Subject: Gene Links Autism to Bipolar Disorder &
 Schizophrenia, Offers Hope for Treatment

 NAAR News List
 

 National Alliance for Autism Research
 FOR IMMEDIATE RELEASE Contact: Eric London, M.D.,
 V.P. Medical Affairs
 888 .777.NAAR
 Date: 4/16/01

 Autism Gene Discovered

 GENE LINKS AUTISM TO
 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."

 The National 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

 Molecular Psychiatry

 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 gene.
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.

 Because housekeeping 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.

 Structural defects 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.

 Nevertheless, many 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.

 6. Keller's 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.

 See also:

 http://www.uic.edu/depts/paff/opa/releases/2000/schizo_release.html
 

 Margaret H. Dupuis
Dept. of English
Western Michigan University
 Kalamazoo, Michigan 49008
 (616) 387-2604

 NAAR News List <NAARnews-owner@listbot.com> wrote:
 Date: 25 Apr 2001 04:33:10 -0000
 From: "NAAR News List" <NAARnews-owner@listbot.com>
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