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Suspension of Mark Geier is upheld

19 Apr

Mark Geier is a name well known in the autism world of alternative medicine as well as a major source of papers purporting to link autism to mercury. He had a medical practice, was licensed in multple states, presented repeatedly at autism parent alt-med conventions, and served as a witness for the vaccine court.

Mr. Geier’s license to practice medicine was suspended last year. Since then he has tried a few avenues to get his ability to practice reinstated, at least while he is pursuing appeals. The Maryland State Board of Physicians has denied his request and issued a (second) cease and desist order informing him to stop practicing medicine.

Mr. Geier and his son, David Geier, took a theory from Prof. Simon Baron-Cohen: the “extreme male brain” concept of autism. Where Prof. Baron-Cohen focused on the effects of fetal testosterone levels on brain development, the Geier team somehow arrived at the idea that autistics have mercury bound in to testosterone in their brains. One can read an analysis of this theory at A Photon in the Darkness, Miscellaneous Mercury Nonsense. As you can imagine from the title of that article, the autism/mercury/testosterone idea was an obviously bad idea from the start.

Unfortunately, the Geiers took this bad idea from theory to practice. They further hypothesized that these mercury/testosterone sheets prevented chelators from removing the mercury. So, they futher hypothesied, by reducing the amount of testosterone in the body, the mercury bound in these supposed mercury/testosterone sheets would be released allowing chelators to remove the mercury. Why lower levels of testosterone would lead to these supposed mercury/testosterone complexes breaking down is not well explained. Which is another way of saying it doesn’t make sense.

It is worth noting that these sheets, or matrices as the Geiers dubbed them, of mercury and testosterone do exist. In laboratories. After boiling mercury compounds in beakers of benzene. As Prometheus wrote back in 2006:

This is not a condition even remotely similar to anything found in living tissue – of any vertebrate species. In other words, it isn’t likely to happen in autistic children unless you dissolve them in hot benzene.

Basically every link in their logic chain was bad. But this did not stop the Geiers from applying Lupron as a treatment. The drugs for reducing testosterone production (such as Lupron) are expensive. Insurance doesn’t pay for Lupron to reduce testosterone levels in disabled children so that non-existent mercury/testosterone sheets will break down by some unexplained mechanism so that chelators can remove the mercury which is not really linked to autism. Probably because of the insurance angle, the Geier’s prescribed Lupron and similar drugs not for the supposed ability to help the chelating process, but to treat precocious puberty. Early onset of puberty.

According to the Maryland Board, based on records and testimony from patient’s parents, the Geiers failed to do the basic work involved in diagnosing precocious puberty and, in some cases, diagnosed precocious puberty in children who were old enough to be going through puberty.

Sound complicated? They were diagnosing precocious puberty without the proper tests in children who didn’t have it in order to prescribe drugs to reduce testosterone levels so that mercury/testosterone sheets which don’t exist in their brains will break down and allow a chelator to remove the mercury which doesn’t cause autism.

Lupron is not a mild drug. It reduces sex hormones and delays puberty. Children are supposed to go through puberty at a given time in their lives and delaying it comes at a cost. In addition the drug itself has side effects. From the recent decision upholding the suspension of Mr. Geier’s license:

Lupron treatment carries a very high risk of skin abscesses and infections, and it is contraindicated in patients with a history of seizures. Dr. Geier nevertheless prescribed it for Patient B, who had a history or uncontrolled seizures. Nor did Dr. Geier perform all of the necessary diagnostic procedures before prescribing Lupron. Nor did Dr. Geier physically examine Patient B until almost three years after he began prescribing for him. See Proposed Decision at 33, 37-38. This is only one example of the truly risky behavior that Dr. Geier engaged in with these patients.

Mr. Geier’s license to practice medicine was suspended last year by the Maryland Board of Medical Practice. He tried to defend himself in a series of actions since, with this action being the final word.

