The safety and efficacy of Ritalin

Another article reiterating the peculiar longterm efficacy and safety of Ritalin (methylphenidate). The side-effect data is based on chart review, so it's particularly meaningful (22%). The primary value of the study is to show that ritalin works as well in the real world as in clinical trials.

J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study

* Barbaresi WJ, et al

Department of Pediatric and Adolescent Medicine, Division of Developmental and Behavioral Pediatrics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. barbaresi.william@mayo.edu

The purpose of this study was to offer detailed information about stimulant medication treatment provided throughout childhood to 379 children with research-identified attention-deficit hyperactivity disorder (ADHD) in the 1976-1982 Rochester, MN, birth cohort. Subjects were retrospectively followed from birth until a mean of 17.2 years of age. The complete medical record of each subject was reviewed. The history and results of each episode of stimulant treatment were compared by gender, DSM-IV subtype of ADHD, and type of stimulant medication. Overall, 77.8% of subjects were treated with stimulants. Boys were 1.8 times more likely than girls to be treated. The median age at initiation (9.8 years), median duration of treatment (33.8 months), and likelihood of developing at least one side effect (22.3%) were not significantly different by gender. Overall, 73.1% of episodes of stimulant treatment were associated with a favorable response. The likelihood of a favorable response was comparable for boys and girls. Treatment was initiated earlier for children with either ADHD combined type or ADHD hyperactive-impulsive type than for children with ADHD predominantly inattentive type and duration of treatment was longer for ADHD combined type. There was no association between DSM-IV subtype and likelihood of a favorable response or of side effects. Dextroamphetamine and methylphenidate were equally likely to be associated with a favorable response, but dextroamphetamine was more likely to be associated with side effects. These results demonstrate that the effectiveness of stimulant medication treatment of ADHD provided throughout childhood is comparable to the efficacy of stimulant treatment demonstrated in clinical trials.

There's something interesting about a medication that's this safe and effective. We don't see that very often in medicine, even physiologic substances like thyroid hormone have more side-effects.

Behavioral interventions: a bit of a fraud?

We're multi-year veterans of a range of neurobehavioral disorders. We also have medical degrees and attend a range of meetings that discuss the management of autism, ADHD, etc. Finally, we have access to a wide range of reputable and experienced psychologists, psychiatrists, social workers, medical subspecialists, etc. We have a healthy fear of longterm neurochemicals (drugs), but we use 'em and are pretty darned happy they exist. Even so, we're predisposed to prefer behavioral interventions.

Which is all to say, we ought to have a nice library of behavioral interventions at our fingertips.

If they existed.

Which, I'm beginning to suspect, they don't.

We've practiced everything we've been told, read about and invented that has any kind of evidence base, but it hasn't taken long to run out of ideas. We rely on a small set of moderately effective interventions and medication adjustment. It's been years since any specialist suggested a behavioral intervention that was new to us.

At the end of the day, I suspect there aren't that many useful behavioral interventions out there. The ones that work could probably fit on an index card, and their implementations could fit in a few short papers.

So here's my modest proposal. Until we get a wider range of behavioral therapies for ADHD, EBD, ODD, autism, CD and the rest of the alphabet -- let's be a bit more modest about how many good behavioral interventions really exist. Don't let speakers get away with vague references to "behavioral interventions" -- pin 'em to the wall and demand four examples. They won't mention the topic again ... :-).

Scrambled letters and reading disability, not to mention emergent memes and urban myths

This is fascinating on several levels. Today a colleague sent me the 'scrambled letter' email that's been bouncing around the net for a few years. His version looked like this:

I cdnuolt blveiee taht I cluod aulaclty uesdnatnrd waht I was rdanieg.

The phaonmneal pweor of the hmuan mnid Aoccdrnig to rscheearch at Cmabrigde Uinervtisy, it deosn't mttaer in waht oredr the ltteers in a wrod are, the olny iprmoatnt tihng is taht the frist and lsatltteer be in the rghit pclae.

