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AUTISM FIRST STEPS
AUTISM DAILY NEWSLETTER
Tuesday, November 20, 2001
INDEX:
* Rate of Disease Much Higher Than Had Been Thought
* Children's Immune System May Be Influenced in Womb
* Signals from nervous system influence immune system, study
shows
* CAUCUS for Autism Meeting
* CPA: Oral Risperidone Safe and Effective for
Long-Term Treatment of Behaviour Disorders
* How Fragile X Syndrome Leads To Mental Retardation
* How Fragile X Syndrome Leads To Mental Retardation
***********************************
Rate of Disease Much Higher Than Had Been Thought
NewsRx.com
November 15, 2001
One out of four students in special-education classes has a tic-related
disorder, like Tourette syndrome, and the rate of Tourette among students in
the general population is 50 to 75 times higher than has been traditionally
thought by doctors, according to a study published in the journal Neurology.
The neurologists who did the study say that Tourette comes in many forms,
including variations much milder than the profanity-spewing, limb-jerking
characters seen on TV shows like Ally mucosal and LA Law. Doctors say the
findings should raise awareness among teachers and doctors that children who
are performing poorly in school and who have tics may need medical treatment,
and that such treatment could ease school difficulties for these students.
"Most people view Tourette as a very rare, unusual disorder with bizarre
symptoms, but it's really very common, usually with mild symptoms," says
Roger Karla, MD, a professor of neurology at the University of Rochester
Medical Center and lead author of the Neurology paper. "The cases you see
on TV are the most severe cases, and they're just the tip of the iceberg. Most
cases of Tourette are much milder and don't progress to the severe form."
In the study of 1596 children in Rochester, New York, 8% of children in special
education met the criteria for Tourette, and about 27% had some tic disorder.
In the general population, 3% had Tourette, and 20% had a tic disorder. The
rate of 3% in the general population is about 50 to 75 times higher than
typical estimates.
While tics like barking obscenities or jerking one's head are easy to spot,
there are a slew of other repetitive and involuntary movements or vocalizations
- tics - that are usually overlooked by family, friends and coworkers as
strange or annoying habits, Kurlan says. Common tics include rapid
eye-blinking, scrunching up one's nose, little jerks of the head, facial
twitches, or even constant sniffing or clearing one's throat repeatedly.
"The fact that a child has tics probably signifies a subtle brain
developmental disorder. It's like a window into the brain: When you see a child
with tics, it's a sign that the wiring isn't quite right," says Kurlan,
chief of the Cognitive and Behavioral Neurology Unit at the university's Strong
Memorial Hospital, where he treats more than 400 Tourette patients regularly.
"Tics are observable markers that this person is more likely to have
problems in school."
Researchers have linked Tourette syndrome to an area of the brain known as the
basal ganglia, which is involved in controlling movement and plays an important
role in attention, concentration, and decision-making. The same part of the
brain is affected in people with obsessive-compulsive disorder, attention
deficit-hyperactivity disorder (ADHD), and some learning disabilities.
So it's no surprise that the same factors that affect children with ADHD and
these other disorders are also stumbling blocks for children with Tourette.
Students with the disorder are five times as likely as others to end up in
special education. People with Tourette typically are impulsive, have trouble
concentrating and are easily distracted; friends or colleagues might say
they're filled with nervous energy or seem to fidget continually.
Kurlan says that with a little training, teachers should be able to recognize
most tics and thus identify some students more likely than their peers to have
difficulty in school.
"A good proportion of these kids has a recognized medical condition that's
amenable to treatment. Many of the symptoms of Tourette are treatable, so that
if you recognize it, you can treat it and perhaps improve the child's school
performance and their ability to make friends.
"If a child is doing well, there certainly wouldn't be much to do in terms
of intervening," Kurlan says. "On the other hand, maybe a child isn't
doing all that well. If the child is struggling in school or having trouble
making friends, perhaps causes like ADHD or Tourette should be evaluated, and
treatment should be considered for that student."
Kurlan first became aware of the possible extent of the disorder in 1983, when
a man who had been diagnosed with Huntington's disease hitchhiked more than
2,000 miles to seek a second opinion from Kurlan. The man actually had
Tourette, and within an hour - the most astonishing moment in his career,
Kurlan recalls - the patient had described 20 relatives with similar symptoms.
