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AUTISM FIRST STEPS
AUTISM DAILY NEWSLETTER
Saturday, November 17, 2001
INDEX:
* Scientists
identify specific genes in the brain affected by fragile X syndrome
* Signals
from nervous system influence immune system, study shows
* Survey: Many
Kids with ADHD Are Not Being Treated
*
Federal research grant brings new center to study autism to NJ
*
New Ritalin Drug Ok'd, Makers Say
*
Rate of Disease Much Higher Than Had Been Thought
***************************************
Scientists
identify specific genes in the brain affected by fragile X syndrome
Contact:
Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University Health Sciences Center
Scientists identify specific genes in the brain affected by
fragile X syndrome
Scientists have identified for the first
time specific genes in the brain that are affected by the lack of FMRP — the
protein that is absent in individuals with fragile X syndrome, the most
frequent cause of inherited mental retardation in humans. The finding,
published in the Nov. 16 issue of the journal Cell, provides the first clear
evidence that fragile X syndrome may be caused by the dysregulation of specific
mRNA (messenger RNA) molecules and their encoded proteins. The research group
included scientists from Emory University, the Rockefeller University, Duke
University and the Howard Hughes Medical Institute. "We expect these
discoveries to elucidate the proximal cause of fragile X syndrome as well as to
provide new targets for drug therapy ," said principal investigator
Stephen T. Warren, Ph.D., W. T. Timmie professor and chairman of the department
of human genetics at Emory University School of Medicine and a Howard Hughes
Medical Institute investigator. The paper’s first authors are Emory School of
Medicine investigators Victoria Brown, Ph.D., and Peng Jin, Ph.D. Dr. Jin also
is a Howard Hughes Medical Institute associate. Using DNA microarray
"chip" technology, the scientists identified 432 mRNAs (expressed
genes) from cells in the mouse brain that normally are associated with FMRP.
When they compared these to cells derived from patients with fragile X
syndrome, they identified 251 of those same mRNAs (approximately 2% of the
expressed genes) that were dysregulated in the absence of FMRP. Although scientists
have known that FMRP is a protein that binds with RNA and is involved in the
regulation of translation, they have not known until now the specific identify
of the mRNAs associated with FMRP nor the consequences of the lack of FMRP for
message translation. In related research, led by Robert B. Darnell, M.D.,
Ph.D., of The Rockefeller University, working with Dr. Warren’s laboratory at
Emory, the scientists discovered specific binding sites for FMRP on RNA —
molecular structures called G-quartets. G-quartets are unusual structures of
RNA formed by specific guanine bases in series. Guanine is one of the four
amino-acid bases (A, T, G, and C) that are combined in different sequences
within the DNA to make genes. The research also is published in the Nov. 16
issue of Cell."Learning the actual binding site of the FMRP allows us to
actually dissect the interaction between FMRP and its associated messages,
including constructing a ‘reporter’ gene that could be a key to drug
discovery," Dr. Warren said. In 1991, Dr. Warren and his colleagues
discovered the FMR1 gene and were among the first to develop genetic tests to
diagnose fragile X syndrome. In 1993, they discovered FMRP, the protein
expressed by the normal FMR1 gene, and learned that fragile X syndrome occurs
when the FMR1 gene does not produce the FMRP protein. Suppression of the FMRP
protein is responsible for the symptoms of the disease, namely mental
retardation, attention deficit disorder and connective tissue disorders. The
most recently identified genes reported in the Cell manuscript also provide
candidate genes responsible for the genetic causes of these associated
problems, such as autism, of which nearly 20% of fragile X patients suffer.In
the past few years there has been a dramatic increase in the understanding of
the molecular basis of the fragile X syndrome, with many of the major
discoveries originating in Dr. Warren’s laboratory. For example, the scientists
have learned that most affected fragile X patients share a common genetic
mutation called triplet repeats. All genes are made of combinations of four
chemicals, abbreviated A, C, G and T. Within the FMR1 gene, the triple
combination of CGG, CGG, etc., is usually repeated only 30 times in unaffected
persons, but between 230 to 1,000 times in those affected by fragile X
syndrome.With this knowledge, genetic counselors have been able to help
carriers of FMR1 predict the probability of giving birth to a child affected by
the syndrome, and pediatricians and medical geneticists have been able to
provide perinatal testing of babies to determine if they might be affected by
fragile X syndrome. "Our current research illuminates what might be going
on in a neuron that could lead to mental retardation besides the simple absence
of the FMRP protein," said Dr. Warren. "Our next step will be to
further understand and modulate these proteins that are the real cause of
fragile X. Already we know that some of these proteins affect the ability of a
neuron to form a connection with another neuron. We hope the novel proteins we
have identified will lead to pathways involved in learning and memory."###
The research was supported by the National Institutes of Health and the Howard
Hughes Medical Institute .
