Genetics of autism: inheritance from an asymptomatic mother with a spontaneous mutation

This was published in Scientific American news in July, but I've only just come across it. The authors are attempting to describe the phenomenon of familial autism in which neither parent appears to be autistic nor to have a family history of autism ... (emphases mine)

New Theory about Autism Roots: Scientific American 7/24/07

... Wigler's rethinking of autism's cause stems from an exhaustive analysis of risk based on a database of families with more than one autistic child. (The Autism Genetic Resource Exchange, or AGRE, manages the database.) The team determined that most cases of autism arise from novel, spontaneous mutations passed down from one or both parents, resulting in large gaps in a person's genome often encompassing several genes, which are then disrupted or inactivated. (This loss of genetic code—known as copy number variation—results in an offspring receiving only one of the standard two copies of a gene, which could cause an insufficient amount of protein to be produced by those genes.) In most instances, this mutation will result in an autistic child. However, in some cases—more likely in girls than boys—the recipient of this mutation will not produce any symptoms.

"When that child matures and becomes a parent, they have a 50 percent chance of transmitting … [their mutation] … to a child that might not be as lucky as they were, especially if … [its] … a boy," Wigler says. "So, they will be transmitting this with close to a 50 percent frequency—and that is the source of the high-risk families."

Wigler says that the team will continue to update its model as new figures are added to the AGRE database and try to gain new insight into the mechanism that gives girls greater resistance than boys. "To understand that [disparity] at a molecular or genetic level would be very important, because you could theoretically treat kids … you could detect something early and intervene," Wigler says. "I view it as the most important thing to understand."

Maja Bucan, a professor of genetics at the University of Pennsylvania, says that the new autism model is a creative way to interpret the familial data. "It's important to come up with new theories and then just test them once we have more data," she explains. "I don't think we have enough data [yet] to say whether this theory is right or wrong."

According to Wigler, the new model "certainly changes the way you think about autism. The paradigm shift is … something can be genetic without being heritable. The field has ignored the contribution of spontaneous mutation for a whole range of things that matter a lot to society," which, he adds, includes schizophrenia and morbid childhood obesity.

This is in line, as the final comment suggests, with a new belief that many common disorders have a genetic root but not a family history; they arise from spontaneous mutations. The key in this model is that women who are afflicted with the mutation may not present with autism; women have redundant systems that protect against expressing the disorder (phenotype). Their male children, however, can inherit the genes and, lacking the protection females have, develop the disorder.

It this is shown to be true it will have implications for our understanding of schizophrenia, autism, and the evolution of the human brain and mind.

Special needs: moving to 5th grade

I haven't had many posts in this blog recently, but, of course, if you're using a blog reader that shouldn't matter. If you're just checking this web page periodically ... well, you should be using a blog reader.

One reason I don't post so much is that our personal situation(s) have been relatively stable. I'll have something more to say about personal care assistant (PCA) funding in Minnesota soon, but for now I'll comment on the particular problems of late primary education and special needs.

A low IQ special needs child is coming to the end of the "mainstream" road by late primary school. That's when some children are reading at the college level while the special needs child is struggling with very basic literacy. Now we're shifting to preparing for non-mainstream education, and continuing to push for as much literacy as possible. We have a minor interest in arithmetic, but really functional reading is our only academic goal.

There's very little science to help us. Reading research focuses on children with normal abilities or focal reading disorders. Complex multi-factorial reading disorders are well beyond the bounds of what reading science can help us with. If a child has reasonable word recognition skills, but awful word attack skills, do we push on their weakness, build on their strengths, or balance both? Many people may think they know, but none have any data. For now we have an opportunistic balanced approach, based largely on what our child can be incented to try. One big factor is that phonics reading materials assume the interests of a 1-2 year old child. Our child's interests are much closer to those of his chronological age group. There's almost nothing written for the interests of a 10-12 year old and the reading ability of a 6-7 yo.

Lately our 5th grade teacher has been sending home assignments using "High Noon Reading Fluency" exercises, level A (1st grade theoretically, though the A to D reading excerpts all seem rather similarly difficult to me). This is helpful, because we assume he can only spend a very limited amount of time with our child. So this gives us something we can build on at home and on the weekend - especially if we can do the work and evaluation, but have the teacher deliver the result and exercises. Our child is very keen on pleasing teachers, so we do best to leverage that. We've ordered a complete set from RLAC; I chose them because I liked the sample PDF they provided, the quality of their website descriptions, and the free shipping.

I'll post on how it goes. We have, by the way, used a variety of reading software packages over the years, but our child does much better with physical paper. I think the cognitive burden of the user interactions is much lower with paper, so he can bring everything he has to the reading task. Electronic interactions are too distracting, and they demand cognitive cycles for the electronic interaction alone. He needs everything he has.

There's another interesting aspect to this search. It turns out that the Google Search "high noon reading fluency" is the "key" to a range of interesting online educational resources for special needs and neurotypical children. Try it and explore ...

[1] Google Reader and Bloglines are my favorites, the reader built into IE 7 is obscure and limited, but simple once you figure it out, Safari has a fine reader, Firefox's reader is so-so.

Food additives and hyperactivity?

Ouch! What a pain this will be if it's true.

Some Food Additives Raise Hyperactivity, Study Finds - New York Times

... Common food additives and colorings can increase hyperactive behavior in a broad range of children, a study being released today found. It was the first time researchers conclusively and scientifically confirmed a link that had long been suspected by many parents. Numerous support groups for attention deficit hyperactivity disorder have for years recommended removing such ingredients from diets, although experts have continued to debate the evidence. But the new, carefully controlled study shows that some artificial additives increase hyperactivity and decrease attention span in a wide range of children, not just those for whom overactivity has been diagnosed as a learning problem....

