FW: Autism Gene Discovered/ Birth Proteins & Later Autism

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Autism Gene Discovered/ Birth Proteins & Later Autism

FEAT DAILY NEWSLETTER Sacramento, California http://www.feat.org

" Healing Autism: No Finer a Cause on the Planet "

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April 29, 2001 Search www.feat.org/search/news.asp

Significant Medical Findings

Also: NGF Proteins Present At Birth Linked To Later Autism

Autism Gene Discovered

Gene Links Autism To Bipolar Disorder And Schizophrenia, Offers Hope For

Treatment

http://www.listbot.com/cgi-bin/subscriber?Act=view_message & list_id=NAARnews &

msg_num=9 & start_num=

In a surprise finding from an international research team led by

researchers at the Campus BioMedico University in Rome, Italy, Drs. Flavio

Keller and 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 phannaceutical 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.

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.

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Reelin Gene Alleles And Haplotypes As A Factor Predisposing To Autistic

Disorder (Abstract)

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.

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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.

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

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NGF Proteins Present At Birth Linked To Later Autism

[This is a more detailed report on this subject first posted three

days ago.]

http://unisci.com/stories/20012/0426011.htm

A new study shows that elevated concentrations of proteins present at

birth in the blood may be associated with the development of autism and

mental retardation later in childhood.

The identification of a biological marker early in life and before the

onset of symptoms could lead to earlier and more definitive diagnoses,

better clinical definitions, and the discovery of interventional therapies

for the disorders.

Investigators at the National Institute of Neurological Disorders and

Stroke (NINDS), the March of Dimes/California Birth Defects Monitoring

Program and the MIND Institute at the University of California, ,

collaborated on the study, which will appear in the May 2001 issue of the

ls of Neurology.

The investigators examined and compared archived neonatal blood

samples from children born in four northern California counties from 1983 to

1985 who later developed autism, mental retardation, cerebral palsy or

developed normally.

The investigators measured concentrations of several neural growth

factors and found that the growth factors were significantly elevated in the

neonatal blood of children who later developed autism or mental retardation,

but not in the blood from children who developed cerebral palsy or blood

from the normal controls.

" Finding that major regulators of brain development were different in

children with autism from normal controls in the first days of life opens an

exciting new avenue of research, " says Karin B. , M.D., Senior

Investigator in the Neuroepidemiology Branch of the NINDS. " We think this

work will be a step to better understanding the biologic basis of autism and

hope it will lead to better ways to treat and perhaps prevent autism. "

" We have these promising new results because the California Department of

Health Services had the foresight many years ago to save specimens from the

newborn screening program, " added study co-author Judith K. Grether, Ph.D.,

of the California Department of Health Services. " This archive of newborn

blood specimens is an incredible treasure, providing a tremendously valuable

resource for scientific study of a wide range of developmental disabilities

and birth defects. "

Neural growth factors are important to the formation of the central nervous

system during embryonic development. Previous research shows that many of

these growth factors play a vital role in the production of new brain cells

and the organization of those cells into distinct networks.

The investigators hypothesize that an abnormal abundance of these

proteins may disrupt the normal process of cell migration, differentiation

and programmed death during early nervous system development. Animal studies

have shown that an early shortage of one of these proteins leads to

microcephaly and other developmental problems.

The investigators speculate that a breakdown in the regulation of

factors that influence early brain development is important in autism and

mental retardation.

Since these disorders cannot be clinically diagnosed until later in

childhood, the identification of molecular markers could be helpful in the

early diagnosis of the disorders and in the design of future clinical

studies to test therapies.

The researchers plan to continue their work to further elucidate the

biological and genetic mechanisms that underlie the development of autism

and other developmental disorders.

Autism is a pervasive developmental disorder that affects

approximately 10 to 20 people in every 10,000 and affects males about four

times more frequently than females. Symptoms of autism may surface in

children around the age of 2.

People with classical autism show three types of symptoms: impaired

social interaction, problems with verbal and nonverbal communication, and

unusual or severely limited activities and interests. People with autism may

also show abnormal responses to sensory stimuli, such as touch, sounds and

sights. Twin studies suggest that autism has a strong genetic component.

Mental retardation is a term that is applied to people who show

significantly delayed or impaired mental, intellectual, and social

development. People with mental retardation generally score below 70 points

on an intelligence quotient (IQ) test and have trouble adapting to complex

social situations.

Cerebral palsy is a term used to describe a group of chronic disorders

caused by faulty early development of or damage to motor areas in the brain.

Symptoms of cerebral palsy include difficulties with control of limb

movement. Some people with cerebral palsy may also have mental impairment.

(Reference: , K. B.; Grether, J. K.; Croen, L. A.; Dambrosia, J.

M.; Dickens, B. F.; Jelliffe, L. L.; Hansen, R. L.; , T. M.

" Neuropeptides and Neurotrophins in Neonatal Blood of Children with Autism

or Mental Retardation. " ls of Neurology, May 2001, Vol. 49[5], 597-606.)

NINDS is part of the National Institutes of Health in Bethesda, land.

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Lenny Schafer, Editor PhD Ron Sleith Kay Stammers

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