Kurlan put together a research team to visit the isolated village in northern
Alberta which the patient called home, for a study of the genetic roots of
Tourette. The Mennonite community of 700 was made up heavily of descendants of
a single Russian ancestor, and tales of Tourette-like behavior were rife.
"After several flights, we arrived at the six-room hotel in town, and the
very first person we met, the man checking us in at the hotel, had obvious
Tourette. We looked at each other in total amazement. We knew we had come to
the right place," Kurlan says. Through interviews and exams of the man's
relatives, the team ultimately found about 200 members of the extended family
of 2500 people with the disorder.
Kurlan thinks that the rate of Tourette has been underestimated because the
patients who seek out treatment in a doctor's office are usually those with the
most severe symptoms. In past studies, doctors have relied on questionnaires
and a review of medical records to identify patients without conducting direct
interviews or exams.
"Our eyes were opened by going out into the community, when we explored
what Tourette is like in the real world. It's not a severe illness with bizarre
symptoms; most people had relatively mild symptoms and did not go to their
doctors for help. Most live a pretty normal life and are not disabled by
tics."
Using his experience in northern Alberta as a springboard, Kurlan returned to
Rochester and conducted a series of studies indicating that the disorder is
much more common in the general population than previously thought.
The Neurology study, funded by the National Institute of Neurological Disorders
and Stroke (NINDS), was done in the city of Rochester and in 10 suburban school
districts and included students ages 8 to 17. Teachers and parents answered
questions about the students, and then students were interviewed for an hour by
technicians trained to assess tics and separate out possible causes like
boredom, hyperactivity, or simple restlessness.
His results back the findings of two recent smaller studies which estimated
Tourette in about 1% of people, significantly higher than previous estimates.
Every day - in airports, at the office, and in the hospital - Kurlan sees
people who likely have Tourette, just as anyone with a trained eye would see
among any large group of people, he says. He likes to tell the story of famed
neurologist and author Oliver Sacks, who often said that on the day he
recognized his very first patient with Tourette syndrome, he saw several more
cases on the way home from work.
Other authors on the paper include biostatistician Michael McDermott, PhD;
nurse Cheryl Deeley; neuropsychologist Peter Como, PhD; child psychiatrist
Bruce Miller, MD; epidemiologist Elaine Andresen, PhD; and programmer Christine
Brower and statistician Sarah Eapen. This article was prepared by Pain &
Central Nervous System Week editors from staff and other reports.
***************************************
Children's
Immune System May Be Influenced in Womb
By Melissa Schorr
NEW YORK (Reuters Health) - The rigor of a child's immune system could be
established before birth, say investigators who believe that the prenatal
environment may play a role in whether or not an infant becomes more or less
susceptible to asthma and allergies later in childhood.
Previous research has found that first-born children or those who have few
siblings are more likely to have asthma and allergies than those with many
siblings. Many researchers have suggested this may be due to the ``hygiene
hypothesis'': children with many siblings are more exposed to germs early on
and develop stronger immune systems, while children who are first-born or only
children do not receive this benefit.
However, researchers suggest that the prenatal environment may also play a role
in the infant's developing immune system. ''The question was: is this happening
after birth, or is this happening before birth?'' Dr. Wilfried Karmaus, an
associate professor or epidemiology at the Michigan State University in East
Lansing, Michigan told Reuters Health.
Karmaus and colleagues hypothesized that a change in the mother's body between
her first and later pregnancies can cause a shift in the womb that affects the
child's immune system.
``There may be changes in the endocrine response in the first pregnancy
different from second and third pregnancy,'' he explained.
For example, endocrine disruptors--such environment-contaminating chemicals
like PCBs--may be higher during a woman's first pregnancy because the chemicals
are released during breast-feeding and each subsequent pregnancy. The woman's
vulnerability to infections during each pregnancy may also play a role, he
suggested.
To explore that association, the researchers looked at nearly 1,000 infants
born on the Isle of Wight in England between 1989 and 1990. They tested the
infant's umbilical cord blood for levels of immunoglobulin E (IgE), an antibody
linked to allergies.
In their report, published in the November 15th issue of the American Journal
of Epidemiology, the researchers note that first-born children were twice as
likely to have a higher concentration of IgE, with 16% of first-born children
having a certain level of IgE compared with only 8% of third-born children.