The rset can be a taotl mses and you can sitll raed it wouthit a porbelm. Tihs is bcuseae the huamn mnid deos not raed ervey lteter by istlef, but the wrod as a wlohe. Amzanig huh?;

Most people can read the text easily if they scan or defocus a bit, but it would be very difficult for a non-fluent reader to decipher the strings using a phonics approach. Thinking this over, I thought of a person I know who reads at the 2nd grade level (mostly) but seems to derive significant, measurable, meaning from 4th grade texts that he cannot read aloud. I wondered about a connection, so I googled on 'Cambridge scrambled words' and discovered a neat story of layers.

Matt Davis on the Cambridge scrambled letter meme

... Aoccdrnig to a rscheearch at Cmabrigde Uinervtisy, it deosn't mttaer in waht oredr the ltteers in a wrod are, the olny iprmoetnt tihng is taht the frist and lsat ltteer be at the rghit pclae. The rset can be a toatl mses and you can sitll raed it wouthit porbelm. Tihs is bcuseae the huamn mnid deos not raed ervey lteter by istlef, but the wrod as a wlohe...

...This text circulated on the internet in September 2003. I first became aware of it when a journalist contacted a my colleague Sian Miller on 16th September, trying to track down the original source. It's been passed on many times, and in the way of most internet memes has mutated along the way. It struck me as interesting - especially when I received a version that mentioned Cambridge University! I work at Cognition and Brain Sciences Unit, in Cambridge, UK, a Medical Research Council unit that includes a large group investigating how the brain processes language. If there's a new piece of research on reading that's been conducted in Cambridge, I thought I should have heard of it before...

I've written this page, to try to explain the science behind this meme. There are elements of truth in this, but also some things which scientists studying the psychology of language (psycholinguists) know to be incorrect. I'm going to break down the meme, one line at a time to illustrate these points, pointing out what I think is the relevant research on the role of letter order on reading. Again, this is only my view of the current state of reading research, as it relates to this meme. If you think I've missed something important, let me know...

Ironically the rest of the page, which Matt has added too in a haphazard fashion, is quite hard to follow. The paragraphs, essentially, are scrambled. (Cambridge is also mis-spelled in the URL, but that's obviously an example of dry English wit). Matt collects examples in languages with varied linguistic structures, demonstrates that not all scrambles are equallyl readable, references software for generating readable "scrambles", but then discovers the truth buried in the myth ...

... [later] I've found a ... page that tracked down the original demonstration of the effect of letter randomisation to Graham Rawlinson. Graham wrote a letter to New Scientist in 1999 (in response to a paper by Saberi & Perrot (Nature, 1999) on the effect of reversing short chunks of speech). You can read the letter here, or in a link to New Scientist, here. In it Graham says:

"This reminds me of my PhD at Nottingham University (1976), which showed that randomising letters in the middle of words had little or no effect on the ability of skilled readers to understand the text. Indeed one rapid reader noticed only four or five errors in an A4 page of muddled text."

It's possible that with the publicity offered by the internet, that Dr. Rawlinson's research might be more widely read in future. For those wanting to cite this in their own research the full reference is:

Rawlinson, G. E. (1976) The significance of letter position in word recognition. Unpublished PhD Thesis, Psychology Department, University of Nottingham, Nottingham UK. (summary here)

So Dr. Rawlinson's unpublished 1976 thesis (31 years ago) has come to worldwide attention as the result of a propagating urban myth that's not a myth, and this story is best illustrated by a chaotic and scrambled web page that further extends the original work across multiple languages and references newer software for generating readable scrambles.

Now that's a strange loop, and quite post-millennial. The world-mind evidently decided that this research should not be ignored indefinitely. I look forward to Dr. Rawlinson's future television career ...

Diagnosing autism more frequently - means what?

The Strib, our local paper (now on life support) had an impressive graph on the front page yesterday. Alas, the (feeble) web site lacks the graph, which was a typical exponential growth curve implying that within 20 years every child will carry the diagnosis of autism [4].

