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Gene Links Autism to Bipolar Disorder &
Schizophrenia, Offers Hope for Treatment
Alliance for Autism Research
FOR IMMEDIATE RELEASE Contact: Eric London, M.D.,
V.P. Medical Affairs
Autism Gene Discovered
GENE LINKS AUTISM
BIPOLAR DISORDER AND SCHIZOPHRENIA, OFFERS HOPE FOR TREATMENT
In a surprise finding
from an international research team led by
researchers at the Campus BioMedico University in Rome, Italy, Drs. Flavio
Keller and Antonio Persico announced the discoveiy of a gene that may
increase the risk of a child's developing autism three-fold. The gene,
which produces the protein reelin, has recently been associated with
bipolar disorder and schizophrenia.
The reelin gene is known to be involved in proper
"lamination"-or layering- of brain cells in utero.
But unlike many
developmental genes, the reelin gene
continues to be expressed throughout life, potentially giving the
pharmaceutical industry its first "target" for an autism medication. If
reelin proves to be important in autism, pharmacologists can attempt to
create medications that manipulate reelin activity in the brain.
Researchers do not
know what function the protein performs in the
postnatal brain. Some believe it is critical to neural plasticity and learning.
The finding surprised
observers because the Italian
team was not studying reelin. As part of a larger study of autism and
serotonin, they were attempting to replicate work by Karl Reichelt of
Norway finding an abnormal presence of peptides-small pieces of
proteins-in the urine of autistic children.
But Keller and Persico
could not find Reichelt's
peptides in their subjects. When Dr. Reichelt supplied his original samples for re-testing,
two laboratories were unable to identify the peptides in Reichelt's samples, either.
For most researchers
the study would have ended there.
But it didn't. While waiting for the third and final set of lab results,
Keller and Persico-convinced the peptides had to be present-hit upon the
idea of checking them against the vast library of known human proteins.
When they found
that the only protein containing both peptides was reelin,
a protein involved in neurodevelopment, they knew they had struck gold.
Because the gene
for reelin is known, they could
examine it in people with autism. Twenty percent of their autistic population,
they discovered, carried extra-long versions of the gene. The long
variant would be expected to result in a reduction of reelin in the brain.
The findings, published
in the March issue of MOLECULAR PSYCHIATRY,
represent the second autism gene to be reported in a four-month period.
"This is an unprecedented rate of progress for a
complex disorder," said Dr. Eric London, Director of Medical Affairs for the
National Alliance for Autism Research, which funded the research.
"Geneticists estimate as many as 15 different genes may put children at risk of developing autism. To
have two strong gene studies published in four months is nothing short of miraculous."
Alliance for Autism Research was
founded in 1994 to fund biomedical research into the causes, prevention,
treatmfnt and cure of autism and related disorders. Since 1997, NAAR has
committed more than $3 million in grants to 50 scientists in the United
States, Canada, Italy, Spain and Russia. This year alone, NAAR committed
more than $1.5 million in research grants to 20 scientists in the United
States and Europe. For more information about NAAR and autism, please log
onto NAAR's website at www.naar.org.
AM Persico, L
D'Agruma, N Maiorano, A Totaro, R Militerni, C Bravaccio, TH
Wassink for the CLSA, C Schneider, R Melmed, S Trillo, F Montecchi, M
Palermo, T Pascucci, S Puglisi-Allegra~ KL Reichelt,
M Conciatori, R Marino, A Baldi, L Zelante, P Gasparini and F Keller
Autism is viewed
as a complex neurodevelopmental
disorder. Reelin is critically involved in the development of many brain
regions displaying alterations in autistic patients. The authors have
identified a repeated GGC sequence in the gene encoding Reelin that might affect gene
expression. This GGC stretch is "polymorphic",
meaning it differs in length among different individuals. Approximately 90% of the general
population carries either 8 or 10 GGC repeats. Interestingly, longer variants encompassing 11-23 GGC
repeats are found in as many as 20% of autistic patients, and inheriting a
"long" allele leads to a three-fold increase in risk of developing autism.
This finding represents
the first genetic factor
consistently predisposing to autism in several distinct patient samples, and
links autism to a plausible neurodevelopmental mechanism. Although
"long" reelin gene alleles characterizes only 20% of their patients, this result fits exactly
with expected single gene contributions to a complex disorder, such as autism.
reelin: what it may mean for autism
1. The reelin
gene is both a housekeeping gene and a
Developmental genes operate in the womb. A developmental gene directs the
development of some aspect of the body or brain, and then turns off.
