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Category: Medical Education

What Causes Autism Spectrum Disorders

You can break down the “cause” of autism to “nurture and nature,” where nature is genetic causes and nurture is environmental causes.

If you want to skim then skim my bolded text, which I’ve also organized as (a), (b), (c) etc… If you want the full Monty, then read my detailed text with original references. This is a very long answer written in the interest of comprehensiveness (and at the risk of being down-voted because of how insanely long this answer is….)

Genetic Basis of Autism

(a) The genetic basis of autism has been studied in twins — and the type of twins. When researchers compared monozygotic twins (“identical” twins) with dizygotic twins (“fraternal” twins), they saw a higher rate of concordance in identical twins.

In other words, if one identical twin has autism, there is a high probability that the other identical twin also has autism. In fraternal twins, the probability is lower but not zero, especially when you expand the autism definition to include the cognitive or language component. [source: Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., et al. (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63–77]

(b) The familial linkage of autism also supports the genetic basis of autism. Two independent familial studies conducted in 2009 has shown that there is a higher risk of autism in siblings versus the general population. [sources: Geschwind, D. H., & Konopka, G. (2009). Neuroscience in the era of functional genomics and systems biology. Nature, 461, 908–915. Pennington, B. F. (2009). Diagnosing learning disorders: A neuropsy-chological framework. New York: Guilford Press]

(c) The gender dominance (boys are more likely than girls to be diagnosed with autism) of autism further suggests a genetic basis of autism. The general theory is that, like Hemophilia (an X-chromosome-linked disease) is passed from mother to son, autism may also be passed on from mother to son. For a genetics refresher, let me use this designation (a) as the autism gene(s) —

If the mother has the autism genetic variant but does not display classic autism symptoms, then mother is probably:

Mother X X(a)

If the father does not have autism genetic variant, father may look like:

Father X Y

Children with autism in this mating follows this pattern

XX(a) + XY = XX or XY or X(a)X or X(a)Y

It depends on which X chromosome from the mother is paired with the father’s chromosome.

You will have a 25% chance of an offspring with autism, and that offspring will be a boy = X(a)Y.
You will have a 25% chance of an offspring carrying the autism gene but not necessarily EXPRESS the phenotype of autism unless there is a triggering factor (where “nurture” or environmental causes come in), and that offspring will be a girl = X(a)X.
You will also have a 50% chance of a genetically “typical” or “neurotypical” offspring XY son or XX daughter.

Is autism a Y-linked disorder? It would explain why there is a higher rate of boys diagnosed with autism versus girls — but if this is a purely Y-linked disorder then you wouldn’t expect to have any girls diagnosed with autism.

Thus: even with the prevalence of boys being diagnosed with autism versus girls diagnosed with autism, autism may not be a sex-chromosomal-linked condition. We just don’t know, because we don’t even know the whole set of genes that can definitively be assigned to “causing what we can phenotypically diagnose as autism.”

(d) Yet there is also at least 1 study that suggests that autism rate increases when the father’s age increases. [source: Reichenberg, A., Gross, R., Weiser, M., Bresnahan, M., Silverman, J., Harlap, S., et al. (2006). Advancing paternal age and autism. Archives of General Psychiatry, 63, 1026–1032. Full text ] In particular from this study:

Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on maternal age. The note on bias of maternal age is relevant because one can argue that maybe it's due to older mothers -- not older fathers (therefore making this more of the mother's genes at play), and paternal age remains the overriding factor. (e) Scientists have studied various genes that contribute to the spectrum of phenotypes in autism, and these genes are compiled in Chapter 6 of the International Handbook of Autism and Pervasive Developmental Disorders, which you can buy for $559 for the 2011 version [from ]. Genes range from NRXN1 (Neurexin 1) and NRXN2 (Neurexin 2) to RELN (Reelin), FOXP2 (Forkhead box P2), CNTNAP2 (Contactin-associated protein-like 2), and PTEN (phosphatase and tensin homolog -- yes, cancer biologists, this is a tumor suppressor gene!), APP (Amyloid beta(A4) precursor protein -- correlates with self-injurious and aggressive behavior). I'm not going to list the entire table here, but you get an idea of the diversity of genes involved and why autism is a "broad spectrum disorder". Environmental Basis of Autism (a) The support for the role of nurture / environmental role in autism is attractive because this is where "hope" is made. Think about it: if I tell you that cancer is wholly genetic, I don't care how well you take care of yourself you're going to die of a certain type of cancer, you're not going to feel very hopeful. But if you believe that there are indeed a strong genetic basis in cancer YET you can also wield a certain span of control over your environment to counter the genes -- you feel more hopeful. I truly think that the subscribing belief to the environmental basis of autism has led to more quackery in the field of autism intervention than if parents wholly subscribe to the primarily genetic basis of autism (but I won't digress on that here.) (b) For one, the genetic basis of autism has led to the discrediting of the "Refrigerator Mother" theory posited by Bruno Bettelheim ( Mothers did not "create" or "cause" autism in their children by being unloving and aloof. (c) For another, "environment" and "nurture" are difficult to be scientific about. There are claims of autism being caused by chemical substances (such as mercury found in vaccines or lead poisoning), food allergies (basis of the gluten-free casein-free diets), food colorings -- for a consumer article on the blurry lines of environmental causes of autism read -- but in order for us critical consumers to accept these claims as "true" we need to have good scientific studies that look at whether these "cause" autism. (d) As an example, the dietary intervention is particularly contentious -- you have parents who claim with utmost sincerity that dietary interventions have been key in their children's improvement in autism symptoms (some go as far as claiming "cure" -- again I won't go there and I won't use that word). They upload videos of their children's "before and after" dietary interventions. But these children also receive interventions that have been proven through research and replicated in many other studies (translation: behavioral interventions like Applied Behavior Analysis as pioneered by the late Lovaas). So how do we know how much is the diet and how much is contributed by ABA? Published peer-reviewed studies of dietary interventions have shown that children with autism who have demonstrated a sensitivity to glutein/casein based foods and children with celiac disease will see improvement in symptoms when on the diet. However, if you exclude these children from the study and look at children without these sensitivities, the diet has not shown to improve outcomes in autism symptoms: J Autism Dev Disord. 2006 Apr;36(3):413-20. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. College of Nursing, University of Florida, Gainesville, 32610, USA. Abstract This study tested the efficacy of a gluten-free and casein-free (GFCF) diet in treating autism using a randomized, double blind repeated measures crossover design. The sample included 15 children aged 2-16 years with autism spectrum disorder. Data on autistic symptoms and urinary peptide levels were collected in the subjects' homes over the 12 weeks that they were on the diet. Group data indicated no statistically significant findings even though several parents reported improvement in their children. Although preliminary, this study demonstrates how a controlled clinical trial of the GFCF diet can be conducted, and suggests directions for future research. Notable: "Group data indicated no statistically significant findings even though several parents reported improvement in their children." IN CONCLUSION (yes yes I'm getting there)... My opinion is that autism is primarily a genetically-driven neurological disorder spanning a wide spectrum of genes that contribute collectively to a particular "phenotype" (how the symptoms manifest, the degree of severity) in a person. Whether the reason why we see more boys than girls diagnosed with autism may be due to a sex-chromosomal (X or Y) linkage, we may speculate but we cannot tell whether this is due to the "X" chromosome contributing, "Y" chromosome contributing, or X or Y chromosome not contributing. Whatever environmental causes that may "trigger" autism, is likely to trigger a genetic component that otherwise remains dormant, as opposed to "causing de novo" autism that would otherwise not exist on a genetic level. I personally do not believe in children "becoming autistic" because they are eating certain foods, gotten a seizure due to vaccines, or by wearing a certain type of fabric for their clothes. HOWEVER, I do believe that children who have genetic components that can be triggered, may be vulnerable to specific environmental assaults. [in other words, please don't flood me with hate mail, I'm not saying there isn't a link, I'm only saying there may not be a cause.] Finally, just because parents subscribe to genetic bases of autism does not mean there is no hope. There is a genetic basis of major depressive disorders (I come from a family of undiagnosed depressives and I believe I have those genes and I have suffered from depression) -- but this doesn't mean we don't have bona fide, scientifically-based interventions that produce acceptable outcomes in terms of quality of life. I will never claim that I've been "cured" of depression -- I don't believe this is true for myself. But I have an excellent quality of life and I am happy with my life -- even as I live with depression genes that can be triggered by specific environmental assaults. Link out to: Markram's Intense World Theory -- A Unifying Theory of the Neurobiology of Autism

How Antibiotics Work

Both ‘gram positive’ and ‘gram negative’ (named for each type of bacteria’s ability to hold the gram stain due to thickness of its peptidoglycan cell wall) bacteria are susceptible to different types of antibiotics based on the drug’s ability to inhibit peptidoglycan synthesis of the cell wall, integral to the bacteria’s physical structure.

Gram negative bacteria has an unique outer membrane which acts as an effective protection and barrier against many detergents and antibiotics.