The Board “entirely agrees” with the a previous decision that allowing Mr. Geier to continue to practice medicine while awaiting the determination of formal charges raises the likelihood of serious harm to public health and safety:

The ALJ concluded that “allowing [Dr. Geier] to continue practicing medicine while formal charges are pending raises a substantial liltelihood of risk of serious harm to the public health, safety, or welfare.” The Board entirely agrees. For Dr. Geier to practice medicine at this time would constitute a danger to the patient community.(3)

The footnote (3) in the above statement was already quoted in this artice–look above to the paragraph on “Lupron treatment carries a very high risk…”

The Board repeated this position in their conclusion:

“I conclude that for all these reasons, the Patients’ health, safety or welfare was at risk of serious harm.. Further, the existence of all these problems throughout all the Records raises a substantial likelihood that the risk of serious harm to the Patients was also posed to many other children with autism treated by the Respondent. I find that this meets the necessary standard for summary suspension of the Respondent’s license: allowing him to continue practicing medicine while formal charges are pending raises a substantial likelihood of risk of serious harm to the public health, safety, or welfare,”

One very troubling argument made by Mr. Geier was that he was not required to have an Institutional Review Board for his research. One of the charges against Mr. Geier involved an IRB he instituted–where he, his son, his wife, a patient’s mother and other interested parties were members of the IRB. The Board did not address whether such a board was required, but did dismiss the charge based on the lack of evidence put forth by the State. More discussion on the IRB can be found at Neurodiversity.com in the article An Elusive Institute.

The Respondent argued both that he was not required by federal law to have an Internal Review Board and, that even if he was bound by such a requirement, the State failed to produce any evidence that his board operated in a flawed manner. The State did not dispute this argument in its response to the Motion. I agree with the Respondent that the State failed to produce sufficient evidence to survive a motion for judgment on the allegations related to an Internal Review Board. See COMAR 28.02.01.12E. C’ Md. Rule 2-519. I will recommend that this portion of the Motion be granted and further recommend that paragraphs 157 through 162 of the Order for Summary Suspension be dismissed.

The thought that somene (Mr. Geier in this case) believes that research could be performed on anyone, not just disabled children, without the protection of an IRB is frightening.

In what is to this reader the most ironic statement by Mr. Geier in this action:

Finally, Dr. Geier accuses the ALJ of establishing a new and unwarranted standard for the medical care of children with autism. Again, Dr. Geier fails to acknowledge that the ALJ relied to some extent on the testimony of his own expert witnesses, and on his own sworn statement, to make her findings regarding the standard of care and the deficiencies in Dr. Geier’s practice.

Yes. Dr. Geier accuses the ALJ of establishing a “new and unwarranted standard for the medical care of children with autism.” Mr. Geier, who while he may not have been the first to promote chelation for autism has been one of the primary proponents, Mr. Geier is part of the team who invented the idea of Lupron as a part of a chelation protocol. A “new and unwarranted standard for medical care of children with autism”.

In addition to this decision, and the cease and desist order, Mr. Geier’s licenses to practice have been suspended in California, New Jersey, Indiana, Florida, Ohio, Washington and Virgina.

The Maryland Board accepted James Adams (a materials scientist) as an expert on chelation, at the behest of Mr. Geier. The opinions offered by Mr. Adams differ from those of medical toxicologists (a group of physicians trained and in practice to treat poisoning):

The Respondent [Geier] testified in his sworn statement that he orders chelation therapy for hispatients on “various” schedules “every other day or a few days on and a few days off for a couple of months – three months.” State’s Ex, 8 at 34. Yet, the Respondent’s expert on chelation, Dr. Adams, testified credibly that patients need an even longer break between rounds of chelation: three days of chelation followed by eleven days off. Dr. Adams also testified that chelation therapy should only be initiated after a patient is given a short “challenge” dose of chelation to ensure that the patient actually needs the therapy. If administered to a patient who does not need it, chelation poses serious risks of injury to the brain and other organs. It is imperative, therefore, that a physician only administer chelation on a limited basis to the patients who actually need it. The Respondent not only skipped the challenge step necessary to ensure chelation was even necessary, but then went full force into chelation therapy on an intensive schedule (with an experimental drug.not FDA-approved for that purpose) without appropriate rest breaks. In several cases, moreover, the Respondent failed to regularly monitor the effects of chelation, and in two cases he prescribed it for patients that he knew he could not monitor.

The concept of a “challenge test” for diagnosing mercury intoxication is covered by the American College of Medical Toxicologists in American College of Medical Toxicology Position Statement on Post-Chelator Challenge Urinary Metal Testing. Who concluded:

“It is, therefore, the position of the American College of Medical Toxicology that post-challenge urinary metal testing has not been scientifically validated, has no demonstrated benefit, and may be harmful when applied in the assessment and treatment of patients in whom there is concern for metal poisoning.

I hope that the Maryland Board looks into this issue of challenge testing before ruling again on such issues.