I'll need to read the original article to decide how real this is, how large the alleged effect was, etc. It was a true randomized and ostensibly blinded study, so it's definitely interesting. I'd like to see some correlation from animal studies and, above all, we need the results to be replicated in other studies. I've seen some very strong results disappear on re-examination, and this is is a big enough deal that we need to know more.

It would be cool if we learn something new about how diet alters behavior, but I'm going to be pretty cautious for now. It'll be a few years before the essential secondary studies are complete. If I were to bet, I'd bet that the results won't hold up -- but I wouldn't bet much!

Tim Page: a life with Asperger's

Tim Page, a critic and writer, tells his personal story of 52 years with Asperger's / high functioning autism:

Personal History: Parallel Play: Reporting & Essays: The New Yorker

.... I received a grade of “Unsatisfactory” in Social Development from the Mansfield Public Schools that year. I did not work to the best of my ability, did not show neatness and care in assignments, did not coöperate with the group, and did not exercise self-control. About the only positive assessment was that I worked well independently. Of course: then as now, it was all that I could do.

In the years since the phrase became a cliché, I have received any number of compliments for my supposed ability to “think outside the box.” Actually, it has been a struggle for me to perceive just what these “boxes” were—why they were there, why other people regarded them as important, where their borderlines might be, how to live safely within and without them. My efforts have been only partly successful: after fifty-two years, I am left with the melancholy sensation that my life has been spent in a perpetual state of parallel play, alongside, but distinctly apart from, the rest of humanity...

Mr. Pages's pre-college years were particularly difficult. He reiterates the truism that life improves for most atypicals when high school ends -- the adult world has far more latitude than the world of early education. He believes were he a child today that things would have been much easier -- I think he's right. It's not that we have great "treatments" for Asperger's or high-functioning autism, but I do think we have much better ways to accomodate and manage atypical minds.

I don't share Mr. Page's faith in a clear dividing line between "high-functioning autism" and "Asperger's". Were he to start over today he could be as easily given one label as the other. I think his story will be of particular interest to teachers, parents, friends and caregivers of persons with high IQ autism and/or Asperger's. His ongoing functional improvement, even in the absence of specific interventions, is noteworthy.

ODD? Conduct disorder? Antisocial disorder? Not always a disadvantage

Craig Venter is a famously difficult man. Vain. Egocentric. Argumentative. Difficult to work with. Compelled to defy convention.

He's also fabulously rich and a certified historic figure. He has recently sequenced his own genome and published the results. They are of interest to parents of difficult children ...

J. Craig Venter - In the Genome Race, the Sequel Is Personal - New York Times

...Dr. Venter reports that he has variants that increase his risk of alcoholism, coronary artery disease, obesity, Alzheimer’s disease, antisocial behavior and conduct disorder...

... Next month, Dr. Venter will publish an autobiography, “A Life Decoded.” The book describes the twists and turns that led him down the unlikely path into scientific research. “Rebellious and disobedient,” as he describes himself, he dedicated his teenage years to the pursuit of young women and the California surf, to the detriment of his academic career.

He was drafted at the time of the Vietnam war and enlisted in the Navy. Because of a high I.Q. score, he was given a choice of any Navy career, from nuclear engineering to electronics. He chose the hospital corps school, because it was the only course that did not require any further enlistment. Only too late did he discover the reason. Corpsmen in Vietnam did not usually survive long enough to re-enlist — the half-life of medics in the field was six weeks, he writes.

Learning how to manipulate the Navy bureaucracy, he got himself assigned to the Navy hospital in Da Nang, where chances of survival were better. But the work was harrowing. He witnessed several hundred soldiers die on his operating table, mostly when he was massaging their heart or trying to breathe life into them.

“I learned more than any 20-year-old should ever have to about triage, about sorting those you can salvage from those you cannot do anything for except ease their pain as they died,” Dr. Venter writes in the autobiography.

He escaped from Vietnam with his life and an interest in medical research. With his lack of academic skills, this was a hard field for him to break into, but by 1975 he had a Ph.D. By the late 1980s, he was starting to make his mark as one of the few scientists who could get useful results out of the first DNA sequencing machines that were then becoming available.

He was the first to sequence the genome of a bacterium, Hemophilus influenzae, even though his grant application was turned down by the National Institutes of Health on the advice of experts who said his method would not work. With the human genome, an even greater prize, the pace of competition was intense, especially when his approach turned out to be more efficient than the one his rivals had chosen.

In the book, Dr. Venter says that detractors badmouthed his work, pressured other scientists not to cooperate with him and tried strenuously to block publication of his report, of which they had earlier maneuvered to be made co-authors.

“Like most human endeavors, science is driven in no small part by envy,” he writes.

Dr. Venter has never fully lost his youthful disrespect for authority and establishments. His investment in himself — choosing his own genome to sequence, naming his laboratory the J. Craig Venter Institute — may come across as vainglorious, but it can also be seen as a signal of survival, defying the establishments he believes have sought to crush him. However nettlesome he may seem to some of his colleagues, he has the charm and the personal skills to have recruited many highly able researchers to his teams.

Another reason for his success has been his skill at raising private finances to achieve research goals after being denied support from the National Institutes of Health. That a scientist of his ability has been forced to work outside the N.I.H.’s peer-review system puts peer review in a strange light. If his diploid human genome should become a standard, the success is one that he will have earned by perseverance and defiance of long odds.

My last post was about an astronaut with asperger's syndrome. Now I'm writing about an extremely "successful" man who, but for his IQ, would perhaps have been diagnosed with ADHD/ODD as a child.

One of the more interesting results of understanding the genes for behavior will be changing how we perceive cognitive and behavioral traits. Sometimes a bit of ODD can have advantages (an IQ of 150 probably helps though).