Researchers: New understanding of autism is near - etched unmistakably in DNA

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Warning: The article doesn't contain the word " environmental " .

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Autism

Connor, 12, and his bother Murdock-Gould,16, pose with their

parents Lauretta and Murdock-Gould at their home in Port

Washington on Friday, August 03, 2007. (Newsday/Ana P. Gutierrez /

August 3, 2007)

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Researchers: New understanding of autism is near

BY DELTHIA RICKS

delthia.ricks@...

August 14, 2007

http://www.newsday.com/news/health/ny-hsauti125331613aug14,0,1913106.story

Attorney Gould and his wife, Lauretta Murdock, the founder of a

school in New Hyde Park, were not prepared for the phone call they

recently received.

It was from a neighbor, someone they had never met. The caller was

frightened. The Gould's 16-year-old son, , had casually entered the

neighbor's house through an unlocked door, startling the home's occupants.

" We were so lucky. God were we lucky, " said Gould, of Port Washington.

was oblivious to the panic. At a time when home invasions are in

the public consciousness - and homeowners might be armed - Gould feels

fortunate his neighbors sensed something different about and were

able to coax him to give them his home phone number.

The teen is autistic, as is his 12-year-old brother, Connor.

Yet, the Gould/Murdock household is not atypical. Families nationwide

are facing the realities of autism, and sometimes with more than one

child. Murdock is one of Long Island's leading experts on the condition,

having established Mosaic, a New Hyde Park school for autistic children.

No longer rare

Once considered rare, autism now affects one in every 150 children in

the United States, according to statistics from the federal Centers for

Disease Control and Prevention. Advocacy groups call it an epidemic with

an end nowhere in sight.

While many parents of autistic children - Murdock included - suspect

thimerosal, a mercury-based preservative used in routine childhood

vaccines as the disorder's cause, most scientists suspect it lurks in

the human genome, etched unmistakably in the DNA. Although thimerosal

has been removed from most routine vaccines, it still exists in trace

amounts in a few, according to the U.S. Food and Drug Administration.

" Since our sons were diagnosed we've never had a vacation. I can't

remember when either of us has gotten more than five hours of sleep.

It's exhausting, " said Gould, who maintains a diary of his sons'

journeys through childhood. " Both parents are on board 24 hours a day

but it most often falls on the mothers. I see what my wife goes through

and it breaks my heart. "

As Gould and Murdock worry about their sons, molecular geneticist

Wigler, a few miles away at Cold Spring Harbor Laboratory,

believes he and his colleagues are on the cusp of understanding why

autism occurs and how some families can be affected more than once.

Wigler and his team have discovered how certain spontaneous genetic

mutations are relatively common and how they can be passed on by very

healthy parents to their offspring. Frequencies of the mutations

increase, the team found, as people age.

Last month, the Cold Spring Harbor team developed a grand unification

theory that stitched together previous notions about the genetics of

autism and demonstrated how DNA variants - often transmitted from

mothers to sons but not exclusively so - may lie at the disorder's

roots. Boys are three times more likely than girls to develop autism,

Wigler said.

He's calling on the CDC to use laboratory techniques similar to the ones

he and his Cold Spring Harbor collaborators have developed to assess the

prevalence of autism-related mutations in the U.S. population. Screening

would help provide guidance on the rate of autism's growth in the

population, he said.

Seeking genetic clues

Autism is a relatively new area of research for Wigler at the renowned

Cold Spring Harbor lab, where Nobel Prize winner , one of

the discoverers of DNA's helical structure, is chancellor. For nearly

three decades, Wigler explored the inner sanctum of cancer cells in a

series of studies that helped reveal some of the secrets about life

itself. Since 2003, he and his team have been studying autism, a

neurodevelopmental disorder, using the same kind of technology that

helped illuminate the genetics of cancer.

" I had been doing cancer research since I came to the lab in 1977 and

the basic method that we used in cancer was to ask what's different

about the genome of cancer compared with the normal genome?

