So here is part 1. originally posted January 10th 2010 with part 2. to follow shortly.
This is undoubtedly one of my longer blogs coming in at something like 3500 words. I hope you have the patience to see it through as the implications are very important, and in myfollow up blogs I will be suggesting courses of action you can participate inif you feel as strongly about this issue as I and some of my colleagues do.
Those who have followed my comments on the sundry blogs throughout the Autism Hub will have noted my dual scepticisms, about the current definitions of autism, and the genetic etiology of the same.
It is time for me to set down my reasoning for the latter at least (the former having been covered before, although it does have some bearing on the following).
It is vitally important for the future of all of us (Autistic and ‘neurotypical’) that the common misconceptions about the genetics of autism are cleared up. This is not just because of the inaccuracy of all the reporting, there are significant reasons why it must be countered.
I hope I do not have to go back over the whole sordid history of Eugenics, the institutionalisations, the enforced sterilisations, (in otherwise ‘liberal countries) leading inexorably to the T4 extermination programme in Nazi Germany in order to point out the evils of this ideology.
However the new millennium seems to have brought in it’s wake an increasing threat of it’s revival, no it is more than a threat it’s has had it's resurgence as a new reality.
Let us go back, in the Uk at least to 2000, and the widely reported attempts of a British couple to select the sex of there embryo in order to ensure a female child.
Guardian News
At the time the Human Fertilisation and Embryo Authority refused this request as it was outlawed, except on medical grounds.
There we have it, “on medical grounds” a slippery slope if ever there was one as we will see.
Fast forward to June 2006 where it was reported that the University College Hospital, London were reportedly seeking permission from the same authority for their IVF clinic to discard all male embryos in families with a history of autism, in order to ensure that no more autistic children were born.
Daily Mail
I hope I do not have to point out the crudeness of this instrument, which must rank in infamy along with King Herod’s solution to elimination a rival to his kingship by slaughtering all male born children. Even if it were desirable to eliminate autistic embryo’s this strategy would be eliminating far more potentiality than that, given that there was no evidence whatever to give even an estimate of the risk.
I wrote to the HFEA at the time, and in return received assurances that no such application had actually been made. So was this an example of journalistic licence and false reporting, or was UCH using this as an opportunity to sound out public opinion first? I do not know.
Fast forward again to the Human Fertilisation and Embryology Act of 2008 which contained several changes to the regulation of pre implantation genetic diagnosis including a requirement for the HFEA to be satisfied that there is a significant risk of the resulting child developing a serious condition, before permitting it’s use.
Significant risk eh, but then what is the risk, and never mind the risk even then is it ethical or even scientific?
Professor Simon Baron Cohen of Cambridge Universities Autism Research Centre, has also been siezed upon by the press
to put the counter argument, somewhat weakly and mistakenly in the form of suggesting that this form of genetic selection could end up costing the positive traits of autism too.
I say weakly because that form of argument merely invokes another as to whether one form of autistic person is more valuable than another, which goes right back to the roots of genetics and infers that intellectual impairment is still cause enough for an individual not to have any right to be.
As if the still unresolved spectre of pre implantation diagnosis were not enough, the genetic discrimination is more real than that as reported in this article, where autism in the family is considered
No this is not hypothetical it is actual discrimination enough to refuse donor eggs or sperm from ‘infected’ parents. If that is the parents, where does it leave us as diagnosed individuals if we were to volunteer.
I am not going to go down the side road into the ethics of IVF, whether you support it or not does not hide the fact that it is being used to make eugenically based decisions on the worth of future human beings.
From that it is but a short step to the next stage, that of deliberately aborting suspected autistic foetuses, a fate already suffered by those in other genetic minorities, such as Trisomy (otherwise known as ‘Down’s’)
So to the science itself ...
