Genes to Grow On.(role of genes in developmental disorders)
by Bruce Bower
Science News - Feb 26, 2000
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."
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COPYRIGHT 2000 Science Service, Inc.
in association with The Gale Group and LookSmart. COPYRIGHT 2000 Gale Group
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