the following: A) multiple anomalies not specific to a well-delineated genetic syndrome, B. Apparently non-syndromic developmental delay/intellectual disability, and C) autism spectrum disorders.”

That the sort of none-sense application arising from these genetic studies.

No need to point out that none of it will ever help autism or the affected families.

There is here a total leap of faith in what these studies actually mean, together with a total misunderstanding of what autism is- published evidence of immune impairment, oxidative stress, methylation issue, mitochondrial problem and environmental triggers are being ignored.