Controlling nerve cell connectivity - more developments

A day or two ago my post on Fragile X and autism research included a discussion of a general theme in current autism research ...

... Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.

The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect....

The idea is that neuronal connectivity is a delicate, dynamic, balance. Too much connectivity, or too little, can both prevent cognition from working correctly.

So now there's research on modulating neuronal interconnectivity. If they worked safely these drugs would inevitably be used on "normal" brains, probably illegally, but they could be of enormous benefit to persons with impaired cognition.

Note in this review the implication that autism and schizophrenia may be, in a simplistic sense, two sides of one coin.

A Switch to Turn Off Autism?: Scientific American

Scientists say they have pinpointed a gene in the brain that can calm nerve cells that become too jumpy, potentially paving the way for new therapies to treat autism and other neurological disorders...

... The brain is continually trying to strike a balance between too much and too little nerve cell activity. Neurologists believe that when the balance tips, disorders such as autism and schizophrenia may occur. They are not sure why neurons (nerve cells) go berserk. But Greenberg says he and his colleagues located a gene in mice and rats that helps keep neural activity in check—and may one day be manipulated to prevent or reverse neurological problems.

Researchers report in Nature that they discovered a gene called Npas4 churns out a protein that keeps neurons from becoming overexcited when they fire (communicate with one another through connections known as synapses). When scientists blocked the protein, the nerve cells fired or sent out more signals than normal; when they beefed up production, the neurons quieted down...

As scientists learn more about how brain cells stay balanced, Greenberg says they will be able to identify people who are genetically at risk for neurological disorders and develop new drugs to prevent and treat them. He notes that some of the other genes that Npas4 affects also have been linked to autism...

Drugs to treat these disorders are years away from common use -- if ever. In the near term understanding the protein products of these genes may help us better classify and organize brain disorders, though we can also expect that prenatal testing will lead to more abortions.

These developments may also increase the value of doing genetic testing on persons with cognitive disorders, so that if appropriate trials are available one might, very carefully, consider enrolling.

Autism and ADHD are not so different after all

More evidence that our current categorization of early onset cognitive disorders needs a rewrite.

Evidence for overlapping genetic influences on aut...[J Child Psychol Psychiatry. 2008] - PubMed Result

BACKGROUND: High levels of clinical comorbidity have been reported between autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). This study takes an individual differences approach to determine the degree of phenotypic and aetiological overlap between autistic traits and ADHD behaviours in the general population.

METHODS: The Twins Early Development Study is a community sample born in England and Wales. Families with twins born in 1994-6 were invited to join; 6,771 families participated in the study when the twins were 8 years old. Parents completed the Childhood Asperger Syndrome Test and the Conners' DSM-IV subscales....

RESULTS: Significant correlations were found between autistic and ADHD traits in the general population (.54 for parent data, .51 for teacher data). In the bivariate models, all genetic correlations were >.50, indicating a moderate degree of overlap in genetic influences on autistic and ADHD traits...

CONCLUSIONS: These results suggest there are some common genetic influences operating across autistic traits and ADHD behaviours throughout normal variation and at the extreme. This is relevant for molecular genetic research, as well as for psychiatrists and psychologists, who may have assumed these two sets of behaviours are independent.

I suspect all clinicians with significant experience with autism are accustomed to children who have features of both ADHD and autism. So no surprises there. Unfortunately, most studies of ADHD or autism focus on "pure" subjects, so they exclude children who have features of both.

That means there's very little research about children with both ADHD and autism spectrum disorder -- we don't know what medications, behavioral or educational interventions are most effective.

These results may justify research on the large number of children and adults who aren't "pure" examples.

Lessons from gene deletions affecting learning and autism both

On the one hand, this article annoyed me. It demonstrates the usual confusion between association and causation, and it extrapolates from an exotic genetic disorder to the much larger group of children labeled as "autistic".

The reasoning errors, incidentally are not the journalist's. They come from the researchers. Researchers are as prone to this fallacy as anyone else.

On the other hand, it has some interesting hints. So I'll delete the worst parts, and focus on the interesting hints.

Autism Genes That Control Early Learning: Scientific American

A new genetic analysis of large, inbred Middle Eastern families... pinpointed six new genes that may contribute to autism ....

They report in Science that all of the linked genes are involved in forming new and stronger connections, called synapses, between nerve cells in the brain, which is the biological basis of learning and memory formation...