So what does the increase, and the current estimate from a recent CDC study of 1/150 children, mean? First, here's some text from the article (emphases mine) ...

Autism everywhere
By David Peterson, Star Tribune
Last update: April 09, 2007 – 11:55 PM

... The number of kids classed as autistic is exploding. A recent study by the federal Centers for Disease Control and Prevention reported that autism is found in one in 150 children -- and researchers involved in the study say that may be an understatement. In Minnesota schools, the state's Department of Education reports, the number of students identified as autistic jumped from fewer than 1,000 students a decade ago to nearly 10,000 today.

In months, three committees of the Minnesota Legislature will hold hearings to explore the reasons why. "Special ed costs are exploding," said Roseville DFL Rep. Mindy Greiling, who chairs the K-12 division of the Minnesota House Finance Committee. "People who know a lot about it tell us that it's not just that we're getting better at identifying autism, there is actually more and more autism," she said.

"Herbicides, pesticides, various pollutants can cause brain disorders in fetuses and babies, and we want to look at that, not only to save costs but save the human costs of these tragedies," Greiling said...

... Nationally, advocacy groups are expressing alarm, using the words crisis, epidemic, even national emergency to describe the increase. In Minnesota, however, advocates are more restrained. Mary Powell, executive director of the Autism Society of Minnesota, speaks of "dramatic" increases in caseloads but hastens to note that that's partly because the definition is widening.

A debate simmers over what's behind the increase. Some people blame vaccinations though extensive medical studies haven't found a link, according to MayoClinic.com. Others, like Greiling, point to environmental influences...

The Combating Autism Act of 2006, which President Bush signed in December, authorizes nearly $1 billion over the next five years to combat autism through research, screening, early detection and early intervention.

Autism intervention is costly. According to the United States Government Office of Accountability, programs for a school-aged child with autism costs $18,800 per year compared with $12,500 for average special education per pupil expenditures.

"We struggle almost every day for resources for kids," said Dr. Dan McLellan, a pediatrician specializing in child development at Children's Hospitals and Clinics of Minnesota. The challenge for school districts is significant, said Anne Harrington, autism resource specialist for the Minneapolis schools. "We're scrambling to keep up with the needs."

Insurance companies, said McLellan, don't always help. "One big problem is that many decline coverage because contracts exclude 'developmental delays,' " he said. "We see it as a disorder. Some health plans still see it as a delay that schools can take care of."

A spokeswoman for the insurance industry said that varies according to the benefits package. "There is often a discussion of where the medical component leaves off and where the educational arena might begin," said Susan Pisano, vice president of communications for the Washington, D.C., trade group America's Health Insurance Plans.

... Researchers emphasize that they were prevented from using key data sources that would likely have pushed the ratio higher...

I'm willing to bet the increase has nothing to do with herbicides, pesticides, immunizations, mercury, gluten, etc (though if we were to find the prevalence is five times higher in China I might reduce the bet -- except it's not). We've not found any fruitful leads when exploring those domains -- despite a remarkably vacuous Discover magazine article that was enthusiastically received by the Autism Society of America. (Kudos, by the way, to Mary Powell of the MN society for a sober response in this article.)

So what's going on? There's a reason I emphasized one line in the article as bold and red. Diagnostic labels drive resources. Autism, like all disorders of the mind, lacks the insurance coverage given, say, cerebral palsy (a disorder of the brain with physically disabling manifestations). On the other hand, the label of autism delivers enhanced educational resources, whereas low IQ does not.

8% of the population has cognitive abilities in the bottom 8% of the population [1]. That's a rate of 12 in 150. If half these children get relabeled as autism the prevalence will reach 6/150, or 600% higher than it is now, before the trend levels off.

Why would children in the bottom 8% of the cognitive curve get relabeled as autistic, Asperger's, or "autism-spectrum disorder"? Because otherwise they won't get the educational resources they need and deserve. The definition of autism and autism-spectrum disorders is very problematic, and given the latitude to assign the diagnosis parents, teachers and clinicians will rightly do what's in the best interests of the child.