The research team conducted a skin prick test--an allergy test--on the children
at age 4 and found that those with higher levels of IgE did show a significant
increase in allergic reactions. However, they did not find a direct correlation
between birth order and skin allergic reactions.
``We have to move our explanation from postnatal to prenatal,'' Karmaus noted.
``The sibling effect may have its origin in utero.''
SOURCE: American Journal of Epidemiology 2001;154:909-915.
***************************************
Signals
from nervous system influence immune system, study shows
In a discovery that demonstrates a clear link between the mind and body at a
molecular level, scientists have shown that a chemical signal which normally
allows nerve cells to communicate with each other –to alter sleep cycles, for
example -- can also re-direct actions of the immune system.
The research in mice confirms mounting evidence from studies of cultured cells
that the nervous system directly influences the immune system. It has prompted
new experiments to determine if the nerve-generated signal or its receptors in
the immune system might make good drug targets to control asthma or allergies.
“This is the first clue of a practical pharmacological approach to using the
nervous system for both improving immune defenses and damping harmful immune
responses at their roots in diseases as diverse as arthritis and asthma,” said
Edward Goetzl, MD, professor of medicine and immunology at the University of
California, San Francisco.
Goetzl is lead author on a scientific paper on the research in the November 20
issue of the Proceedings of the National Academy of Sciences. The work is a
collaboration between UCSF and the University of Edinburgh. Goetzl is also
senior author on a companion paper on the research in FASEB Journal. (FASEB
stands for the Federation of the American Societies for Experimental Biology.)
The finding is based on experiments with “knockout” mice whose immune cells can’t
receive the normal neuropeptide signal known as vasoactive intestinal peptide,
or VIP.
In the nervous system, VIP normally stimulates nerve cell signaling and
survival, and regulates neural biological clocks. The scientists found that VIP
also affects the migration of the immune system’s T cells and T cell secretion
of protein signals for other immune cells, both of which are central to the
body’s normal defense against infection. Through its action on T cells, VIP can
affect the process in which the immune system turns against the body, such as
in asthma and arthritis.
In the PNAS paper and in the companion paper in the FASEB Journal, the
researchers showed that the strength of the VIP signal received by the T cells
regulates the balance between two types of immune T cells, Th1 and Th2. Th1 is
normally involved with protection from bacterial invasion and other defenses,
but Th1 in excess can lead to autoimmune disorders. Th2 protects from parasitic
infections and autoimmunity, but in excess can lead to allergies.
The researchers discovered the effect of VIP on the Th1/Th2 balance by
examining the relative production of the Th cells’ protein products, known as
cytokines. When the balance is tipped toward Th1 in knockout mice lacking a
critical form of a VIP receptor, allergy is suppressed and resistance to some
types of infections is boosted, along with other reactions, they found.
The research did not determine if the impact of the neuropeptide VIP is sufficient
to change the course of infections, inflammation or autoimmune disease in which
T cells are involved.
The researchers caution that VIP has such broad effects on immune function that
blocking its action with drugs might risk triggering one kind of immune malady
while it relieves another. However, the new findings clearly demonstrate the
potential of neuroregulation of T cell functions and suggest the potential
value of developing VIP-like drugs with greater immune selection than VIP
itself, Goetzl added.
Senior author on the PNAS paper is Anthony Harmar, PhD,
Professor of neurosciences at University of Edinburgh.
Co-authors are post-doctoral fellows
Julia K Voice, PhD, and Glenn Dorsam, PhD, in the UCSF medicine and immunology
departments; and
Yvonne Kong, research assistant in the same departments.
Also on the study are post-doctoral fellows
Sanbing Shen, PhD; Katrine M. West, PhD; and Christine F. Morrison, PhD, all at
University of Edinburgh
******************
CAUCUS for Autism Meeting
Date: Tuesday, November 20, 2001
Time: 7:00PM - 9:00PM EST (GMT-05:00)
Topic of this meeting is HOW TO SURVIVE THE HOLIDAYS!
Meetings held at the Upper Main Line YMCA, 1416 Berwyn-Paoli
Road, Berwyn, PA call 610-647-YMCA or www.UMLY.org for
directions.