The researchers studied 88 families in which one or more children had been diagnosed with autism, and the parents of each autistic child were cousins. Marrying second and third—and even first cousins—is not uncommon in the Middle East...s

The team found a total of six mutations affecting genes that had previously not been linked to autism. The mutations came in the form of deletions, where part or all of both copies of the genes were missing in a child with the disorder. All of the genes are known to be involved in parts of the same process: creating and strengthening synapses...

...Walsh says the team believes these deletions—which in most cases found here only remove some, but not all, of the DNA that makes up a gene—may mean that the genes can regain some of their normal function. In fact, some of these genes may just be switched off. "This presents the possibility that in some kids we could get the gene going again without necessarily having to put it back in the brain," he says...

...Walsh notes that many children diagnosed with autism tend to show vast improvement when they are placed in environments that allow them to practice learning repetitively. He says that these activities essentially train the neurons to make up for their lost function.

From a science perspective it's another advance in studying neurodiversity, and it fits in the context that large numbers of "normal" people have significant neuro gene deletions.

From a parent's perspective, I was struck by the idea that these neurons can form connections, but they take a lot of persistence to form. In particular, highly repetive learning.

It's hard to do that kind of teaching in a conventional classroom. It bores most students and teachers to tears. This fits with our experience in trying to teach reading however ...

When ADHD is an adaptive advantage ...

First, the news article (excerpt from FuturePundit: Hyperactivity Gene Helps Nomadic Tribesmen?). Then the anecdote ...

.... Kenyan nomads do better with an ADHD gene whereas those who have converted to settled living do worse with this same version of the DRD4 gene.

A propensity for attention deficit hyperactivity disorder (ADHD) might be beneficial to a group of Kenyan nomads, according to new research published in the open access journal BMC Evolutionary Biology. Scientists have shown that an ADHD-associated version of the gene DRD4 is associated with better health in nomadic tribesmen, and yet may cause malnourishment in their settled cousins....

... A study led by Dan Eisenberg, an anthropology graduate student from Northwestern University in the US, analyzed the correlates of body mass index (BMI) and height with two genetic polymorphisms in dopamine receptor genes, in particular the 48 base pair (bp) repeat polymorphism in the dopamine receptor D4 (DRD4) gene.

The DRD4 gene codes for a receptor for dopamine, one of the chemical messengers used in the brain. According to Eisenberg "this gene is likely to be involved in impulsivity, reward anticipation and addiction". One version of the DRD4 gene, the '7R allele', is believed to be associated with food craving as well as ADHD. By studying adult men of the Ariaal of Kenya, some of whom still live as nomads while others have recently settled, the research team investigated whether this association would have the same implications in different environments. 

While those with the DRD4/7R allele were better nourished in the nomadic population, they were less well-nourished in the settled population...  

...It is possible that in the nomadic setting, a boy with this allele might be able to more effectively defend livestock against raiders or locate food and water sources, but that the same tendencies might not be as beneficial in settled pursuits such as focusing in school, farming or selling goods...

There's a personal connection. 

Today we couldn't find child B at the pool. Since he has the classic Aspie tendency to wander, we became a bit anxious. 

We recruited child A, who, among other traits, has pretty severe ADHD. He also has a weird visual talent. He can pick things or people he's interested in out of a very large amount of visual input -- almost instantaneously. 

I told him we needed his "laser eyes" to find his brother, and I walked behind him. Zip. In 1-3 seconds he says "B is not in the big pool". He walks to where I can barely make out people in the diving pool. Zip. "B is by the climbing wall." A few minutes later I was able to spot Child B where Child A said he was.

In our society Child A is disabled. In a hunter gatherer society, at a slightly older age, he'd walk to high ground, spot game across the veldt, then head home to await delivery of the finest cuts of meat and play with his many children. I, in the same society, would be long dead. 

Adaptation is local.


Update: See also an earlier post on the same theme.

Update 7/5/08: The Economist has a more detailed review.

The candidates and disability policy

Crooked Timber's Michael Berube has summarized the disability policies of the three contending candidates:

Crooked Timber -- Disability and Democracy.

McCain's policy is fairly simple ...

... Yes, well, McCain’s disability policy is much easier to summarize: (a): we need to cut costs; and, following from (a), (b): don’t become disabled...

Clinton does a very good job ...