Consider this article from April of 2006 ...

Respectful Insolence: Evidence against an "autism epidemic"

... Shattuck analyzes special education figures that are being used to bolster claims of an autism "epidemic" and finds them wanting. In essence, diagnostic substitution can explain nearly all of the apparent increase of autism as recorded by the number of children receiving special education services.

...Dr. Shattuck starts with an example from a different condition, mental retardation as one of his reasons for suspecting diagnostic substitution as a cause of the perceived "epidemic":

...Second, prior research has established a precedent of diagnostic substitution in special education enrollment. From 1976 to 1992 the number of children in the mental retardation (MR) category decreased by 41%, whereas the number in the learning disabilities (LD) category increased 198%. There is considerable evidence that suggests this was because of a growing likelihood that schools would use the LD label for children with mild MR, presumably because a label of LD was increasingly seen as carrying less stigma than MR. Finally, a recent epidemiological study depicted a downward deflection in the incidence trend of other developmental disorders just as the trend for autism made a sharp upturn in the early 1990s, again suggesting the possibility of diagnostic substitution.

Shattuck has the data, but he's missed completely the driver. It's not "social stigma" (though autism, and especially Asperger's, is a much less depressing term than "mental retardation"), it's that most school systems don't deliver enhanced educational and social resources to children who are on the low end of the cognitive curve.

So, obviously, I think a lot of the growth in the diagnosis of autism-spectrum disorders is being driven by diagnostic substitution. I think the substitution is driven by a just and honorable desire to provide children with the educational resources they need in an increasingly complex, competitive, uncertain and demanding world. The substitution can occur without the necessity of deception because we don't have good models to categorize disorders of behavior and cognition.

BUT, is there anything else going on? Is there a "real" change in either the prevalence, or the nature, of cognitive disorders in children? What would we find if we compared the "bottom" [2] 8% of 1950 with the "bottom" of 2007? Would the minds measure out differently? My wife thinks there's a difference, and she's often right about such things. Old-time clinicians think their young patients look different. Does some of the "diagnostic substitution" reflect an underlying change in the nature of cognitive disability? Is there a real rise in the rate of disability?

Those are biologically interesting questions. I would not be surprised if there have been some real changes, but more on the level of a 50% increase or change rather than a 1000% increase. That's still, by the way we measure things, a pretty significant increase over a period of 10 years.

I suspect differential mating (like-marries-like) plays a role [3], and one can always speculate about environmental effects (ultrasound and neuronal migration?). If I had to really, really, speculate however, I'd wonder about an infectious disease process [4] ...

[1] I know it's a tautology. It's also important.
[2] It's important to remember that what puts one at the "bottom" of today's world might play out differently in another world. I suspect that for most of human history my eagle-eyed, hyper-alert, hyper visual processor son would have been supporting me rather than vice-versa.
[3] This, by the way, is probably how the human mind evolves. This should vary by country and culture so it's a testable hypothesis.
[4] Not to be confused with an immunization side-effect
[5] I made up the 15 years number, but eyeballing the curve that seems about right for an exponential-seeming process that increases 10 fold in 10 years.

Autism and trauma to the prefrontal ventromedial cortext

Adults with injuries to the ventromedial prefrontal cortex have social cue problems and a utilitarian style of moral decision making.

Dysfunction of the ventromedial prefrontal cortex has also been implicated in some types of autism.

Reversing the cognitive dysfunction of Down's Syndrome

Yesterday I wrote about an experiment that reversed an artificially induced autism-like syndrome in mice and mentioned an old science fiction story - Flowers for Algernon. Today I'm stunned by another, similar, story (emphases mine)

Drug May Counteract Down Syndrome: Scientific American

Researchers may have finally found a drug candidate for reducing the mental retardation caused by Down syndrome, which afflicts more than 350,000 people in the U.S. Researchers gave low doses of a human drug to mice bred to mimic the learning and memory problems in people with Down syndrome. After as little as two weeks, the impaired mice performed as well as normal ones in learning tests, and the improvement lasted for up to two months after treatment ended.