" Many of the tools to do that were developed by me, " Wigler said, " so we

turned to those tools to ask questions about autism. "

Since the 1940s scientists have been trying to understand the

complexities of autism, a brain disorder that begins in early childhood

and can range from mild to severe. Some people with the condition may

have an absence of language skills while others go on to earn college

degrees. The disorder is marked by poor social interaction,

obsessive-compulsive behavior and avoidance of affection and love.

Many who are severely affected never develop the skills of daily living.

Gould is considered high-functioning, yet he still wandered into

his neighbor's house uninvited. Experts now use the term autism spectrum

disorders to define the many ways in which the disorder manifests.

Wigler's hunt for autism-related genes is fueled by a $13.7 million

grant from Simons, the Long Island billionaire who heads

Renaissance Technologies Corp., the East Setauket enterprise that is one

of the world's most successful hedge funds.

Simons, a former chairman of Stony Brook University's math department,

has more than a philanthropic interest in autism. His daughter, Audrey,

has Asperger's syndrome, one of several autism spectrum disorders.

With his wife, Marilyn, the couple is building a multimillion-dollar war

chest to fund investigations into the cause of autism. Their nonprofit,

The Simons Foundation, also has awarded a $10 million grant to

scientists at Yale University, who likewise are pursuing autism-related

gene research.

Based on his work to date, Wigler surmises a clear genetic understanding

of the numerous ways in which autism manifests may be tantalizingly

close: " I expect that we'll have a very good bead on a number of the

[genetic] causes, " of autism in the not-too-distant future, Wigler said.

" And I suspect there will be a way to treat children to lessen the

symptoms. "

With his Cold Spring Harbor collaborators, Sebat and Lakshmi

Muthuswamy, Wigler has found that spontaneous mutations specific to

autism occur with a relative degree of frequency in the human genome.

These random strikes are technically known as copy number variants, or

CNVs. The Cold Spring Harbor team defines these mutating hits as a major

cause of autism.

" Down syndrome is an example of a spontaneous mutation, " Wigler

explained. " The mother doesn't have Down, the father doesn't have it,

but they create a child who has an extra copy of chromosome 21.

" Almost all cases [of spontaneous mutations] happen in the mother and

are transmitted by the mother, " he said, adding that the trait for Down

is transmitted at the moment of conception. The trait is not hereditary

in the same sense a " disease gene " is transmitted from one generation to

the next.

He cites two well known disease genes: BRCA 1 and BRCA 2, either of

which can lead to breast cancer when mutated. Mutant forms of the genes

are indelibly scripted in the human genome, which means carriers will

invariably pass the gene to a new generation.

As people age, their genes increasingly acquire mutations that are not

fixed through DNA repair mechanisms. That's why a spontaneous strike can

lead to Down syndrome. And that is also why autism can similarly occur

through CNVs, Wigler said.

" The older the mother, the more likely she has acquired spontaneous

mutations in [her chromosomes], " and will transmit them at conception,

Wigler said. Less frequently, but just as likely, Wigler said, fathers

can transmit autism traits as well.

Support from the Simons Foundation has allowed the researchers to

collect genetic samples from 264 families nationwide, involving more

than 1,000 individuals. Within these families, Wigler and colleagues

were able to identify 118 families they dubbed as " simplex " where only

one member displayed symptoms of autism and 47 families that were

identified as " multiplex, " with two or more affected siblings. The rest

were controls.

By studying families, the team was able to determine whether a child's

genes were identical to the parents' or whether they contained variants.

The investigation revealed the variants were most prevalent among people

with autism.

" This is about the most exciting thing that has ever come along, " said

Portia Iversen, an Emmy-winning television art director, who established

the Cure Autism Now Foundation.

Iversen, who lives in Los Angeles, has a 15-year-old autistic son. She

and her husband, Shestack, have developed a genetic registry,

compiled from families affected by autism. The genetic information was

shared with Cold Spring Harbor scientists to aid their gene hunt.