Firstly I will dispose somewhat cursorily with Professor Simon Baron Cohen’s hypothesis as to the etiology of autism. I do not believe it, not because it is necessarily wrong (that remains unproven) but because the methodology is suspect, in that the whole of it is grounded upon the historic diagnostic ratios favouring more diagnoses amongst boys to the ratio of 1:4.
My argument with that is, that it is simply social artefact, an recognition of the phenomenon that more boys are diagnosed, for whatever reason, than an indicator of any prevalence. I have to remind that counting the numbers of diagnosed individuals is a measure of incidence, the rate at which a particular condition is recognised during any time period, it does not guarantee that this rate equals the prevalence, that is to say the true underlying number of individuals alive at any one time with the condition, be they diagnosed or not.
We can already see the drift away from the once commonly held belief that as much as 75% of all autistic individuals are intellectually retarded, in favour of almost the opposite statistic (and I can give a citation if needed) through the mechanism of diagnostic shift in favour of diagnosing autism across the notorious ‘bell curve’ of intelligence.
In legal parlance there is an element of doubt in Professor Baron Cohen’s hypothesis sufficient to regard it as no basis on which to make legal decisions regarding PGD, donor worth, or termination. That should be enough.
Then to the genetics of autism itself. For as long as this new eugenic argument has been raging, the notion of autism’s hereditability has been raging.
In support of my position, I intend this time to quote directly and at length from a small selection of scientific papers on the subject.
Before I do, I have to state my bias, and that is in my observation there have been so many of these papers, none of them conclusive, and some of them contradictory, to believe that there is any simple gene that switches autism on and off, notwithstanding if Prof Baron Cohen does ultimately turn out to be correct genetics may not be enough in itself. Whether he is right or not, there is more to etiology of any condition than genetics alone, another rabbit hole I could go down in so far as explaining why.
In 2002, Badner and Gershon in Molecular Psychiatry 7(1) pages 56-66. State in the abstract
“Although the concept of meta-analysis of multiple linkage scans of a genetic trait is not new, it can be difficult to apply to published data given the lack of consistency in theOkay it is disengenous to selectively quote from abstracts as the full title of the paper,presentation of linkage results. In complex inheritance common diseases, there are many instances where one or two studies meet genome-wide criteria for significant or suggestive linkage but several other studies do not show even nominally significant results with the same region.”
“Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7.” reveals that they believe that contrary to their advisory, they did go on to state that there methodology at least suggested a link in a particular region
“One possibility for resolvingdifferences between study results would be to combine an available result parameter of several studies. We describe here a method of regionalmeta-analysis, the multiple-scan probability (MSP), which can be used onpublished results. It combines the reported P-values of individual studies,after correcting each value for the size of the region containing a minimumP-value. Analyses of the power of MSP and of its type I error rates arepresented. The type I error rate is at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied. We alsodemonstrate appropriate criteria for this type of meta-analysis when the mostsignificant study is included, and when that study is used to define a regionof interest and then excluded. In our simulations, meta-analysis is at least aspowerful as pooling data. Finally, we apply this method of meta-analysis to theevidence for linkage of autism susceptibility loci and demonstrate evidence fora susceptibility locus at 7q.”I do not think I was wrong to select the first paragraph of the abstract for special attention though as it sums up the correct atmosphere of scepticism inwhich any author should approach their paper. There is a lot of differencebetween the suggestion of a profitable line of enquiry and a foregone conclusion, that is where the press consistently get it wrong whenever any new paper is announced.
However this was an old study, so let me move forward to 2006 again.
In the same journal 2006 Jan;11(1) pages 29-36 Trikolinos et al report (again
in a meta-analysis, that is to say a study of many papers)
“Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtainedthrough Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. Forautism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestivesignificance was reached for the chromosomal regions 17p11.2-q12 and10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggeststhat the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.”The key word is in the title of the paper Heterogeneity ... “A heterogeneity-based genome search meta-analysis for autism-spectrum disorders”
Again the study does no more than point out the suggestion of profitable research in specific Chromosonal regions not all of them (if my reading is correct) in the same region as suggested by the previous paper although there is some corroboration for it. The rider on the investigation bears repeating “while autism-spectrum disorders seem to have quite diverse linkage signals
across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.”