Gram negative bacteria therefore would not be susceptible to drugs like penicillin and must be treated with other types of antibiotics specifically inhibiting its unique outer membrane.

Gram staining:

Gram negative bacteria:

The reason why it’s important to understand both the replication mechanisms and the structural differences in different types of bacteria is because any “rational” design of drugs that would serve as an effective antibiotic would target mechanisms specific to procaryotic replication without affecting eucaryotic replication (that would affect mammalian cells for instance, i.e. our own cells), and furthermore, target any specific traits of the bacteria we want to kill without affect the regular microbial flora in our bodies.

CME and Pharma: Doctors Want Support That They Can’t Trust

“Doctors want CMEs paid for them but can’t trust the people they want to help pay for their continuing medical education.” That’s how I sum up the below survey published by Archives of Internal Medicine.

Look at what the conclusion said: “Although the medical professionals responding to this survey were concerned about bias introduced from commercial funding of CME, many were not willing to pay higher fees to offset or eliminate such funding sources.”

If doctors are so concerned about ethics and bias, then they need to put up the money and pay for their own continuing education to stay current in their fields so that they can do their jobs. But based on “reality”, doctors are more concerned about their bottom-line and the survey suggests that their bottom-line trumps whatever concerns about bias they may have.

Clinician Attitudes About Commercial Support of Continuing Medical Education

Results of a Detailed Survey

Jeffrey A. Tabas, MD; Christy Boscardin, PhD; Donna M. Jacobsen, BS; Michael A. Steinman, MD; Paul A. Volberding, MD; Robert B. Baron, MD, MS

Arch Intern Med. 2011;171(9):840-846. doi:10.1001/archinternmed.2011.179

Background Pharmaceutical and medical device company funding supports up to 60% of accredited continuing medical education (CME) costs in the United States. Some have proposed measures to limit the size, scope, and potential influence of commercial support for CME activities. We sought to determine whether participants at CME activities perceive that commercial support introduces bias, whether this is affected by the amount or type of support, and whether they would be willing to accept higher fees or fewer amenities to decrease the need for such funding.

Methods We delivered a structured questionnaire to 1347 participants at a series of 5 live CME activities about the impact of commercial support on bias and their willingness to pay additional amounts to eliminate the need for commercial support.

Results Of the 770 respondents (a 57% response rate), most (88%) believed that commercial support introduces bias, with greater amounts of support introducing greater risk of bias. Only 15%, however, supported elimination of commercial support from CME activities, and less than half (42%) were willing to pay increased registration fees to decrease or eliminate commercial support. Participants who perceived bias from commercial support more frequently agreed to increase registration fees to decrease such support (2- to 3-fold odds ratio). Participants greatly underestimated the costs of ancillary activities, such as food, as well as the degree of support actually provided by commercial funding.

Conclusion Although the medical professionals responding to this survey were concerned about bias introduced from commercial funding of CME, many were not willing to pay higher fees to offset or eliminate such funding sources.

Updated Heart Attack Treatment Guidelines

This week the American Heart Association and the American College of Cardiology have published updated treatment guidelines for heart attacks (or, as the journal article titled it, “Update of the Clinical Competence Statement on Cardiac Interventional Procedures”). The entire update is currently available in full from the Journal of the American College of Cardiology (JACC) via this link (technical). According to Reuters Health, which reported on this update, the guidelines focus on identifying patients at risk early and the right treatment. In patients with “low risk”, medication therapy is recommended, and tests of cardiac functions are suggested. In patients with “high risk” intervention including angioplasty is recommended.

Backgrounder on Diabetes Drug Avandia Controversy

I’ve been tracking the various developments and commentaries on the controversy surrounding diabetes drug Avandia (rosiglitazone, manufactured by GlaxoSmithKline). For those of you interested in background information and commentaries relating to the use of Avandia and increased risk for heart disease, as well as the affordability of chronic medications like diabetes drugs, I’ve compiled a short reading list including abstracts to the original research articles to help you get started. Please read my conflict of interest disclosure at the end of this article. (more…)

How Much Vermont Psychiatrists and Endocrinologists Received from Drug Companies

Gardiner Harris of New York Times wrote about Vermont’s disclosure of the amount of funds that the states doctors received from drug companies. While the focus was on psychiatrists, because they received top total dollars, I was particularly intrigued that endocrinologists as a specialty followed a close second. Those of you familiar with the field (I briefly worked in the field when I was a pharma employee) know that compared to psychiatrists, endocrinologists are a much smaller group as a specialty.

moneyparachute.gif Still, I was concerned that psychiatrists earn so much money from drug companies because in general, doctors can earn money from drug companies mainly through consulting fees (including speaking fees) or from participating in clinical trials. In neuroscience, clinical trials tend to be very large and time-consuming to have any meaning behind the results. This means psychiatrists wouldn’t make much money per year from clinical trial participation alone, and the bulk of their revenues would come from “consulting” agreements. Consulting agreements usually comprise of speaking engagements and other “advisory board” activities. While we have many more drugs within the psychiatric therapeutic area than endocrinology, why wasn’t cardiovascular specialists a close second or even topping the list? The number of psych drugs could rival the number of cardiovascular drugs on the market.

