(Webmaster's Note: The interviews were conducted by
telephone and some errors were made in the transcription.
The article below contains the corrections, in
bold italics, dealing with Professor
Lenhoff and his research.)
Music, the Brain, and Williams Syndrome
Rare disorder offers
insight into the genetic basis of cognition
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By Brendan A. Maher for "The
Scientist", November 26, 2001
Gloria Lenhoff is
a 46-year-old lyric soprano singer who has performed
with
such diverse groups as the San Diego Master Chorale and
members of Aerosmith.
She can sing nearly2,500 songs in more than 25
languages, reportedly in a perfect
accent. She even has perfect pitch.
But the rest of her world is not perfect.
Gloria is affected by a rare genetic disorder
called Williams syndrome. With an IQ of about 55, Gloria
literally cannot subtract
three from five or make change for a dollar. But what she
and others with her
affliction share is music. Innately connected, they
often have an astute grasp of
music's technical aspects-the beat, rhythm, tone, and
timbre.
Identified more than 40 years ago, Williams
syndrome results from
non-homologous recombination during gametogenesis that
deletes about 20 genes
on one copy of chromosome 7.1 Characteristics of
Williams syndrome include
pixie-like features -upturned nose, small chin, protrusive
ears-as well as stunted
growth, heart problems, poor visuospatial cognition,
sensitivity to loud noises, a
gregarious personality, and an average IQ of about 60. Many
of these individuals
have difficulty with the simplest of mental and physical
tasks, but some abilities,
especially verbal skills, appear to be spared.
Classified by some as a nonverbal
learning disability, this syndrome allows speech and
language aptitude that far exceeds
their other cognitive functions. A Williams-afflicted
person, for example, couldn't
scribble more than a few lines to depict an elephant but
could describe one in expressive,
almost lyrical detail. "It has long gray ears, fan ears,
ears that can blow in the wind. It has
a long trunk that can pick up grass or pick up hay," said a
patient in an experiment
conducted by Ursula Bellugi,
director, Laboratory for Cognitive Neuroscience at the
Salk Institute for Biological Studies.1
©Ursula Bellugi, the Salk
Institute |
The dissociation
between language and spatial cognition in Williams
syndrome is evident in this contrast between the
drawing and verbal description of an elephant by an
18-year-old with Williams syndrome.
| To some, perhaps the
most striking distinction is the
extraordinary connection that these people have with
music. All exhibit a strong affinity for music, and while
their attention span for many tasks is fleeting, they will
spend hours listening to or making music.
Research is scarce, but some evidence shows a high
incidence of perfect pitch, and an uncanny sense of rhythm
among this group.2,3 One boy with Williams
syndrome was
taught to tap a complicated 7/4-time rhythm with one hand
while keeping 4/4-time with the other.4
Some researchers will not use the word
"savant," but all
admit that a connection with music exists, and that it and
the other anomalies in this syndrome might help to further
knowledge about disease and how the brain develops and
works.
Lessons from the Heart
Genetic discoveries of Williams syndrome
began at the heart.
"We were interested-still are interested-in obstructive
vascular
disease," says Mark T. Keating,
Howard Hughes Medical Institute investigator and
professor
of cell biology at Harvard Medical School. One such
disease, supravalvular aortic stenosis (SVAS),
exists in many Williams syndrome patients but also
occurs in otherwise healthy patients.
For the latter, this genetic disorder results from a
defective copy of the ELN gene that encodes for
elastin, a substance that comprises about half of the
dry weight of arteries. While conducting
linkage analysis and fluorescence in situ hybridization
(FISH), Keating, then at the University of
Utah, and his team traced Williams syndrome to a de novo
deletion of ELN on Chromosome 7.
They discovered that the responsible microdeletion at
7q11.23, unseen without FISH, included
about 2 million base pairs that were flanked by highly
duplicative chromosome regions.1
Using FISH to identify the deletion region
has reigned as a diagnostic tool for Williams syndrome,
although work done by Stephen Scherer
at Toronto's Hospital for Sick Children department of
genetics and genomic biology, recently uncovered a 1.5
million-base pair inversion of the deletion
area that occurs in roughly 5 percent of Williams patients.5
Scherer says, "There's this fallacy that you
have to have the deletion to have the disease," which can
cause health insurance problems. In 30 percent
of these cases, the parents were found to have the
inversion without the clinical manifestations of
Williams. This inversion increases the likelihood of
unequal crossing over and may be a mechanistic
explanation for the Williams deletion.
Genes in the usual deletion region include
the Drosophila homologue, frizzled (FZD3),
syntaxin 1A (STX1A), replication factor C2 (RFC2),
the gene encoding for LIM-kinase 1 (LIMK1).