Mr. Geier is scheduled to give a talk at a large annual autism-parent convention. Last year, after the first action suspending his license, he was reportedly given a standing ovation at this convention. This reader is at a loss to understand why.

Mayo Clinic to study adult prevalence and outcomes

18 Apr

A five year project was started this year to investigate the epidemiology and current status of adults in the U.S.. At present we have almost no data on adult outcomes. We have little data using on adult prevalence. Studies from the U.K. have reported a prevalence about 1.1% for autistic adults “…with learning disabilities living in private households and communal care establishments in Leicestershire, Lambeth and Sheffield”. This is slightly higher than reported in 2007. The studies were survey based. The survey was calibrated with testing of a subset of the population. However, the study did not involve direct testing of all individuals or record review of all individuals.

The U.K. study was an excellent first step to demonstrate, amongst other factors, the number of adult autistics and their living conditions.

There is nothing close to this in the United States. We can’t make real comparisons of prevalence between adults and children, for example. Not just because we don’t really have the data. Multiple studies have shown that when one tests adults, even those living in settings for the developmentally disabled, many autistics were unidentified before the study.

Here is the project description from the NIH Reporter website:

DESCRIPTION (provided by applicant): autism Spectrum Disorders (ASDs) are lifelong neurodevelopmental conditions with mostly unknown etiology that have a huge impact on affected individuals and their families, and are a major public health concern. This proposal, “autism Spectrum Disorder: Birth Cohort 1976-2000, Epidemiology and Adult Status,” in response to NIH Funding Opportunity Announcement (PA-10-158) describes an epidemiologic, population-based, large birth cohort study of ASDs. Significant gaps exist in the knowledge of ASD incidence and its possible rising trend. Detailed characterization (phenotype) of ASD incident cases and ASD subtypes [Autistic Disorder (AD), Asperger’s Syndrome (AS) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS] is sparse, and potential risk factors (etiologies) are still unknown. Knowledge about adult outcomes of incident ASD cases identified in childhood is almost non-existent. ASD-associated medical costs are high, yet information to improve cost-effective medical management is lacking. A unique set of circumstances, including an already established population-based birth cohort of all children born 1976-2000 to mothers residing in Olmsted County, MN (N=43,934), access to complete, detailed school records for each child in the birth cohort (Independent School District ISD #535 – 41 public, private, home schooled), access to detailed medical records for every child in the birth cohort (Rochester Epidemiology Project-REP; NIH-AR30582), and the Olmsted County Healthcare Expenditure and Utilization Database (OCHEUD) provide the infrastructure to enable the successful completion of this project. This rigorous epidemiologic study involves an experienced multi-disciplinary research team, confirmation of the availability of documented behavioral symptoms of ASD from 1976 forward, with development of a detailed dictionary of descriptive phrases abstracted from medical/school records congruent with DSM-IV-TR criteria (pilot data) and a unique population-based birth cohort. [To help control for changes in special education laws and DSM criteria] this proposal will implement a systematic page by page review of medical and school records of all potential ASD cases regardless of initial school and medical classification and will apply the same uniform research criteria for ASD incident case identification (including DSM-IV-TR criteria), during the 37year study period. We will study the putative rise in incidence of ASD over 37 years, the possible role of certain risk factors on any incidence trend of ASD over time, the “shared risk” hypothesis by estimating the interaction between perinatal risk factors and family history (parents, siblings) of psychiatric disorders, assessing adult ASD current status and outcomes and cost effective medical management analyses. The knowledge achieved through this combined retrospective and prospective epidemiologic approach will substantially advance scientific/clinical knowledge about ASD

The methodology is similar to that of the CDC reports like the recent 1 in 88 study. The researchers will perform a records review. If the studies on children are any indication, many autistics will be identified through the records review.

This is not the same as a whole population study, where all individuals are screened and many tested for autism. Such a study was performed in Korea recently and resulted in a prevalence of 1 in 38, much higher than found elsewhere with non-whole population studies.

This begs the question of when someone will start a full-population study of adult autistics in the U.S. and, more importantly, what we might find from such a study.