************************************
CPA: Oral Risperidone Safe and Effective for Long-Term
Treatment of Behaviour Disorders
By Louise
Gagnon
Special to DG News MONTREAL, QC -- November 19, 2001 -- Oral risperidone
therapy appears to be safe and effective for long-term treatment of young
children with low intelligence and disruptive behaviour disorders. The finding
was presented yesterday (Nov. 18) at the annual scientific meeting of the
Canadian Psychiatric Association, in Montreal, Quebec, Canada. Researchers
enrolled 77 patients between the ages of five and 12 with subaverage
intelligence quotients (IQs), ranging from 36 to 84, who had co-morbid
disruptive behaviour disorders. "It has been observed that children who
suffer from borderline IQ or mental retardation also have a disproportionate
degree of conduct and other psychiatric disorders," explained Dr. Attila
Turgay, the study's principal investigator and chief of psychiatry at the
Scarborough Hospital, in Scarborough, Ontario, Canada. The same subjects had
participated in a previous study, which was double-blinded and randomized half
to risperidone and the other half to placebo. That six-week study demonstrated
risperidone to be efficacious and safe. All subjects were then given
risperidone in an open-label fashion for 48 weeks. Children who had a diagnosis
of pervasive developmental disorder, schizophrenia, or other psychotic
disorders were excluded from the study. Of the 77 patients, 61 had co-morbid
attention deficit hyperactivity disorder. The dosage ranged from 0.02-0.06
mg/kg/day administered once daily. The mean daily dose was 1.38 mg, and the
mode dose was 1.50 mg/day. The average duration of treatment was 322 days. Researchers
employed several scales to determine if symptoms such as aggression and
self-injurious behaviour associated with disruptive behaviour disorders were
reduced following treatment. Differences in the measurement results were
statistically significant at baseline compared to the end of the treatment
period. The drug therapy was effective in maintaining control of the symptoms
of aggression and self-injurious behaviour associated with disruptive behaviour
disorders over a period of nearly a year. "We have picked up patients who
were resistant to treatment," said Dr. Turgay, professor of psychiatry at
the University of Toronto. "We have shown long term use is safe and
effective. The two side effects we had to watch out for was weight gain and
[increased] prolactin levels." The study, entitled "Long-term Safety
and Efficacy of Risperidone in Children with Subaverage IQ and Disruptive
Behaviour Disorders", was funded by Janssen-Ortho Inc.
http://www.docguide.com/dgc.nsf/RegisterGE?OpenForm&code=webfeed
*****************************
ã[1]
How Fragile X Syndrome Leads To
Mental Retardation
Scientists
at last may have determined how mental retardation develops in people with
fragile X syndrome, a condition caused by the inherited loss of an essential
protein, termed the fragile X mental retardation protein (FMRP). The new
research demonstrates that FMRP controls the fate of several specific proteins
in brain cells and thus may explain why the absence of this single protein can
cause the range of physical, cognitive and behavioral abnormalities
characteristic of fragile X syndrome. While these findings may not lead to a
cure for fragile X syndrome, they do offer the potential for future therapies that
would lessen the impact of the disease."This work represents a new
understanding of mental retardation," says Robert B. Darnell, M.D., Ph.D.,
a principal investigator of the current research and a professor at The
Rockefeller University. "Our findings suggest entirely new ways of
thinking about treating the problems these patients have."Katie Clapp,
president of the FRAXA Research Foundation, which largely funded Darnell's
work, and mother of two children with fragile X says, "For the first time,
scientists can explain why these children experience certain symptoms. This
kind of knowledge is very reassuring to the families of children with the
disorder."The latest research, reported in two papers appearing in the
Nov. 16 issue of Cell, was conducted by scientists at The Rockefeller
University in collaboration with researchers from the Emory University School
of Medicine. One study was initiated by Darnell, head of the Laboratory of
Molecular Neuro-Oncology at Rockefeller, and the other by Steven T. Warren,
Ph.D., an investigator at Emory University School of Medicine and Howard Hughes
Medical Institute.Fragile X syndrome, the second leading cause of mental
retardation after Down syndrome and the most common cause of inherited mental
retardation, affects approximately 1 in 2,000 males and 1 in 4,000 females
worldwide. Symptoms include mild to moderate cognitive and behavioral deficits
as well as subtle facial malformations. In addition, the brain cells, or
neurons, of people with the disease have abnormal physical features: their
"dendritic spines" -- the finger-like projections on the ends of