Rare partial deletions, smaller than the typical 2MB
standard, exist, and the varying degrees of
Williams syndrome characteristics they produce offer
important insight in connecting cognitive
function and genetics.
Individuals with a deletion that included
only ELN and LIMK1 had the heart problems and
the
impaired visuospatial constructive cognition associated
with Williams syndrome, but no other
symptoms. It's believed, says Keating, that LIMK1's
role in cytoskeletal control and actin formation
is responsible for developmental deficiencies in the
posterior parietal cortex. Though work from a
UK lab refutes this evidence,1 examining those
rare cases of partial deletions and the traits they
produce can lead to previously unconsidered gene-brain
connections. "For instance," says
Colleen A. Morris, professor of
pediatrics, University of Nevada School of Medicine and
clinical
collaborator with Keating, "most children with Williams
syndrome have anxiety, but anxiety is also
common in the general population. Might there be a gene
within the Williams deleted region that
is important in the general population in terms of
anxiety?"
It's a story that will continue to unfold
as new technology becomes available. Eric
Green, director,
NIH Intramural Sequencing Center, presented six previously
unreported genes in the deletion area
at the American Society of Human Genetics meeting in
October. His lab has been studying the deleted
region in humans and 11 other non-human vertebrates. "In
primates," Green says, "this is a very
complicated region with these large duplicated blocks. In
lower vertebrates it's not so complicated and
it's not duplicated." The evolutionary implications of this
have incited Green to study this gene dense
region on chromosome seven, "in everything from chimpanzees
on down to pufferfish."
The Language of Music
Anecdotal evidence of an intimate
connection with music, a great memory for songs, and the
kind
of auditory finesse that can discern the differences
between vacuum cleaner brands, has followed Williams
people for some time, but little evidence has been
published. Neuropsychologist Audrey
Don, now at the
children's therapy unit at Good Samaritan Hospital in
Seattle, was one of the first to explore the
relationship.
"Cognitively, kids with Williams syndrome are better
with verbal skills. Their word knowledge and use of
words is better than their nonverbal type of thinking,"
she says.
She administered a simple musical test of
tones and beats to people with Williams syndrome and a
control group matched for vocabulary level. She found that
musical ability matches verbal ability and was
higher than the Williams' children overall cognitive
abilities.2 Their parents, providing further
survey
information, reported an extremely strong and emotional
connection with music. A lullaby tape, says Don,
made one infant cry. When the child was older, she was
asked why she wept; the child said the songs were
too sad.
An impromptu study conducted at the
Williams Syndrome Music and Arts Camp in Massachusetts'
Berkshire
Mountains gave another inkling into this particular peak of
Williams cognition. The experimenters asked eight
children to imitate clapped rhythms. They performed as well
as normal, musically trained students who were
matched to their mental age of five to seven years.3
But, the professional musicians that coded the responses
qualified the mistakes of Williams subjects as "wrong in an
interesting way."3 They often missed the exact
sequences, but creatively kept within the realm of the time
signature, much like a jazz musician will jam. The
Williams subjects were three times as likely as controls to
offer what the researchers called "creative
completion" to the test rhythm when giving an incorrect
response.
Howard M. Lenhoff, professor
emeritus, School of Biological Science, University of
California, Irvine, recently
completed a study linking Williams syndrome to a higher
incidence of absolute or perfect pitch, a condition that
normally occurs in one out of 10,000 people in Western
populations; these people often study music from a very
early age. In numerous trials, five musically trained
Williams subjects, including Lenhoff's daughter, Gloria,
displayed near-ceiling levels of absolute pitch. Of the
subjects, which represent about 1/1000 of the Williams
population in Canada and the United States, none could read
musical notes, but all could name notes and associate
them with musical tones. Gloria learned to name notes after
she was 40 years old. Both feats are rare abilities in
Williams people. "They do not need to read or name notes to
perform," said Lenhoff, "Those processes are too
cognitive for them and simply get in their way." Lenhoff
chose those five subjects because of their ability to name
notes. While criticized for choosing outliers, he says, "If
you look for the average, you'll find the average."