This is still an old paper, and there has been a lot of research in the meantime, which ought by now to have discovered the salience of this region 7 by now, but has it?
I will quote both the abstract and the executive summary of a more recent paper
Grigorenko EL. Pathogenesis of autism: a patchwork of genetic causes. Future Neurology. 2009;4(5):591-599.
The abstract:
“Autism spectrum disorders (ASDs)are relatively infrequent but are devastating developmental conditionscharacterized by marked deficiencies in social, communicative and other behavioral domains. It has been known for a substantial period of time thatthese disorders are genetic in nature. However, elucidating the specific mechanisms of these disorders has been difficult. A major reason for such difficulty is the recognized genetic heterogeneity of ASDs. Specifically, many genetic mechanisms related to structural variations in the genome have been reported as possible genetic causes of these disorders. This review briefly exemplifies these genetic mechanisms, presents a concise overview of the evidence for the genetic basis of ASDs and provides an appraisal of the specific structural genetic variants thought to contribute to the pathogenesis of these complex disorders.”
And the executive summary:
"• Autism spectrum disorders (ASDs) form a group of severe developmental conditions, characterized bydeficiencies in social, communicative and behavioral domains of functioning.Note again that key word I have highlighted “heterogeneity” this morerecent review quite clearly acknowledges that since 2006 the complexity ofautism as developmental trajectory. In essence it agrees with what I haveintuited since the beginning of my awareness of genetic research, that thereare many roads to Rome, in that autism “manifests itself by recruiting bothrare and common genetic variants, as well as heritable and de novo geneticmechanisms”. Did I read “de novo” correctly? That is to say that notall genetic susceptibility is hereditable, the recent research positing therole of older parents may have some bearing on that, I don’t know, it would suggest a further line of enquiry.• Early descriptive presentations of cases of ASDs anticipated the role of genetic factors in the etiology of these disorders. These hypotheses were investigated in twin and family studies of probands with ASDs; these disorders are now viewed as developmental disorders with the highest degree of genetic control. However, these nonspecific indicators of the presence of genetic control have been difficult to convert into a clear account of the genetic causality of ASDs.
• The currently dominating view of the genetic bases of ASDs acknowledges the high degree of genetic heterogeneity of these
disorders that manifests itself by recruiting both rare and common genetic variants, as well as heritable and de novo genetic mechanisms.
• Although the specifics of the contributions of all these genetic mechanisms are unclear, it is possible that the impact of the rare variants is more severe and less specific, whereas the impact of the common variants is more defining and related to specific facets of ASDs."
Turning briefly from the scientific to the worst of the UK’s 'gutter press' we read how the press reacts to genetic research
Yes it is our old friend Professor Baron Cohen inthe frame again. Scientists and researchers do indeed need to be careful howthey handle the press when they find themselves in the spotlight, not all areas astute as the Prof Baron Cohen in anticipating the response to theirscientific findings, and indeed the Prof has been caught out before in the waythat the pseudo science has tried to enlist his findings in support of dubioustherapy.
Again I will leave it to the press to enlighten us further 'Miracle drug' called junk science Powerful castration drug pushed for autistic children, but medical experts denounce unproven claims Well the scientists (those who are worthy of the name at least) are getting better in the social responsibility stakes, as I come absolutely up to date with an extensive quotation from a study which is as yet only available online.
Freitag CM, Staal W, Klauck SM, Duketis E, Waltes R. Genetics of autistic disorders: review and clinical implications. European Child and Adolescent Psychiatry. 2009 Nov 26. [Epub ahead of print]
Abstract
"Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism.And it is worth quoting the conclusions of the review further:Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions."