Simons Foundation announces RFA for Explorer Awards

17 Apr

The Simons Foundation is a large source of funding for autism research. They have posted a RFA (request for application) for their Explorer Awards RFA

This award program is designed to enhance our existing support of autism research by providing timely resources to enable focused experiments highly relevant to our mission. A deeper understanding of the mechanisms underlying autism spectrum disorders or potential therapeutic approaches will require investigation at multiple levels, including but not limited to studies focused on gene discovery, molecular mechanisms, circuits, anatomy, and cognition and behavior. We will consider proposals at all of these levels.

The maximum budget is $60,000, including indirect costs for one (1) year, non-renewable.

The full RFA is on the Simons website: Explorer Awards RFA

Autism Science Foundation interview with Celine Saulnier of the Marcus Autism Center

13 Apr

The Autism Science Foundation is hosting an interview with Celine Saulnier of the Marcus Autism Center today at 12 noon Eastern Time. The interview will be on the ASF Facebook page

Autism Science Foundation fundraiser on Philanthroper

12 Apr

The Autism Science Foundation (ASF) is running a fundraiser on Philanthroper. These are short (1 day) fundraisers with small amounts ($1 to $10). Below is the text from the fundraiser.

https://philanthroper.com/deals/autism-science-foundation

“You can make a big difference with money placed in the right scientific hands.”

– Alison Singer, Autism Science Foundation

It’s Autism Awareness Month. We know a lot and a little about it. We know it’s a development disorder affecting about 1:88 people. We know it affects boys four times more than girls. We know it can make simple communication and social interactions impossibly difficult for those who have it.

We don’t know “the cause,” but we strongly suspect a large genetic component since identical twins will usually share a diagnosis.

We do know we need to learn more.

The Autism Science Foundation is a new group of parents and doctors united to fund the freshest, most exciting ideas to track down the causes of autism and develop evidence-based treatments.

And they’re really good at leveraging small grants to young, driven researchers – like doctoral students – to explore promising new ideas.

“That first grant can make a huge difference,” explains President Alison Singer. “That’s the money that’s dried up from the federal government. That’s what makes or breaks someone’s career.”

It’s a smart approach: don’t write the biggest checks, just try to write the most important ones. Fund a researcher just enough to explore an idea and gather preliminary data. Then, with this germinating seed of science, a researcher can apply for a larger grant somewhere else to continue the work.

And sometimes, most of the legwork of this research has been completed in the umbrella of another study – there’s just no way to see it through.

“You’ll have a student working on another grant who says, ‘wow, we should also be looking at this function, or this particular protein,'” explains Singer. “That only takes a little bit of extra money.”

Given the ASF’s focus on young, driven minds, it’s not surprising that they themselves are a hot startup in the world of autism nonprofits. Nor is it surprising that they’ve already funded successful research at Johns Hopkins.

That said, they can only do what they do by raising money.

“We run this foundation on a shoestring,” says Singer. “At the end of the year, and we write those grant checks and the treasury goes down to zero. The money does not do anyone any good sitting in Citibank.”

ASAN’s Ethical, Legal and Social Implications of Autism Research Symposium Goes Live

10 Apr

The Autistic Self Advocacy Network (ASAN) hosted a symposium on the Ethical, Legal and Social Implications of Autism Research recently. They are now making it available online. See the message below:

Dear Friends:

This week, the media reported that over $1 billion has been spent over the course of the last decade on autism research funding. During a time of constant budget cuts and increasing fiscal pressures on government, this is an astonishing sum. What have we purchased for this investment? How successful has the autism research agenda been in making the American dream a reality for Autistic people and our families? Has our society discussed the ethical, legal and social consequences of how autism research findings may be used? We think these questions are worth asking, and with your help, we think it is past time to get more people involved in the discussion.

Last December, the Autistic Self Advocacy Network joined with the Harvard Law Project on Disability and the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics to hold a symposium on the Ethical, Legal and Social Implications (ELSI) of Autism Research. Supported by a grant from the Administration on Developmental Disabilities, the ASAN ELSI Symposium served as the launching point for a robust conversation about changing the way our society approaches autism research. From our partnership with federal research funders to get self-advocates on grant review panels to growing attention to ethical issues on topics like prenatal testing, self-determination in service-provision and more, the need to introduce values into our national autism research dialogue remains stronger than ever.

Over the course of the month of April, we will be releasing captioned videos of December’s ELSI Symposium. The first is already available on our YouTube channel. You can help us get the word out by watching it alone or with your friends and colleagues, sharing it on facebook and twitter, and starting to talk about these things in your own community. The time has come for our voices to be heard.

