Sunday, July 08, 2007

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
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.

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