Could it be that there is much more off-label (unapproved) use of psychiatric drugs than there is for cardiovascular drugs? This was implied by the NYT article, when it noted that psychiatrists who earned a lot of money tend to prescribe psych meds to children the most often. (more…)

Truth in Medical Marketing and CMEs

Recently newsgroup user jkellymdmph asked a question that I had brought up when Google Co-op Health first launched:

How can this group health effort can resist infiltration by aggressive marketing?

jkellymdmph goes on to describe a continuing medical education (CME) event he attended that was supported with an unrestricted grant from a pharmaceutical company. There are two important notes in this story:

1) He thought the CME was very good, and “didn’t notice” that the supporter was a pharma company

2) … until the speaker began to tout the company’s drugs as “the best” (more…)

How Future Doctors Choose Their Specialties

Drs. Paul Ciechanowski and colleagues found that 129 fourth year medical students from Univeristy of Arkansas for Medical Sciences who choose to enter primary care specialties are attracted to a patient centered environment that affords a “secure” relating style. Those who choose to enter non-primary care specialties are attracted to career rewards that afford a “self-reliant” relating style. This study assessed how much the med students’ specialty choices were based on students’ own experiences with caregivers and learned ways of interacting with others (”relationship styles based on attachment theory”).

Choosing a medical specialty specialty is an important decision for medical students because students who change course after making a decision may not receive training funding. Additionally, career choice also predicates the type of work environment that the physician engages in. Fourth year medical students were an appropriate group to study because these students have had significant clinical experiences in medical school and the time to carefully consider their options. (more…)

New Google Co-Op for Health

Google has created clusters of online discussion format called Co-ops.

The Co-op is about “sharing expertise” (source: Google Co-Op website), I assume from whoever feel they have expertise to share. A Google employee posted general criteria about what posts would be stricken from a Co-op group:

  • The posting of commercial advertisements or other promotional material
  • Spamming/excessive multi-posting
  • Chain letters
  • Binary (non-text) postings
  • Forgery of another user’s identity

(Source: Thread ID c603a0b6578b735a)

Currently,”significant contributors” to Google Co-Op’s Health topic National Library of Medicine, Centers for Disease Control and Prevention, Health On The Net Foundation, Harvard Medical School, Mayo Clinic, University of California San Francisco, and Kaiser Permanente. (more…)

What Open Medicine Is and Is Not

A benefit – and side effect – of Internet culture is an embrace toward access and openness. I can access an abundance of free information on the web. I’ve always embraced open source applications, like the one used to create this website, and will continue to do so as long as it’s available.

However, a potential misconception called “Open Medicine” is a side effect of the Internet culture. I do not believe most people who advocate for “Open Medicine” on the web actually understand what “Open Medicine” really means, and all the ramifications and responsibilities that come with the term. When most speak of “Open Medicine” they refer to the idea that medical information should be freely available, transparent, and credible.

I don’t argue with the concept of making healthcare information available, transparent, and credible. After all, I created to provide Accessibility, Honesty, and Integrity in healthcare information.

What I oppose is the misconception built around Open Medicine. In my opinion, here is what Open Medicine is NOT:

Open Medicine is not a blogging network, even if the blogging network is composed of a team of doctors, nurses, scientists, other healthcare “experts”, or anyone who has a burning desire to voice an opinion about a particular healthcare trend or drug.

In considering what Open Medicine really is, we only need to look at the basic definition of “Open” as it relates to this Internet phenomenon:

The basic idea behind open source is very simple: When programmers can read, redistribute, and modify the source code for a piece of software, the software evolves. People improve it, people adapt it, people fix bugs. And this can happen at a speed that, if one is used to the slow pace of conventional software development, seems astonishing. Source: Open Source Initiative.

In other words, Open Medicine can work only when we are allowing access to what is considered proprietary information or intellectual property, for the expressed purpose to enable collaboration to improve and innovate upon this “open” information. (more…)

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