Nothing About Us, Without Us!
Ari Ne’eman
President
Autistic Self Advocacy Network

Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders

9 Apr

A study from the U.C. Davis MIND Institute was published today in the journal Pediatrics: Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders. The link is to the abstract, but the full paper is available free for download.

The paper is part of the CHARGE Study. (CHARGE: Childhood Autism Risks from Genetics and the Environment). The study looked for increased risk of a child being diagnosed autism if the mother had metabolic conditions during pregnancy. The metabolic conditions studied were diabetes, hypertension and obesity. They found a possibly heightened risk of autism for these pregnancies. I wrote a more in-depth summary which is available at the Autism Science Foundation blog .

Woot! Autistics and Thinking Person’s Guide to Autism editor quoted in New York Times

8 Apr

A story out today by Amy Harmon of the New York Times, The Autism Wars, takes on some of the discussion ongoing about the new prevalence numbers out from the CDC. It is well worth the read.

What caught my eye, as one could tell from the title of this article, are paragraphs like these:

But Zoe Gross, 21, whose autism spectrum disorder was diagnosed at age 4, says masking it can take a steep toll. She has an elaborate flow chart to help herself leave her room in the morning (“Do you need a shower? If yes, do you have time for a shower?”). Already, she had to take a term off from Vassar, and without her diagnosis, she says, she would not be able to get the accommodations she needs to succeed when she goes back.

and

Those numbers are, of course, dependent on the definition of autism — and the view of a diagnosis as desirable. For John Elder Robison, whose memoir “Look Me in the Eye” describes his diagnosis in middle age, the realization that his social awkwardness was related to his brain wiring rather than a character flaw proved liberating. “There’s a whole generation of people who grew up lonelier and more isolated and less able to function than they might have been if we had taken steps to integrate them into society,” he said.

and:

“The term has become so diffuse in the public mind that people start to see it as a fad,” said Emily Willingham, who is a co-editor of “The Thinking Person’s Guide to Autism.” “If we could identify individual needs based on specific gaps, instead of considering autism itself as a disorder, that would be preferable. We all have our gaps that need work.”

In the past, many media outlets would (a) fail to seek autistic input and (b) seek input from autism parents with rather strong political agendas. Amy Harmon has been writing about autism for the Times recently and has articles focused on autistics, so I am not surprised by the tone of this article. But I do see this as a step forward in American Media coverage of autism news.

(note: I know three editors from the Thinking Person’s Guide team and have met Mr. Robison).

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads

4 Apr

Below is a press release from the National Institutes of Health (NIH) in the U.S.. on recently published studies on autism risk. These are the studies mentioned by NIMH Director and IACC chair Thomas Insel in his article “The New Genetics of Autism – Why Environment Matters“.

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads
Non-Inherited Mutations Spotlight Role of Environment – NIH-Supported Study, Consortium

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on
Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.
State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”

References
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.
O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.
Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.
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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Thomas Insel: The New Genetics of Autism – Why Environment Matters

4 Apr

Thomas Insel is the director of the National Institute of Mental Health (NIMH) and the chair of the Interagency Autism Coordinating Committee (IACC) in the U.S..

His article can be found here (The New Genetics of Autism – Why Environment Matters) and I have quoted it in full bellow. (As a government publication I feel that it is appropriate to use the entire piece):

Last week’s autism news was about prevalence. The CDC reported a 78 percent increase in autism prevalence since 2002. This week’s autism news is about genetics—three papers in Nature describe new genes associated with autism. For many people, these two stories seem contradictory or, at best, unrelated. Increasing prevalence suggests environmental factors like chemicals and microbes changing over the past decade, whereas genes change over generations. Why is anyone looking for genetic causes when there is such a rapid increase in prevalence? Shouldn’t every research dollar be invested in finding the environmental culprit rather than searching for rare gene variants?