"Implications for genetic counselling
Genetic counselling for AD is challenging, as phenotype and genetic mechanisms are complex. There is a strong need to carefully assess the children and the family, and to exclude all known medical causes of the disorder. The aim of
genetic counselling is to provide information to parents and children, and to estimate the recurrence risk of the disorder. Genetic counselling further is concerned with providing psychologically oriented counselling to help individuals to adapt and adjust to the impact and implications of the disorder in the family. With regard to AD, families as a rule wish to know the
recurrence risk of the disorder. From the results of family studies, a sibling recurrence risk of around 5% (2–8%) can be estimated for idiopathic AD. (266)
If a known genetic cause of the disorder is established, however, a very different recurrence risk might be present in the individual family. For dominant single gene disorders with full penetrance, like TSC, a sibling recurrence risk of 50% is present, if one of the parents carries the disease-causing variant, that is, if the variant is not a de novo mutation. In case of recessive single gene disorders, like SLO, the sibling recurrence risk is 25%. If a child suffers from FRAXA, the recurrence risk in a brother is up to 50%, and a sister will become a carrier in up to 50% or might be mildly affected. On the other hand, in the presence of cytogenetic abnormalities like a chromosome 15q11–q13 duplication or duplicated inversion, the recurrence risk
is similar to the population prevalence, as most duplications and inversions arise de novo during meiosis.
The limited clinical validity of genetic testing for autism and the related ethical concerns have recently been delineated by McMahon et al. (267) It seems of particular relevance to keep in mind the complex genetics and uncertainty principle as well as the right of the individual and the family not to participate in genetic testing.
Future directions
The presented association studies have shown the difficulties in finding disease-causing genetic variants based on a small number of microsatellites, SNPs or haplotypes. High-density SNP association studies might become feasible in the near future, which might enable researchers to assess linkage patterns and haplotype structure at a genome-wide level in different populations and choose the relevant tagging SNPs for adequate haplotype association studies. In addition to more sophisticated association technology, functional analyses of new variants in coding regions should be brought forward. Gene–gene interactions and epigenetic mechanisms additionally seem to be of relevance in AD. (187)
Conclusions
Despite the high heritability estimates for AD, only a few genes increasing the risk for idiopathic AD have been elucidated. As the disorder shows a high phenotypic variability and additional genetic heterogeneity, it is of crucial importance to, first, clearly define the phenotype, especially with regard to the broader spectrum of AD and to the differential diagnosis of other pervasive
developmental disorders like Rett syndrome, and, second, to perform a detailed cytogenetic analysis in every individual with AD and additional testing for FRAXA in individuals with AD and mental retardation in clinical and research settings. With regard to molecular genetic studies on AD, promising new technologies have been developed, and larger samples with higher power."
To put it into plain language, despite the amount of research, and the number of papers published, often with a press fanfare, the current state of knowledge is not sufficient to warrant the less cautious “scatter gun” approach being taken by genetic counsellors, IVF consultants and fringe medical practitioners.
To conclude with another quotation, from January 2009
“There is no single gene/cause for the categories "Artist" or "Scientist" each conditionis contingent upon multiple factors because they are a human category not a natural one, in essence the reason why a single gene or cause will not be found is because "Autism" is also a human category, and as such is not"watertight" it leaks all over the place because that which is called autism is the confluence of many rivers and depending where you stand in the lake you might feel the influence and currents of any one of them more than another.Yes it is one of mine.Therefore those who pin the argument for autistic's rights on the outcome of a science which can describe us in a positive way are on a hiding to nothing as the remedies are societal and to hope for a scientific justification is to bend science according to ones will, which of course is what all scientists and philosophers do anyway.
Autism finds itself wholly within the social model of disability for an explanation of how it is studied, valued, devalued or otherwise debated."
A little further reading:
- Critical thinking is not a bad
thing. - Duhem, Quine, Wittgenstein and the
sociology of scientific knowledge: continuity or
self-legitimating?Dominique Raynaud - Whichever way you look at it, it’s
still Autism
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