Developmental genes do not operate in the child or
adult (although "reactivated" developmental genes may be involved in cancer in adult life-)
Housekeeping genes operate in the here-and-now.
Housekeeping genes are the body's "operating system": everything we do,
think, feel or say is carried out by housekeeping genes.
genes operate in the present, they may be easier to
treat. Defects in developmental genes often result in structural defects,
or differences, in the body or brain. Patty Rodier's work on the HoxA
gene, which is involved in very early development of the brain stem,
implies that autistic children aie born with a structural difference or defect in the cerebellum.
or differences can be treated
chemically. Parkinson's disease, in which dopamine-producing cells in the sub stantia nigra
progressively die off, can be treated in the early stages with the
medication levodopa, or L-dopa, which the brain uses to make dopamine. Put
very simply, structural differences naturally result
in biochemical differences. Pharmacologists develop medications to treat the biochemical
difference. And, of course, stem cell researchers hope one day
soon to be able to replace missing or damaged cells with new and healthy cells.
or perhaps most autism
researchers hope to discover that autism results largely from differences or
defects in housekeeping genes. A defect or difference in a housekeeping gene
creates a biochemical difference, such as low levels of synaptic serotonin
in clinical depression, for instance. Pharmaceutical companies
know a tremendous amount about how to create medications that
"up-regulate" or "down-regulate" chemicals and their
functions in the brain and body. If the association between Keller's reelin "allele"
and autism is replicated-and if researchers find evidence that the
reelin allele causes autistic symptoms-pharmaceutical companies can
develop a medication to manipulate reelin function in the brain.
2. Dr. Keller
reports that the reelin protein in autism
should be normal. The problem should simply be reduced levels: too little reelin.
3. Some researchers
believe that reelin is important to
learning and memory. If true this would obviously be highly relevant to
the treatment of autism. (Reelin research is so new that a parent who
did a Medline search found that every abstract on reelin had been
published within the past 6 months. It wasn't until recently that researchers
knew the reelin gene continued to function throughout life.)
4. In post
mortem studies of autistic brains, researchers at the University
of Minnesota (Fatemi, et al) found a 43% reduction in reelin levels in the
Purkinje cells of the cerebellum compared to non-autistic brains. Because
researchers suspect that many or most people with autism have reduced
numbers of Purkinje cells, Fatemi's finding may raise the possibility that
a reelin medication could benefit many people with autism, whether or not
they have the particular reelin gene variant Keller has identified.
5. The reelin
receptor, or part of it, is also the
receptor for low density lipids (or "bad" cholesterol.) Clarence Schutt,
Ph.D., chairman of NAAR's board of trustees, Director of the Graduate Program
in Molecular Biophysics at Princeton University, interprets this
to mean that autism could prove to be a cholesterol disorder. It's possible.
reelin "allele," or "variant," is a normal
version of a normal gene. Ed Cook, M.D., of the University of Chicago,
conservatively estimates that at least 50% of the population
carries autism genes. (See http://www-psy.bsd.uchicago.edu/--student/ldn.html)
In a recent lecture Ian Lipkin, M.D., an authority on chronic nervous
system disorders and their links to infections agents such as viruses or
bacteria, told audience members that 100% of the population could
logically carry one or more autism susceptibility genes.
7. A team
at the University of Illinois has found
reduced levels of reelin in schizophrenia and bipolar disorder. This is
intriguing in light of the strong association of bipolar disorder and autism in
population studies. Robert DeLong, M.D., of Duke University, has
advanced the hypothesis that autism is a "phenotype" of the genes for bipolar
disorder when they are expressed in infancy. In other words, when the genes
for bipolar disorder become active at birth the individual becomes
autistic. When the genes are not expressed until late adolescence the individual
becomes bipolar. Both autism and bipolar disorder are phenotypes of these genes.
Margaret H. Dupuis
Dept. of English
Western Michigan University
Kalamazoo, Michigan 49008
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Date: 25 Apr 2001 04:33:10 -0000
From: "NAAR News List" <NAARnewsfirstname.lastname@example.org>
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