But there is a catch: the drug was taken off the market 25 years ago after being found to cause dangerous seizures in some people. And many compounds that boost learning in mice fail in human trials.

... Researchers tested the drug, pentylenetetrazole (PTZ), as well as two other compounds—picrotoxin and a gingko biloba extract called bilobalide—because they all interfere with tiny ion channels on brain cells (neurons). When activated, the channels, known as GABAA receptors, inhibit the cells, making it harder for them to form new synapses, or connections, with neighboring neurons.

The deficits of Down syndrome may occur because the brain contains too many such inhibitory signals, says Stanford University neurobiologist Craig Garner, whose group performed the experiments. "In order to learn, you have to have a period during which synapses can get stronger or weaker," he says. "This changing is what's not possible when you have too much inhibition."

So Garner, his student Fabian Fernandez, and their colleagues gave their mice either low doses of PTZ mixed with milk, or low-dose injections of picrotoxin or bilobalide, daily for two to four weeks to slightly raise the level of excitation in the brain. Immediately after treatment, the animals' scores on two memory tests—for recognizing objects they had seen before or remembering how they last entered a maze—were on par with normal mice; two months later, they still did much better than they normally would, the researchers report in a paper appearing online February 25 in Nature Neuroscience.

The treatment "is allowing the normal properties of neurons to work," Garner says. "This slowly over time leads to an improved circuit."

Reeves says there may be other ways to treat Down syndrome, but "you can see your way to clinical testing most easily from here," because researchers identified specific chemicals. "It's hugely promising," he says. "Maybe it will have a big effect, but we don't know that." The inhibition model is plausible, but still unproved in people, he notes, and until researchers better understand the mechanisms by which the compounds work, "I'm wary of rushing into the clinic."

Garner says clinical trials of PTZ could begin in the next year or two, and evaluating them might take five to 10 years. He notes that although PTZ is nearly 100 years old and was used to treat psychiatric disorders and later dementia, researchers never concluded it was effective. It also caused seizures (at doses 100-fold higher than those given to the mice), so the FDA revoked its approval in 1982.

In Down syndrome, chromosome 21 is present in three copies instead of two. Similarly, the mice used in the study have a duplicated piece of chromosome 16. As in Down syndrome, these animals have malformed facial bones and problems forming new memories...

This is so stunning we must consider the possibility of fraud, but Nature Neuroscience must have been extra cautious given these results.

I would expect this not to work in humans, or to have very nasty side-effects with longterm use, but the game has most definitely changed.

Are cognitive improvements preceded by behavioral deterioration?

After several weeks of discouraging behavioral deterioration, a child of my acquaintance abruptly demonstrated a new sent of cognitive skills. As of the past few days, he is able to connect "good behavior" with the accelerated return of privileges, to make an internal and prolonged attempt to "behave well", to comprehend the delayed gratification of earning a future allowance [1] incrementally, to grasp the meaning of a "budget" and of "change", and to understand that "change" can be saved for future actions.

This is a staggering amount of new capability that appears to have manifested all at once, though clearly it must have been building for some time. It implies a significant new range of behavioral affordances (levers) that we and he can use.

I find it interesting that these new capabilities were preceded by weeks of discouraging behaviors that felt like a regression. Is this correlation entirely coincidental? In retrospect it seems we've seen this before -- a step forward preceded by a half-step forward.

This suggests a testable hypothesis:

1. Significant cognitive improvements reflect significant changes to the deep structures and networks of the prefrontal cortex.
2. These transformations are akin to redoing the engine and transmission of a running vehicle, or rewiring the circuits of a flying 747, or replacing the software of a running server module by module. In each of these cases we would expect system performance to deteriorate, even to "crash" periodically.
3. We would then expect, in humans, that major changes to critical cortical systems would be associated with substantial behavior and cognitive disruptions.