***************************************
Signals
from nervous system influence immune system, study shows
Contact: Wallace Ravven
wravven@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
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. The research
was funded by the National Institutes of Health and the Medical Research
Council of the United Kingdom.
***************************************
Survey: Many
Kids with ADHD Are Not Being Treated
Survey: Many Kids with ADHD Are Not Being
Treated
By Suzanne
RostlerNEW YORK (Reuters Health) - Many parents of children with
attention-deficit/ hyperactivity disorder (ADHD) could be doing more to help
their child succeed in school and get along with peers and family, results of a
national survey suggest.According to the report by researchers at New York
University, 45% of parents of children with ADHD said behavior therapy had been
recommended for their child but only 21% had acted on the advice. Similarly,
89% of parents said their child had been prescribed medication to treat the
disorder but only 55% said their child was currently taking the
medication.However, parents who used behavioral therapy or medication reported
that these treatments improved their child's academic performance and ability
to participate in extracurricular activities.Dr. Harold S. Koplewicz, director
of the New York University Child Study Center, which developed the survey, said
many parents may feel stigmatized by their child's diagnosis and do not want outsiders,
such as the school nurse, to be involved in treatment. But there are now
medications for ADHD that can be taken before school and don't need to be taken
again until the end of the day, he told Reuters Health in an interview.ADHD
``is an all-day, everyday problem that requires very specialized treatment or
else kids will get picked on, have trouble in school and in after-school
activities, and face social rejection,'' Koplewicz explained. Ultimately, he
added, the disorder will affect the child's self-esteem.ADHD is characterized
by impulsive behavior, difficulty paying attention and academic and behavioral
problems. Up to 5% of school-age children are estimated to have ADHD, with boys
diagnosed up to four times more often than girls.Last month, the American
Academy of Pediatrics issued guidelines aimed at helping pediatricians treat
school-age children with ADHD. According to their report, stimulant medication
is at least somewhat effective at reducing symptoms and improving
relationships.The national survey of parents of more than 500 children aged 6
to 14 also revealed the extent to which the disorder permeates peer and family
relationships, and impairs a child's social development.For instance, parents
of children with the disorder were more than three times more likely to report
that their child had problems getting along with children in the neighborhood
and half as likely to report that their child has many good friends, compared
with parents of children without the disorder.And 8% parents of children with
ADHD said their child did not have any good friends, compared with 1% of
parents of children without ADHD.Children with the disorder were also more than
twice as likely to get picked on at school, according to parents. And 22% of
parents of kids with ADHD reported that their child had behavioral or social
problems that limited his or her participation in after-school activities,
compared with 7% of parents whose kids did not have ADHD.Nearly three quarters
of parents (72%) said their child with ADHD had trouble getting along with
siblings or other family members, compared with just over half (53%) of parents
of children without ADHD.The survey results support the findings of another
recent study showing that children with ADHD are more likely to enter
adolescence with few close friendships and less peer acceptance.In other
findings, 50% of parents of children with ADHD reported that another family
member had been diagnosed with the disorder, supporting the theory that ADHD is
at least partly genetic.The survey was sponsored by McNeil Consumer &
Specialty Pharmaceuticals.
**************************************
Federal
research grant brings new center to study autism to NJ
Jersey/Metro News
Federal research grant brings new center to study autism to NJ By
LINDA A. JOHNSON
The Associated Press
11/16/01 4:27 PMPISCATAWAY, N.J. (AP) -- Scientists at a new
children's environmental health research center run by New Jersey's biggest
universities will try to solve the mystery of what causes autism and related
neurological disorders. Environmental Protection Agency Administrator and
former New Jersey Gov. Christie Whitman on Friday announced a 5-year, $5
million federal grant to fund the Center For Childhood Neurotoxicology and
Exposure Assessment. Its scientists will investigate the links between
"neurotoxins," or chemicals around us considered toxic to
still-developing brains, and neurological conditions in children. The research
will focus on autism, attention deficit disorder and learning disabilities. The
center is based at the Environmental and Occupational Health Science Institute
at Rutgers University's Piscataway campus. The institute, a joint project of
Rutgers and UMDNJ-Robert Wood Johnson Medical School, was chosen for the
breadth of expertise of its researchers and physicians in disciplines from
neurotoxicology and exposure assessment to genetics and treatment of
learning-disabled children. "Your work is going to help us provide our
children, and our grandchildren, with a healthy and safe environment in which
they can grow up and mature to achieve their best results," Whitman said.
EPA and the National Institute of Environmental Health Sciences is funding
research at the center, and eleven others nationwide, with the aim of finding
ways to prevent -- rather than just treat -- conditions likely related to toxic
exposures, Whitman said. "We've witnessed some alarming increases in
learning disabilities, attention deficit disorder and autism," she said.