The simple answer is that some autism is genetic. Autism, like schizophrenia and mood disorders, includes many syndromes. Indeed, we should probably speak of the “autisms.” Some of these autisms are single gene disorders, such as Fragile X, tuberous sclerosis, and Rett syndrome. While these rare genetic disorders account for less than 5 percent of children within the autism spectrum, children with any of these disorders are at high risk for autism, roughly a 30-fold higher risk than the general population and higher than any of the other known risk factors. Recent genomics research has discovered that many children diagnosed within the autism spectrum have other genetic mutations that have not yet been designated as named syndromes. Each of these mutations is rare, but in aggregate they may account for 10 – 20 percent or more of what we have been calling the autisms.1

The new papers published today in Nature use an approach called whole exome sequencing, mapping every base of DNA across the exome—the 1.5 percent of the genome known to code for protein. The three research groups are members of the Autism Sequencing Consortium (ASC), an international team of autism genetics researchers. All three look for de novo or spontaneous mutations, changes in DNA sequence that are not found in either parent. Recent sequencing studies in the general population have demonstrated that each of us diverges genomically from our parents — the process of reproduction introduces variation even beyond the random mixture of the genomes we inherit from mom and dad. People with autism and schizophrenia are far more likely to have large de novo copy number variants, sometimes a million bases of DNA that are abnormally duplicated or deleted and not found in either parent.
These new papers go beyond the previous discovery of de novo copy number variants to identify de novo single base changes associated with autism. This is tough sailing because there are so many of these changes in all of us and most of these single base changes have no impact. These studies tried to improve the odds of success by focusing on individuals from families with no one else affected (these are called “simplex” families), and sometimes comparing the individual with autism to a sibling without autism. The results are intriguing.

There is no breakthrough or single gene that is a major new cause of autism. But the role of genetics becomes even more evident when these single base changes are considered. For instance, an individual with autism is nearly 6-fold more likely to have a functional variant in genes expressed in the brain. Sanders et al. estimate as many as 14 percent of affected individuals have such a risk variant.2 This 14 percent is in addition to the 10–20 percent with a large copy number variant or identified genetic syndrome. O’Roak et al. find that 39 percent of these variants are related to a specific biochemical pathway, important for brain signaling.3 And Neale et al., while cautioning that the net effect of all of these changes still leave much of the risk for autism unexplained, note the roles of a few specific genes as genuine risk factors.4

Stepping back from this flood of genomic information, what is most important? First, these reports along with previous publications confirm that genetic risk is both complex and substantial. While individual genes appear to confer limited risk, the aggregate effect of spontaneous coding mutations across the genome is now estimated to increase the risk of autism by 5–20-fold.4 Complex genetics does not mean modest effects.

Second, the kinds of small and large genetic changes associated with autism are common in everyone. Risk is conferred not by the size of the mutation or the number of mutations (we all have many) but by the location. Increasingly, we see that interference with the genes involved in development of synapses confer risk; a similar change upstream or downstream does not.
A third point takes us back to the questions we started with. It is important to understand that de novo mutations may represent environmental effects. In other words, environmental factors can cause changes in our DNA that can raise the risk for autism and other disorders. One of these papers reports that spontaneous changes are four times more likely to show up in paternally inherited DNA and are correlated with paternal age.2 The father’s germline, his sperm cells, turn over throughout the lifespan. Presumably, with advancing paternal age, there are a greater number of spontaneous mutations and a greater likelihood that some of these will affect risk genes. Environmental factors and exposures can cause sperm cells to develop mutations that are not found in the father’s somatic, or body cell, DNA, but these new, spontaneous mutations can be passed to the next generation, raising the risk for developing autism. In the initial report of the relationship between autism and paternal age, boys with autism were 6-fold more likely to have a father in his 40s vs his 20s. In girls with autism, this difference went up to 17-fold.5 Paternal age has, of course, increased in the past few decades. This does not explain the increasing prevalence of autism, but it may contribute.

Is autism genetic or environmental? These new studies suggest it can be both. Genetics will not identify the environmental factors, but it may reveal some of the many syndromes within the autism spectrum (as in other neurodevelopmental disorders), it can define risk (as in other medical disorders), and it should yield clues to the biology of autism (revealing potential targets for new treatments). These three new papers on spontaneous mutations are an important milestone in a long journey. In parallel we need to find environmental factors, recognizing that there will be many causes for the autisms and many roads to find them.

Finally, an unavoidable insight from these new papers is that autism even when genetic may be spontaneous and not inherited in the sense that one or both parents carry some reduced form of the syndrome. Perhaps this insight will finally reduce the “blame the parents” legacy perpetuated for too long in the absence of scientific evidence.

References
1Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci. 2011 Sep;15(9):409-16. Epub 2011 Aug 18. PubMed PMID: 21855394.1
2Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.
3O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.
4Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.
5Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E. Advancing paternal age and autism. Arch Gen Psychiatry. 2006 Sep;63(9):1026-32. PubMed PMID: 16953005.

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