... A Hillary Clinton Administration would be quite good on disability/ health and disability/ employment, and generally good for my kid – this one, not the college senior who turns 22 today...

but her web site does a poor job of displaying her disability policies.

Obama's plan is "... remarkably enough, at once broader and more specific than Clinton’s". For example:

... proposes “a comprehensive study of students with disabilities and transition to work and higher education” – something that (a) has never been done and (b) is of great interest to teenagers with disabilities and their loved ones. “As president,” we’re told, “Barack Obama will initiate such a study and task his Secretary of Education with researching: the barriers that keep students with disabilities from seeking and completing higher education; the barriers that prevent students from making a direct transition to work; the extent to which students with disabilities are able to access loans and grants; reasons college students with disabilities drop out at a higher rate; and best practices from schools that have effectively recruited and graduated students with disabilities that can be implemented more widely.” This is, as you might imagine, a (cough) special interest of mine. But that’s not just because I have a 16-year-old with Down syndrome. In recent years I’ve had many fine students at Penn State – twenty-year-olds with dyslexia, or Asperger’s Syndrome, or arthritis, or mild cerebral palsy – request “reasonable accommodation” from me on final exams. And I’ve been amazed and appalled at how few many of my colleagues (here or elsewhere) seem to believe that they’re under no obligation to provide reasonable accommodation for everyone. (Guess what? If you teach in the United States, you have that obligation! It’s a real federal law!) So I’m thinking that “a comprehensive study of students with disabilities and transition to work and higher education” might not be a time-wasting exercise for disabliity-policy wonks. I’m thinking that it might actually make a world of difference for students with disabilities – in high school, in transition, and in college...

Among the topics Berube reviews are:

• limitations on the ability of insurers to discriminate on the basis of preexisting conditions
• fudning of IDEA (the grossly under-funded Individuals with Disabilities Education Act).
• federal employment support for persons with disabilities
• Tom Harkin's ADA Restoration Act (overturn Supreme Court decisions that have limited the ADA's scope).
• Genetic Information Nondiscrimination Act (GINA), which prohibits discrimination on the basis of genetic information by employers and health insurers. (Tom Coburn has blocked passage of this in the Senate).

The bottom line of course is that either Hilary or Obama are light years better than McCain for persons with disabilities and their supporters.

A breakthrough in understanding the genetics of schizophrenia -- and perhaps of autism too

A major publication in Science on the genetics of schizophrenia is summarized in Gordon's Notes

Gordon's Notes: What is schizophrenia? Not what we thought.

... note only 15% percent of "schizophrenics" fit this pattern. I'll summarize the key implications:

• Schizophrenia is not a disease. It's the name given a fairly large number of unique disorders of brain development that have, among their endpoints, social withdrawal, hallucinations, and fixed beliefs.
• A good number of cases of "autism" and "schizophrenia" are different manifestations of overlapping sets of mutations.
• There may be"no genes for most instances autism and schizophrenia". There are sets of large scale mutations that are similar between close genetic relatives, but similar appearances are resulting from disorders of quite different components of brain development.
• One in twenty seemingly normal people have big, ugly looking mutations that ought to be messing up their brain development. Yet they seem "normal". Seventeen in twenty persons with "schizophrenia" do NOT have these nasty scattered "sledgehammer" mutations. (So called because it's as though something took a sledgehammer to the genome.)
• The age onset of schizophrenia is determined by when the disordered developmental genes are activated. There's a lot of this going on in late teen years. The implication is that the same thing explains why "autism" presents around ages 2-3, and why it can seem to appear fairly suddenly. This may also explain why some conditions seem to improve at other ages. Schizophrenia syndromes often improves in middle age, for example.
• If every person with autism has a somewhat unique disorder, then treatments and prognosis are also unique. This validates the age old practice of asking someone with a cognitive/psychiatric disorder what treatments have worked for relatives.

I'm seeing a growing consensus that "autism" will turn out to have a similar picture. The trend is clear, autism is also going to turn out to be a diverse collection of disorders of brain development and injury response with diverse genetic causes. These as yet unnamed disorders will turn out to have different prognoses and different therapies.

A mouse model for schizophrenia

This was announced in July of 2007, but I completely missed it. I only read of it in a recent 'top 10 science stories' article.

Hopkins team develops first mouse model of schizophrenia

Johns Hopkins researchers have genetically engineered the first mouse that models both the anatomical and behavioral defects of schizophrenia, a complex and debilitating brain disorder that affects over 2 million Americans.