Autism, usually diagnosed by age three, leaves children with limited ability to
communicate or interact socially; many obsessively perform repetitive behaviors
such as spinning in circles. Its increasing prevalence is of particular concern
in New Jersey, where state and federal researchers investigated an autism
cluster among children in Brick Township. A report the scientists published
this month in the journal Pediatrics shows one in 150 children in Brick have
autism, or more than three times the estimated national prevalence. Young
children are believed more vulnerable than adults to the effects of chemicals
around them in homes, schools and outdoors because of their smaller size,
faster metabolism and other factors. In particular, toddlers spend considerable
time crawling on carpeting and tile made and cleaned with chemicals, and
touching surfaces where lead dust or air pollutants may have settled. Then they
put their hands into their mouths. Scientists at the new center will try to
find whether such exposures are "environmental triggers" for autism
and related conditions. Dr. George Lambert, the center's director, said that while
genetic factors are one cause of autism, chemicals in the environment likely
play a role because research among twins shows if one has autism, there's a 35
percent chance the other won't. Genes and chemicals may interact, as well.
Dozens of researchers and clinicians at the center will work on parallel tracks
and share information with each other and, periodically, with scientists at the
other eleven centers. In Piscataway, one group will test the environment of
individual children with autism and other learning disabilities -- their homes,
yards, schools and other places they go -- to seek common chemical exposures to
investigate. Children's brains will be scanned to see if higher exposures to
toxins cause different patterns of brain development. Other scientists will
study the effects of suspected chemicals on the brain cells and behavior of rat
fetuses and pups whose mothers were exposed to the chemicals. The first
chemicals to be tested are mercury, lead and valproic acid, a drug given to
some pregnant women to control seizures. "It's quite conceivable we'll
have an answer soon," perhaps in 10 years, on what causes autism, said Dr.
Stuart Cook, president of the University of Medicine and Dentistry of New
Jersey, which includes Robert Wood Johnson and two other medical schools. The
two federal agencies fund three other new research centers, along with eight
that are a few years old, at other U.S. universities and medical centers. They
focus on links between toxins that may affect children and conditions including
asthma, lead poisoning and behavioral problems.
***************************************
New
Ritalin Drug Ok'd, Makers Say
New Ritalin Drug Ok'd, Makers Say
The Record, Bergen County, NJ
LEWIS KRAUSKOPF, Staff Writer Novenber 16, 2001
Two New Jersey drug companies said Thursday they won approval from the Food and
Drug Administration to sell a refined version of Ritalin, the controversial
children's stimulant. The new drug, called Focalin, is designed to provide the
same effectiveness as Ritalin with half the dosage. Novartis Pharmaceuticals
Corp. of East Hanover and Warren-based Celgene Corp. developed Focalin, which
will be available beginning next year for treatment of attention-deficit hyperactivity
disorder. "For children who are taking a drug for long periods of time,
the less drug you need in your system the better off you are," said John
Jackson, Celgene's chief executive officer. A recent study by the American
Academy of Pediatricians found that ADHD affects between 4 percent and 12
percent of all school-age children. Although Ritalin, available for about 50
years, is synonymous with stimulants to treat the disorder, several players
compete in the market. Last year, doctors wrote nearly 20 million prescriptions
for stimulants, including Concerta, Metadate, and Adderall, totaling $758
million in sales in the United States, according to IMS Health, a healthcare
information company. The expanded Ritalin franchise is expected to include Focalin
and a once-a-day version called Ritalin LA, which moved closer to FDA approval
last month. Celgene will receive royalties on sales from the entire Ritalin
franchise from Novartis, which developed the original Ritalin. Analysts
previously expected annual sales for all Ritalin products to reach between $250
million to $450 million within the next few years. The recommended starting
dose for Focalin will be 2.5 milligrams, and patients switching from Ritalin
should start at half their usual dosage, according to the companies. Novartis
will launch Focalin in late January, although the company is still developing
the size of the sales force to market the treatment to doctors, said Gina
Moran, a Novartis spokeswoman. Moran said the company had no plans to market
the drug directly to consumers, a tactic used by competitors that has been
criticized. Dr. Peter Heilbroner, a Ridgewood pediatric neurologist who
prescribes Ritalin, said the new version could provide a wider range of dosages
and may have fewer side effects. "It could expand the number of treatment
options," Heilbroner said. American shares of Novartis, the Swiss drug
giant which bases its North American presence in New Jersey, rose 17 cents, to
$38.20. Celgene's share price remained unchanged Thursday, at $36.99.
(C) 2001 The Record, Bergen County, NJ. via ProQuest Information and Learning
Company; All Rights Reserved
***************************************
Rate
of Disease Much Higher Than Had Been Thought
Rate of Disease Much Higher Than Had Been Thought
NewsRx.com
Novenber 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 McBeal 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 Kurlan, 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. To see more of the NewsRx.com, or to subscribe,
go to http://www.newsrx.com .
©Copyright 2001, Pain & Central Nervous System Week via NewsRx.com &
NewsRx.net
***************************************
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