neurons that are required for communication with other neurons -- are unusually
long and spindly.The disease originates when genetic mutations in the FMRP gene,
which lies on the X chromosome, cause FMRP not to be produced. But unlike the
well-studied Down syndrome, which occurs when a portion of a chromosome is
duplicated in the womb, much remains unclear about the molecular basis of
fragile X syndrome. "The problem of fragile X is intriguing, because the
loss of a single protein causes a variety of behavioral and physical
changes," says Jennifer Darnell, Ph.D., lead author of one of the Cell
reports and a research assistant professor at Rockefeller. "Before this,
the consequences of losing the fragile X mental retardation protein on other
brain proteins was unknown."Previously, it was known that FMRP, first
identified a decade ago, binds to messenger RNA (mRNA) molecules -- which carry
genetic information (DNA) from a body cell's nucleus to its protein-making
machinery -- yet the specific mRNAs involved as well as the overall purpose of
this protein remained elusive.Now, the researchers present several important
clues, which together suggest that FMRP may turn up or down the production of
certain brain proteins by binding to their mRNA molecules, and thus influencing
the cell's protein-making machinery. This type of protein regulation is a
crucial aspect of every cell's life, and in the case of brain cells, is
essential for learning and memory formation. A key feature of the current work
is the identification of the specific mRNAs that FMRP binds to, as well as the
finding that these molecules are misregulated in the cells of fragile X
patients."We found FMRP binding sites in a population of mRNAs shown to be
abnormally regulated in fragile X patients," says Jennifer Darnell.
"The proteins coded for by these mRNAs are likely to underlie the problems
these patients have." Darnell, a Rockefeller alumna, first became
interested in FMRP about five years ago because of its similarity to another
RNA-binding protein, Nova, under study in the laboratory of her husband, Robert
Darnell. She identified the FMRP mRNA targets by first discovering that FMRP
recognizes and tightly binds loop-like structures in RNA, called G-quartets,
which represent novel human RNA-binding sites. This finding is intriguing
because these structures, which resemble in appearance loose knots along a
string, are typically found in DNA and not RNA; the only known case of these
structures existing in RNA is in bacteriophage RNA, where, perhaps not
coincidentally, they play a role in mRNA regulation. A bacteriophage is a tiny
virus that only infects bacteria.After searching a computer database of known
mRNAs for the G-quartets, she hit upon a significant finding: several of the
the mRNAs targeted by FMRP, and their corresponding proteins, play a role in
learning and memory, the development of the bones of the face and in the
formation of the nervous system -- all brain activities involved in fragile X
syndrome. "Most of the mRNAs we identified as FMRP targets are involved in
some aspect of synaptic biology," says Jennifer Darnell. Synapses are the
point of contact between neurons, where information is exchanged between the
axon of one neuron to the dendrite of a second neuron. "It is possible
that FMRP is responsible for shuttling certain proteins out to the individual
dendritic spines of neurons, and/or subsequently activating them at the
appropriate time during development, as well as during adult memory
formation," says Jennifer Darnell. "This would explain how specific
neuronal connections are strengthened to form memories." Meanwhile,
Warren's group at Emory also had independently identified mRNA targets of FMRP,
only using a different technique called microarray, or "DNA chip,"
analysis. The two groups, which had initially met at the 2001 annual meeting on
fragile X syndrome at Cold Spring Harbor, collaborated and, working together,
discovered that nearly 70 percent of Warren's targets contained the G-quartets.
Finally, the researchers demonstrated that these recently characterized FMRP
targets - identified in a test tube in Jennifer Darnell's case - are in fact
misregulated in patients' cells, thereby linking their molecular findings to
what's really happening in people's bodies.Because FMRP seems to play a role in
both the developing and the adult brain, it may eventually be possible to treat
some of the symptoms of fragile X syndrome. In addition, the discovery of
several specific mRNAs involved in the disease has opened the door to new drug
targets; it one day may be possible to manipulate the individual mRNAs, or
proteins, responsible for the various symptoms of fragile X as a means to treat
the disease. The research was funded by the FRAXA Research Foundation and by
the National Institute of Child Health and Human Development and the National
Institutes of Health. - By Joseph Bonner
[Contact: Joseph Bonner]
****************************************
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