In contrast to current animal studies that rely on drugs that can only mimic the manifestations of schizophrenia, such as delusions, mood changes and paranoia, this new mouse is based on a genetic change relevant to the disease. Thus, this mouse should greatly help with understanding disease progression and developing new therapies.

Animal models of schizophrenia have been hard to design since many different causes underlie this disease. However, Akira Sawa, M.D., Ph.D., associate professor of psychiatry and neuroscience and director of the program in molecular psychiatry and his colleagues took advantage of the recent discovery of a major risk factor for this disease: the DISC1 gene (short for disrupted in schizophrenia), which makes a protein that helps nerve cells assume their proper positions in the brain.

As reported online this week in Proceedings of the National Academy of Sciences, the researchers generated mice that make an incomplete, shortened form of the DISC1 protein in addition to the regular type. The short form of the protein attaches to the full-length one, disrupting its normal duties.

As these mice matured, they became more agitated when placed in an open field, had trouble finding hidden food, and did not swim as long as regular mice; such behaviors parallel the hyperactivity, smell defects and apathy observed in schizophrenia patients. Magnetic resonance imaging (MRI), taken in collaboration with Susumu Mori, Ph.D., professor of radiology, also revealed characteristic defects in brain structure, including enlarged lateral ventricles, a region that circulates the spinal fluid and helps protect against physical trauma.

Sawa notes that the defects in these mice were not as severe as those typically seen in people with schizophrenia, because more than one gene is required to trigger the clinical disease. “However, this mouse model will help us fill many gaps in schizophrenia research,” he says. “We can use them to explore how external factors like stress or viruses may worsen symptoms. The animals can also be bred with other strains of genetically engineered mice to try to pinpoint additional schizophrenia genes.”

Mouse models for human disorders of the mind are hugely important. In 2006 I wished for a murine autism model (twice, actually) and in 2007 there were hints of some models (MECP2 based). I didn't realize that a DISC1 model also existed for schizophrenia.

Of course as I always mention, autism and schizophrenia are fuzzy labels we apply to what's likely to turn out to be many diverse neurologic disorders.

A mouse model is to thought disorders as the telescope was to learning about the universe. It's progress we can celebrate.

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.

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).

Williams syndrome: the NYT Magazine review

Williams syndrome has some features in common with autism, but it is, scientifically, much easier to study. For one thing it's much better defined than autism; persons with "Williams syndrome" resemble one another more more closely than persons with "autism". For another, we have a reasonable understanding of the gene injury involved, and we can expect to match up the gene products with the "phenotype" (behaviors).

The NYT Magazine has an extensive review with an excellent video as well. After watching the video, I think I know a woman (through a hockey organization I work with) who has the disorder.

One thing to consider while reading the article. Williams syndrome is fairly well characterized because of the physics of our chromosomes. The defect involves a patch that is prone to being "wrongly ripped", but the absence is not lethal. It is very likely that some of these genes are injured in other ways, or they vary in other ways. Persons with these variations won't have Williams syndrome, but they will have some characteristics of Williams syndrome. Some of those characteristics will have adaptive advantages, some won't. Something to remember when conversing with a "normal" person who's very talkative, doesn't seem to know when to pause for breath, and isn't very good at abstract thought ...

Emphases mine (I chopped out long digressions on the evolution of mind that are of much less concrete interest):

Williams syndrome - David Dobbs - New York Times
July 8, 2007
The Gregarious Brain
By DAVID DOBBS
David Dobbs writes frequently about science and medicine. His last article for the magazine was about depression.

If a person suffers the small genetic accident that creates Williams syndrome, he’ll live with not only some fairly conventional cognitive deficits, like trouble with space and numbers, but also a strange set of traits that researchers call the Williams social phenotype or, less formally, the “Williams personality”: a love of company and conversation combined, often awkwardly, with a poor understanding of social dynamics and a lack of social inhibition...

... (Some people with the disorder as well as many who work with them simply call it Williams.) Williams syndrome rises from a genetic accident during meiosis, when DNA’s double helix is divided into two separate strands, each strand then becoming the genetic material in egg or sperm. Normally the two strands part cleanly, like a zipper’s two halves. But in Williams, about 25 teeth in one of the zippers — 25 genes out of 30,000 in egg or sperm — are torn loose during this parting. When that strand joins another from the other parent to eventually form an embryo, the segment of the DNA missing those 25 genes can’t do its work.