This could be tested by longitudinal measurement of cognitive performance and behavior in a cohort of children, looking for correlation between behavior disruption and subsequent cognitive improvement.

In the meantime, the hypothesis is useful for getting parents, family and teachers through those nasty and discouraging bad patches. Consider them as "growing pains of the mind".

[1] The current allowance scheme, which has been substantially more successful than expected, works like this:

• allowance is displayed in a visible jar in the kitchen. Any removal of items from the jar causes a reset to the starter level.
  
• 50 cents at the start of a cycle
  
• 5 - 10 cent payments for various positive actions (we don't pay for the absence of negative actions, that has never worked in any form) such as getting dressed on awakening, unloading the dishwasher, feeding the dog, staying in bed until 6:30am, paying a game for 10 minutes with a sibling, etc.
• allowance claimed after 7am Saturday.
• all of the siblings get the same amount of money as the child who earns the allowance.

The last of these is the inspired step -- providing an incentive for sibling collaboration and fostering favor/reward sibling transactions. We may migrate to separate transactions and varying share levels as things evolve.

Reversing a severe brain disorder in adult mice

Mice with an artificially disabled gene (MECP2) developed a severe autism-like disorder. After the mice became adults researchers reactivated the gene. The disorder largely resolved...

Progress Is Reported on a Type of Autism - New York Times

Researchers have found that Rett syndrome, a severe form of autism, may not be so entirely beyond repair as supposed. In mice that carry the same genetic defect as human patients and have similar symptoms, the disease can be substantially reversed, even in adult mice, by correcting the errant gene.

.... Rett syndrome strikes mostly girls, who around the age of 3 start to lose their speech and movement faculties. It is one of the spectrum of autistic disorders, but unlike most of the others it is caused by mutations in a single gene. [jf: in the last few days there's a suggestion that other forms of autism maybe associated with up to 6 single gene defects.]

The gene, known as MECP2, was identified in 1990 by Adrian Bird, a molecular biologist now at Edinburgh University. In 1999, Ruthie Amir and Huda Zoghbi at the Baylor College of Medicine discovered that mutated forms of this gene are the cause of Rett syndrome.

Dr. Bird, as part of his continuing study of what the gene does, engineered a strain of mice whose MECP2 genes had been inactivated with the insertion of an extra block of DNA. When the mice were several weeks old, they started to develop the symptoms of Rett syndrome, including the loss of movement control seen in human patients.

Dr. Bird and his colleague Jacky Guy had engineered a second gene into the mice, one with the ability to snip out the interfering block of DNA in MECP2. The second gene could be activated at will by dosing the mice with the drug tamoxifen. When the stricken mice were fed tamoxifen, even at quite advanced ages, they lost the symptoms of Rett syndrome, Dr. Bird and his colleagues reported last week in the journal Science.

A similar finding was published this month in The Proceedings of the National Academy of Sciences by Dr. Rudolph Jaenisch and colleagues at the Whitehead Institute, though in this study the mice’s recovery was not as complete.

Dr. Bird believes that the mice’s symptoms are reversible because the MECP2 gene is not involved in any of the steps that lead neurons to grow and make the right connections among themselves. The gene comes into play only afterward, in maintaining the genetic decisions the developing neurons have made. Among the most important of these are steps to permanently switch off many genes that the neurons will no longer need. Each of the various symptoms of Rett syndrome presumably arises because a specific gene that should have been shut down is left on, causing havoc.

The MECP2 gene plays a central role in this silencing process. Its job is to recognize chemical tags called methyl groups that get added to DNA at what are called CpG sites, and to recruit proteins that silence or switch off the genes at these regions. “What MECP2 does is to go where the methyl groups tell it to go,” Dr. Bird said. “So when you put it back, normal service is resumed.”

Dr. Bird believes that this is the first time a neurological disease has been corrected by restoring a missing component of cells, and that researchers should now reconsider the view that little can be done to repair the brain after birth. “Our result shows it’s not too late,” he said, “so there’s no excuse for not going hell-for-leather to find some sort of therapy.”

