Genes to Grow On.

Development takes some unique turns for a group of kids missing a few genes

Carl sidles up to people that he has never met and starts conversations with the ease of a cocktail party schmoozer and the urgency of a congressional lobbyist. The 8-1/2-year-old boy has received countless warnings from his parents about talking to strangers. He just can't help himself.

Given his small size and smooth banter, many of Carl's new acquaintances peg him as a bright, elfin-faced go-getter. Beneath that first impression, however, lie some unusual intellectual peaks and valleys, as well as an IQ indicating moderate retardation.

True, Carl expresses himself well and shows sensitivity to others' feelings. He has a good memory for the birthdays of close relatives and friends. After hearing an adult read a list of up to nine objects, the youngster can usually repeat the items in their correct order, a sign of robust short-term memory.

Carl reads stories at the first-grade level, plays T-ball and soccer, belongs to Cub Scouts, and likes country music.

Yet his perception of the world literally lacks depth. The child's drawings of houses and other scenes dissolve into a mass of squiggles. He can't arrange colored blocks to match simple examples. Carl also can't tie his shoes or fasten small buttons, struggles at cutting with a knife, and finds it tough to concentrate on a task for more than 5 or 10 minutes.

Genetic tests have confirmed that Carl has Williams syndrome, a condition that occurs in about 1 in 20,000 newborns. People with the syndrome lack a small part of one of the two copies of chromosome 7. This missing section contains at least 16, and perhaps 30, genes. That's a big enough loss to have major consequences, even though correct versions of these genes remain intact on the other copy of the chromosome.

First described more than 40 years ago, Williams syndrome includes mild or moderate mental retardation, impaired perception of three-dimensional space, marked problems in using numbers, small stature, elfin facial features, heart and blood vessel defects, and excess concentrations of calcium in the blood during childhood.

Outspoken affability toward friends and strangers alike combined with intense concern for others' feelings also characterize Williams syndrome. Memory for faces and spoken words often approaches or reaches normal range.

Scientific explorations of Williams syndrome, which have intensified in the past few years, increasingly challenge bedrock assumptions that have long guided work on developmental and genetic disorders.

Traditional research on mind and brain function has focused on brain-damaged adults who have lost particular thinking abilities, such as spatial perception or face recognition. Investigators have theorized that each facet of thought depends on a specialized brain network, or module. Specific sets of genes contain blueprints for module construction, in their view.

Put another way, genes make the neural utensils that set a person's developmental table. Aspects of an adequate environment--from childhood nutrition to schooling to family life--then put food on the plates. A person with a genetic defect might not be able to spoon up what life offers.

The alternative view treats brain modules observed in adults, and even in school-age children, as products of prolonged development. Genes participate in this process but don't dictate its outcome (SN: 3/20/99, p. 184).

In this scenario, a gene generates proteins in a considerable range of patterns that reflect a number of influences. Brokers of gene activity include the external environment, such as cultural practices and conventions; the internal environment, such as characteristics of the cell a gene resides in; and the activity of other genes. Genetically influenced traits in turn prod individuals to choose and modify their own environments.

As the interplay of these forces drives development, it fashions specialized brains out of far humbler origins, according to this theory. This process requires the extended period of brain development that humans have evolved. From this perspective, developmental disorders have fuzzy borders. A genetic defect nudges a person's development in a general direction, leaving plenty of room for individuals with, say, Williams syndrome, to create variations on that theme.

"The dynamics of development itself, not isolated gene functions, are the key to understanding developmental disorders," says Annette Karmiloff-Smith, a psychologist at University College London. "We need to study these disorders from early infancy onward, not just when they reach their end state in school-age children and adults."

In the spirit of that conviction, Karmiloff-Smith has begun to explore the mental lives of 2-to-3-year-olds with Williams syndrome. Her initial findings, published in the Dec. 17, 1999 SCIENCE, support the notion that the condition follows a winding, and at times surprising, developmental path. Genetic defects influence the path's direction but don't determine its final destination, she argues.

Toddlers with Williams syndrome exhibit a cognitive profile that is in some ways the opposite of that observed in their older counterparts, the British researcher holds. The younger ones display relatively poor recognition of simple, spoken words but have fewer problems on a rudimentary number test.

Later in life, verbal ability usually exceeds math skills in people with Williams syndrome.

Karmiloff-Smith and her coworkers first conducted a number experiment with 13 toddlers, age 2 to 3, with Williams syndrome and 22 kids of the same age with Down's syndrome. In that condition, an extra chromosome 21 underlies retardation and characteristic facial features. The two groups had comparable scores on tests of overall intelligence.

The researchers also studied 16 healthy infants, ages 1 to 2, with no genetic defect. At that age, their intelligence scores roughly matched those of the older Williams and Down's syndrome toddlers. The fourth group tested consisted of 14 healthy toddlers with intact DNA, ages 2 to 3; they scored higher than the other groups on general intelligence.

Children looked at cards, two at a time. Each card showed two examples of an everyday object--teddy bears, chairs, and so on. After getting accustomed to this setup, the youngsters saw a new pair of cards, one with two objects and the other with three objects.