The resulting cognitive deficits lie mainly in the realm of abstract thought. Many with Williams have so vague a concept of space, for instance, that even as adults they will fail at six-piece jigsaw puzzles, easily get lost, draw like a preschooler and struggle to replicate a simple T or X shape built with a half-dozen building blocks. Few can balance a checkbook. These deficits generally erase about 35 points from whatever I.Q. the person would have inherited without the deletion. Since the average I.Q. is 100, this leaves most people with Williams with I.Q.’s in the 60s. Though some can hold simple jobs, they require assistance managing their lives.

The low I.Q., however, ignores two traits that define Williams more distinctly than do its deficits: an exuberant gregariousness and near-normal language skills. Williams people talk a lot, and they talk with pretty much anyone. They appear to truly lack social fear. Indeed, functional brain scans have shown that the brain’s main fear processor, the amygdala, which in most of us shows heightened activity when we see angry or worried faces, shows no reaction when a person with Williams views such faces. It’s as if they see all faces as friendly.

People with Williams tend to lack not just social fear but also social savvy. Lost on them are many meanings, machinations, ideas and intentions that most of us infer from facial expression, body language, context and stock phrasings. If you’re talking with someone with Williams syndrome and look at your watch and say: “Oh, my, look at the time! Well it’s been awfully nice talking with you . . . ,” your conversational partner may well smile brightly, agree that “this is nice” and ask if you’ve ever gone to Disney World. Because of this — and because many of us feel uneasy with people with cognitive disorders, or for that matter with anyone profoundly unlike us — people with Williams can have trouble deepening relationships. This saddens and frustrates them. They know no strangers but can claim few friends.

This paradox — the urge to connect, the inability to fully do so — sits at the center of the Williams puzzle, whether considered as a picture of human need (who hasn’t been shut out of a circle he’d like to join?) or, as a growing number of researchers are finding, a clue to the fundamental drives and tensions that shape social behavior. After being ignored for almost three decades, Williams has recently become one of the most energetically researched neurodevelopmental disability after autism, and it is producing more compelling insights. Autism, for starters, is a highly diverse “spectrum disorder” with ill-defined borders, no identified mechanism and no clearly delineated genetic basis. Williams, in contrast, arises from a known genetic cause and produces a predictable set of traits and behaviors. It is “an experiment of nature,” as the title of one paper puts it, perfect for studying not just how genes create intelligence and sociability but also how our powers of thought combine with our desire to bond to create complex social behavior — a huge arena of interaction that largely determines our fates.

Julie R. Korenberg, a neurogeneticist at Cedars-Sinai Medical Center and at the University of California, Los Angeles, who has helped define the Williams deletion and explore its effects, believes the value of Williams syndrome in examining such questions is almost impossible to overstate. “We’ve long figured that major behavioral traits rose in indirect fashion from a wide array of genes,” Korenberg says. “But here we have this really tiny genetic deletion — of the 20-some-odd genes missing, probably just 3 to 6 create the cognitive and social effects — that reliably creates a distinctive behavioral profile. Williams isn’t just a fascinating mix of traits. It is the most compelling model available for studying the genetic bases of human behavior.”

... Williams syndrome was first identified in 1961 by Dr. J. C. P. Williams of New Zealand. Williams, a cardiologist at Greenlane Hospital in Auckland, noticed that a number of the hospital’s young cardiac patients were small in stature, had elfin facial features and seemed friendly but in some ways were mentally slow. His published delineation of this syndrome put Dr. Williams on the map — off which he promptly and mysteriously fell. Twice offered a position at the prestigious Mayo Clinic in Rochester, Minn., he twice failed to show, disappearing the second time, in the late ’60s, from London, his last known location, with the only trace an unclaimed suitcase later found in a luggage office.

The rarity of Williams syndrome — about 1 in 7,500 people have it, compared with about 1 in 150 for autism or 1 in 800 for Down syndrome — rendered it obscure. Unless they had the syndrome’s distinctive cardiovascular problems (which stem from the absence of the gene that makes blood vessels, heart valves and other tissue elastic and which even today limit the average lifespan of a person with Williams to around 50), most people with Williams were simply considered “mentally retarded.”...

... genes (or their absence) do not hard-wire people for certain behaviors. There is no gene for understanding calculus. But genes do shape behavior and personality, and they do so by creating brain structures and functions that favor certain abilities and appetites more than others.