The age at which these
participants began to study music raises provocative
questions. It's commonly accepted that
to develop perfect pitch, one has to study music before age
six, yet all of the Williams subjects, save one, started
after this critical period. Lenhoff predicts that this
short window for gaining perfect pitch is extended in those
with
the syndrome, possibly into adulthood. "In Williams people
it appears that the normal mechanism for closing that
window gets jammed because of abnormal brain development
caused by missing genes." Lenhoff and others
hypothesize that perfect pitch is possessed by infants and
may be critical for speech acquisition in early years,
but in normal populations it then fades with disuse.2
Back to the Brain
The cognitive strengths and weaknesses
of these people have given support to the existence of
multiple
intelligences,3 and a number of neurological
studies are beginning to uncover the connections between
function
and brain. Comparative magnetic resonance imaging (MRI)
studies between Williams and Down patients
uncovered a different profile of development. While the
frontal cortex of all these individuals is smaller than
that
of a normal person, those with Williams syndrome have a
volume proportionate with the rest of the brain, while
in
Down syndrome it is reduced. In both the neocerebellum,
believed to be the most recently evolved part of the
brain,
and Heschl's gyrus, an area within the primary auditory
cortex, size is even comparable to that of normal
subjects.1
The neocerebellum, originally thought to be
involved in movement, has many anatomical connections with
the
frontal cortex, says Paul P. Wang,
assistant professor of pediatrics in child development and
neurology at Children's
Seashore House, University of Pennsylvania Children's
Hospital. "I think we're not ready to make any
earth-shattering
conclusions, but it gives us some clues as to what these
areas of the brain may be important for," says Wang, who is
involved in studies on phonological working memory-a kind
of short-term memory for sounds.
Whether innately gifted in music or not,
Williams people display a unique set of cognitive and
physical symptoms
that could further aid in other research areas, from
cardiovascular disease to the very root of how genetics
translate
into ability. Yet, studies of the connection between music
and Williams syndrome offer a creative outlet and method
to reach out to this population. "For these kids the
emotional engagement really pulls them. Music encourages
something of normalcy and fulfillment," says Don. Morris
speaks of counseling families to use music to instruct and
for its calming effect.
Though she worries that some parents might
be disappointed if their child is not quite the musical
prodigy, she
speculates about what could be learned. "[Music] is one of
the things that's found in all cultures and in all forms.
So I think that it's a basic human characteristic. If there
is a genetic component to that, then that is absolutely
fascinating."
References
1. U. Bellugi et al., "Bridging cognition, the brain and
molecular genetics: evidence from Williams syndrome,"
Trends in Neuroscience, 22[5]: 197-207, 1999.
2. H.M. Lenhoff et al., "Absolute pitch
in Williams syndrome," Music Perception,
18[4]:491-503, 2001.
3. D.J. Levitin et al., "Musical
abilities in individuals with Williams syndrome,"
Music Perception, 15[4]:357-89, 1998.
4. H.M. Lenhoff et al., "Williams
syndrome and the brain," Scientific American,
277[6]: 68-73, 1997.
5. L.R. Osborne et al., "A 1.5
million-base pair inversion polymorphism in families
with Williams-Buren syndrome,
" Nature Genetics, 29[3]:321-5, November 2001.
Mixing Science and
Parenting
For more than 40 years,
biochemist Howard M. Lenhoff studied unusual collagens,
neurotoxins, and the kinetics of peptide-receptor
interaction in the fresh water hydra. Lenhoff's use of
the "grind and find" tactics of his field earned him an
impressive publication record on the nitty-gritty
molecular mechanics of this model organism. But two
years ago, at age 70, Lenhoff switched research gears
to study cognitive neuroscience. The reason: Lenhoff's
daughter, Gloria, has Williams syndrome.
Gloria was born in 1955. Says
Lenhoff, "It was pretty obvious when Gloria was an infant
that she was handicapped mentally and physically." For 34
years, her parents grieved, believing that something they
had done during her gestation period had caused her
problems.
They didn't learn the truth
until years later. Williams syndrome was identified by
cardiologists in the early 1960s but Gloria wasn't
diagnosed with the condition until 1989. As Lenhoff
learned more about the disorder, he attended gatherings of
researchers and physicians who were investigating various
aspects of Williams syndrome. "I harassed them year after
year," he says, "asking that they investigate the many
anecdotal reports of musical talent made by parents
and teachers. Finally, one said, 'Why don't you do it?'"
Having taken an early retirement from the University of
California, Irvine, Lenhoff used the time to convince the
National Science Foundation to award him a small,
high-risk grant for the study. This summer, the results of
this study, in his first peer-reviewed piece, were
published (see accompanying article for citation).
Still, the parent in him
presides. Even though Gloria is living safely in a the
well-run Methodist-affiliated Baddour Center for
handicapped people, Lenhoff and his wife worry about her
future. They recently moved to Oxford, Miss., to be near
her Says dad: "We just want to make sure that
after we die, she will continue to be in a
safe and musically enriched environment."
H.M. Lenhoff et al., "Absolute pitch in
Williams syndrome," Music Perception,
18[4]:491-503, 2001.
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