Past research has established that infants typically gaze for a longer time at new or surprising sights. Williams syndrome toddlers and children in the two genetically intact groups spent much longer looking at the novel display than at the previous ones, indicating that they realized that the number of objects per card had changed, the researchers hold.

Down's syndrome children spent about the same amount of time looking at the old and new displays.

A second experiment examined vocabulary development in the same four groups. Children viewed pairs photographs of everyday objects, sometimes presented silently, sometimes just after an experimenter had loudly told them to "look, look at the chair" (or at some other item about to be shown).

DNA-intact toddlers stared longer at appropriate objects after getting the verbal tip-off. Spoken directions, however, exerted virtually no influence on Williams and Down's syndrome toddlers, Karmiloff-Smith says.

Nonetheless, adults with Williams syndrome display relatively extensive vocabularies. Karmiloff-Smith's findings "provide good evidence that it is an oversimplification to characterize individuals with Williams syndrome as `language good, number poor' based on observations of adults," comments psychologist Dorothy V.M. Bishop of the University of Oxford in England, in the issue of SCIENCE carrying the findings. Both verbal and numerical capacities take hits in Williams syndrome, and spatial perception suffers most, Bishop adds.

Despite the intriguing implications of the new study, the developmental process at work in Williams syndrome remains poorly understood, remarks psychologist Helen B. Tager-Flusberg of the University of Massachusetts in Boston. In particular, she notes, it's not known if Karmiloff-Smith's novel-number task taps into the beginnings of more-complex types of counting or instead represents a basic quantity comparison employed by many nonhuman animals (SN: 11/7/98, p. 296).

"People with Williams syndrome exhibit consistent problems in certain areas of number and language use throughout their lives," Tager-Flusberg asserts.

Accumulating evidence suggests that an inability to think abstractly underlies verbal and numerical difficulties that arise in Williams syndrome, proposes psychologist Carolyn B. Mervis of the University of Louisville (Ky.).

Consider vocabulary. From a survey in which parents reported on conversations with their children at home, Mervis and colleague Byron E Robinson, now of Georgia State University in Atlanta, report that 2-year-olds with Williams syndrome use a far greater variety of words in expressing themselves than 2-year-olds with Down's syndrome do. The results are slated to appear in DEVELOPMENTAL NEUROPSYCHOLOGY.

Compared with kids who are free of genetic defects, however, language use flowers slowly in both Williams syndrome and Down's syndrome, Mervis says. Williams syndrome often includes a lack of appreciation for metaphor and other abstract uses of language, even in adults, she finds.

In Karmiloff-Smith's study, Williams syndrome toddlers likely encountered problems in grasping the abstract concept of a strange adult referring to an object that was about to be shown, she suggests. Their verbal facility rises in more concrete situations, such as communicating with their parents at home.

Numerical performance follows a similar pattern, according to the Louisville researcher. Mervis and her coworkers have found that 9- and 10-year-olds with Williams syndrome or Down's syndrome perform fairly well, and at comparable levels, on straightforward tests in which they count and sort objects in front of them.

In contrast, other researchers have found that performance plummets for children with Williams syndrome who try to solve arithmetic problems in their heads.

Scientists have so far linked two genes to particular elements of Williams syndrome. The elastin gene, expressed sparingly in the brain, produces a connective tissue protein found in skin, ligaments, and the walls of internal organs and blood vessels. Absence of one copy of elastin appears to foster heart problems, unusually flexible joints, and the characteristic facial appearance found in Williams syndrome.

An adjacent gene, LIM-kinase 1, yields a protein thought to coordinate the development of brain cells involved in spatial skills (SN: 7/20/96, p. 39). A person missing one copy of LIM-kinase 1 usually has spatial abilities ranging from extremely poor to slightly below average, Mervis says.

Developmental factors help forge a spectrum of spatial aptitudes among children and adults with Williams syndrome, she proposes. For instance, the small proportion who reconstruct block patterns with moderate success also have relatively strong vocabularies, verbal short-term memories, and nonverbal reasoning skills.

Observations during testing indicate that many of these individuals try to reformulate spatial and nonverbal problems as verbal exercises that they then talk themselves through. In other words, they use verbal strengths to compensate for spatial weaknesses, Mervis suggests.

"Little is known about what most of the missing genes in Williams syndrome actually do," she remarks. "But they clearly contribute to a larger developmental process rather than directly affecting behavior."

Further research into other developmental disorders will reinforce that point, Mervis predicts. For instance, in a devastating condition known as specific language impairment, people have serious problems communicating with others. Some researchers argue that a genetic defect selectively undermines a brain module for grammar use (SN: 2/4/95, p. 70).

Others now see this disorder as a broader disturbance that during development comes to undermine language use. Preliminary brain-scan data suggest that the genetic deficit in this condition interferes with the development of the basal ganglia, a small brain structure with numerous connections to other neural regions.

This can eventually result in the wideranging symptoms of specific language impairment, argues a team of neuroscientists led by Kate E. Watkins of the Montreal Neurological Institute. The condition often includes an inability to coordinate movements of the face and mouth, as well as language problems not involving grammar, they report in the November 1999 AMERICAN JOURNAL OF HUMAN GENETICS.

"There's a great gulf between genes and behavior," Tager-Flusberg maintains. "We need to look much more deeply at how the developmental process works in order to understand developmental disorders."