Reiss and Galaburda’s imaging and autopsy work on Williamses’ brains, for instance, has shown distinct imbalances in structure and synaptic connectivity. This work has led Galaburda to suspect that some of the genes missing in the Williams deletion are “patterning genes,” which direct embryonic development and which in this case dictate brain formation. Work in lab animals has shown that at least one patterning gene choreographs the developmental balance between the brain’s dorsal areas (along the back and the top of the brain) and ventral areas (at the front and bottom). The dorsal areas play a strong role in vision and space and help us recognize other peoples’ intentions; ventral areas figure heavily in language, processing sounds, facial recognition, emotion, music enjoyment and social drive. In an embryo’s first weeks, Galaburda says, patterning genes normally moderate “a sort of turf war going on between these two areas,” with each trying to expand. The results help determine our relative strengths in these areas. We see them in our S.A.T. scores, for example: few of us score the same in math (which draws mostly on dorsal areas) as in language (ventral), and the discrepancy varies widely. The turf war is rarely a draw.

In Williams the imbalance is profound. The brains of people with Williams are on average 15 percent smaller than normal, and almost all this size reduction comes from underdeveloped dorsal regions. Ventral regions, meanwhile, are close to normal and in some areas — auditory processing, for example — are unusually rich in synaptic connections. The genetic deletion predisposes a person not just to weakness in some functions but also to relative (and possibly absolute) strengths in others. The Williams newborn thus arrives facing distinct challenges regarding space and other abstractions but primed to process emotion, sound and language.

This doesn’t mean that specific behaviors are hard-wired. M.I.T. math majors aren’t born doing calculus, and people with Williams don’t enter life telling stories. As Allan Reiss put it: “It’s not just ‘genes make brain make behavior.’ You have environment and experience too.”

... horrible colic that many Williams infants suffer during their first year and before they start to talk well....

... Our extra-big brains allow us to balance bonding and maneuvering in more subtle and complicated ways.

People with Williams, however, don’t do this so well. Generating and detecting deception and veiled meaning requires not just the recognition that people can be bad but a certain level of cognitive power that people with Williams typically lack. In particular it requires what psychologists call “theory of mind,” which is a clear concept of what another person is thinking and the recognition that the other person a) may see the world differently than you do and b) may actually be thinking something different from what he’s saying...

... “And the most important abnormalities in Williams,” he says, “are circuits that have to do with basic regulation of emotions.”

The most significant such finding is a dead connection between the orbitofrontal cortex, an area above the eye sockets and the amygdala, the brain’s fear center. The orbitofrontal cortex (or OFC) is associated with (among other things) prioritizing behavior in social contexts, and earlier studies found that damage to the OFC reduces inhibitions and makes it harder to detect faux pas. The Berman team detected a new contribution to social behavior: They found that while in most people the OFC communicated with the amygdala when viewing threatening faces, the OFC in people with Williams did not. This OFC-amygdala connection worked normally, however, when people with Williams viewed nonsocial threats, like pictures of snakes, sharks or car crashes.

... if Williams confers disadvantage by granting more care than comprehension, reversing this imbalance creates a far more problematic phenotype.

As Robert Sapolsky of the Stanford School of Medicine puts it: “Williams have great interest but little competence. But what about a person who has competence but no warmth, desire or empathy? That’s a sociopath. Sociopaths have great theory of mind. But they couldn’t care less.”

There's a lot here. For example, the incidental comment on infantile colic made my eyebrows jump. Does Williams offer clues to one of the most puzzling and common disorders of infancy -- the mysterious disorder we call "colic"?!

The "dorsal" and "vental" regions remind me of the "left" and "right" hemisphere of the 1980s. Just like "left" and "right" hemispheres the "dorsal" areas sound more "male" and the "ventral" sound more female. One wonders how they morph during adolescence. As to dorsal/ventral balance (and SAT score balance) being rare; I suspect it's not so much that a "balance" is rare but rather that there's a comparatively flat normal distribution -- any point in the curve is 'rare'.

The "patterning genes" are also likely to feature in many stories over the next few years, as we learn how they influence talents and preferences. Sociopaths, of course, are of great interest to all of us these days ...

Incidentally, Williams syndrome, for better and for worse, is likely to go the way of Downs syndrome.