The reconsideration could extend to other neurological diseases in which the neurons appear to be intact. “Given that features of Rett can be reversed in a mouse model,” Dr. Zoghbi said, “one would predict that postnatal disorders like autism and schizophrenia might be reversible.

It's hard not to think of Flowers for Algernon reading this. However, I believe most forms of "schizophrenia" and "autism", both of which are probably collections of nameless diverse disorders do show some structural changes on brain imaging, so it is unlikely they could be fully reversed. We should note that two experiments are described, and in the second the mice did not fully recover. Also mice are far better at healing themselves than humans are. Lastly, and most importantly, this only worked because the gene knockout was designed to be readily reversible. Gene therapy in adult humans has been a miserable failure.

And, of course, the hero of Flowers for Algernon had only a short lived response to treatment.

Even so, it is a stunning result. I imagine that funding agencies and researchers are frantically rewriting grants and guidelines. Now that we know this is conceivable, we will be looking for medications that may alter the expression of defective genes, such as medications used to treat sickle cell anemia.

I suspect any possible therapeutic measures for humans that would do something like this are 20-30 years away. Even so, that is well within the lifespan of today's autistic children.

Neurexin: one of 6 autism genes?

The Autism Genome project has released one gene candidate involved in "autism" on chromosome 2, they suspect they'll find at least five more including one on chromosome 11.

Scientific American: Largest Ever Autism Study Identifies Two Genetic Culprits

The largest genome scan ever conducted to get to the bottom of autism has pinpointed two locations in the human genetic makeup that may trigger the mysterious mental condition. The Autism Genome Project, a collaboration of 120 scientists representing 19 countries and 50 institutions, compared the genomes of 1,168 families with at least two autism sufferers in them to try to track down the regions. The consortium reports its findings in this week's issue of Nature Genetics.

... In the two-fold analysis, the researchers implicated the gene neurexin 1, located on chromosome 2, as well as a swath of sequence on chromosome 11.

Neurexin 1 is part of a three-member family of genes coding for proteins involved in communication between neurons. It is associated with glutamate, the neurotransmitter known to elevate neuronal activity and play a role in early wiring the brain. Glutamate g has been implicated in other syndromes involving mental retardation of which autism is often a symptom, such as Fragile X and tuberous sclerosis. Neurexin 1 is specifically believed to be involved in building glutamate synapses, the links through which glutamate neurons send and receive electrical signals.

... "As for the chromosome 11 location, we think there is another susceptibility gene there and we are actively pursuing it. We are in the neighborhood and have a plan to find it." The section of chromosome 11 identified in the study has been linked to proteins that ferry glutamate across synapses.

... Among the variations found in the Autism Genome Project subjects was the deletion of the neurexin gene. Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism.

As we identify the genes we'll be able to divide autism into subtypes based on gene mutations and combinations of mutations and adaptations. That will help with developing prognostic measures and subtype specific medications and interventions. We'll be able to detect at risk persons earlier, and see if there are interventions that will mitigate disability. One day, perhaps, we may even be able to identify medications and therapies that might facilitate healing of the injured brain -- though that is likely at least 10 years away.

I would not be surprised to learn that there are adaptive advantages to some of these mutations in some persons ...

Update 2/20/07: Thinking it over, it's probably worth pointing out that the major implications of identifying these genes will be eugenic. A significant portion of people carrying the autism-associated variants may opt for sperm egg/selection, selective abortion, etc. I wonder if Isaac Newton would have been born under these circumstances ...

Cognition, autism and schizophrenia

More evidence that genes that underlie some cognitive and behavioral disorders may also have adaptive advantages:

Gordon's Notes: More evidence of hacked wetware: the DARPP-32 gene and schizophrenia

...The sooner we understand how buggy all our minds are, the sooner we'll learn wisdom, tolerance, and forgiveness...

There must be people with near perfect minds, but most of us make do with something a few grades below prime. As we come to understand that, we'll become more sympathetic and supportive of those who struggle with profound disabilities.