Autism-like findings in relatives of autistic children and the evolutionary biology of autism

I came to this reference via medlogs. It's quite fascinating. The more we learn about congenital structural and organizational disorders of the brain and mind, like schizophrenia and autism, the more oddity we see in how they're expressed. Here we learn that some structural aspects of "autism", a "disorder" that seems to be strongly inherited, may manifest in high functioning "non-autistic" adults ...

Brain deficits found in relatives of autism sufferers
Unaffected family members show characteristic abnormalities.
Jim Giles

People can have physical brain abnormalities similar to those found in autistic individuals without having the disorder themselves. These results come from two studies, which were presented at a conference over the weekend. Brain scans show striking similarities between the brains of autistic patients and those of their non-autistic parents and siblings.

... In one study, Eric Peterson of the University of Colorado at Boulder and his colleagues scanned the brains of 40 parents of autistic children and compared the results with functional magnetic imaging (MRI) scans from 40 [jf: normal, non-related] controls. The data look much like those obtained for comparisons between autistic and non-autistic brains, says Peterson. The results were discussed on 13 November at the annual meeting of the Society for Neuroscience in Washington.

Some areas of the brain region known as the prefrontal cortex were smaller than normal in the parents of autistic children, for example. This part of the brain is involved in understanding other peoples' motivations, something that autistic people find difficult and is thought to lie behind the problems they face in interacting socially.

Another typical symptom of autism is the tendency to avoid making eye contact. This behaviour was studied by Brendon Macewicz and colleagues at the University of North Carolina, Chapel Hill. He gave nine families with an autistic child and unaffected brother a digital camera and told them to take pictures of friends and family. Macewicz then mixed up the shots with images of strangers and tracked the childrens' eye movements while asking them to say whether the people they saw in the pictures were familiar or not.

Most people rely heavily on looking at the eyes when asked to complete this task. But autistic children are known to avoid the eyes and focus on other areas of the face. To Macewicz's surprise, the non-autistic siblings did almost exactly the same.

"This piqued our curiosity," he says. The team then ran MRI scans on the brothers, focussing on the part of the brain known as the amygdala. This area is involved in fear and is typically smaller in autistic people. "It was very interesting," says Macewicz. "The children showed a similar decrease in amygdala size to their autistic siblings." The difference was around 5-10%.

The results are intriguing, say the researchers, because the parents and siblings had not been diagnosed with autism. Macewicz says it is likely that in the unaffected siblings other brain areas, perhaps in the frontal lobes, are helping to regulate the amygdala and compensate for its smaller volume.

It may be that a core set of brain abnormalities has to be present for autism to occur, adds Peterson, and that the parents he studied do not have them all. He points out that some autism-related behavioural traits have previously been seen in the relatives of people with the condition, but that these current studies are among the first to show similarities in brain anatomy.

The clinical concept of "autism" is very vague. It's a"diagnosis" made by school systems, social services, psychiatricsts, psychologists, and researchers. There are children than all would label "autistic", but there's no doubt the concept is itself ill-defined. The group studied here is probably more homogenous than the general "autistic" population.

The results are fascinating. I do wonder how many of the parents would have been labeled as "autistic", were they children today.

This study lends credence to the "Silicon Valley nerds" theory of the increasing prevalence of autism -- that many high IQ "autistic" children are the result of increased rates of marriage between persons with autistic traits, who congregate in the tech indutries. It also strengthens the long suspected link between pre-autistic traits and "geekiness".

Classic autism is not a very adaptive condition in most human environments. Autistic children would probably die quickly in a harsh environment. So why is autism a relatively common disorder? We know from many, many examples in human evolution that a serious genetic disease (ex. sickle cell anemia) will persist when some of its component traits have adaptive advantage. It's very likely that some pre-autistic "traits" or genetic components have adaptive advantages.

I would like to know what the correlation of autism is in identical twins ...

Update 2/24/07: Correlation in identical twins can be very high, probably depending on the subtype of "autism":

... different studies have shown that if one identical twin has autism then there is a 63-98% chance that the other twin will have it. For non-identical twins (also called fraternal or dizygotic twins), the chance is between 0-10% that both twins will develop autism. The chance that siblings will be affected by autism is about 3%.

The population risk is supposedly about .7%, so siblings have about a 500% relative risk. The large spread in co-occurrence for twins is very compatible with diverse genetic causes; again we see that the word "autism" is used for a wide variety of distinct but unnamed disorders.