" Every few years they bring new insight into autism, " Iversen said. " So

this is a different lens in how we look at it. Their work sheds new

light on autism. "

Dr. Pomeroy, director of the and Debra Cody Center for Autism

and Developmental Disabilities at Stony Brook University, applauded the

work at Cold Spring Harbor Laboratory. He cautioned, however, that with

a condition as complex as autism, there are no simple answers. Genetics

do not explain everything, Pomeroy said.

Autism's prevalence has increased partially because its definition has

changed over time. Children who now are considered to have autism,

Pomeroy said, 20 years ago would have been dubbed mentally retarded or

developmentally delayed.

But that does not rule out searching for genes. He thinks a dominant

gene eventually will be pinpointed to explain why autism occurs more

than once in some families. " We see families with two, even three

children with autism, " Pomeroy said.

Within families where autism occurs more than once there can be sharp

differences in how the disorder manifests. Studies of twins, he said,

have shown as much as a 50-point IQ difference.

Gould, for instance, sees striking differences in the way autism affects

his sons. And he is not entirely sold on a theory that focuses on older

parents. Gould is 61.

" In a sense I have less fear for my younger son because he doesn't talk

very well and just recently got toilet-trained, " said Gould, worrying

about the public's response to his children. " The older one you wouldn't

know that anything is wrong with him. But he will get in someone's face

and say: " How old are you? Is your mother dead?' People recoil. He's a

big kid. "

Gould gives Wigler's work mixed reviews.

" It seems to me that this smacks of putting the blame on parents. We

don't need to hear things like that. We've got enough guilt. As far as

I'm concerned, it's the rusty sperm theory of autism. "

Alison Singer, executive director of Autism Speaks, a national advocacy

organization, said the Cold Spring Harbor studies are destined to have a

strong impact on how parents understand autism.

" We want them to pursue the science wherever it leads, " Singer said.

" But we don't want to get into a situation where we blame the parents.

When some parents read stories about older fathers or older mothers,

they can become very sensitive. "

Singer said what's missing in Wigler's work is the mechanism that causes

genes to mutate. Susceptibility genes, she said, often need an outside

stimulus to set off a genetic chain of events. Perhaps parents may be

correct who think vaccination underlies autism, said Singer, whose

daughter and brother are autistic.

" In the 1960s, when my brother was diagnosed, there was the theory of

the 'refrigerator mother,' the mother who was too cold, " Singer said.

" They were essentially telling my mother that she wasn't interacting and

bonding with her child. But, of course, we found out that autism is not

the fault of bad parenting. "

Wigler thinks his work will yield practical information that aids the

lay and scientific understanding of autism. It is even possible that

knowing which genes are affected can lead to medications that block the

function of variant DNA.

" Over the last three years our work has been a pilot study, " Wigler

said. " Now we're scaling up to do it with a larger number of families.

We hope to find commonly occurring mutations that may have some value

and to determine how a child is treated, because not all autism is the same.

" Maybe each kind of mutation will require a different kind of care.

That's what we want to find out. "

THE MYSTERY OF AUTISM

Autism is just one part of a larger spectrum of socialization and

communication disorders that mostly affect children. Autism spectrum

disorders (ASD), also known as pervasive developmental disorders (PDDs),

cause severe impairment in thinking, feeling, language and the ability

to relate to others.

ASPERGER'S

SYNDROME

Named for the physician who first noticed the condition. Those affected

demonstrate good verbal skills but have severely impaired social

interactions.

AUTISM

Characterized by abnormal social interaction and communication skills

and a restricted range of interests. Onset is usually before age 3 and

those affected can exhibit delays in language development or have no

language development at all.

PDD-NOS

Short for Pervasive Developmental Disorder Not Otherwise Specified.

Characterized by autism-like symptoms, but the full features of it or

another PDD are not met. Includes children who do not fit classic autism

diagnoses.

RETT SYNDROME

Rare condition, affecting almost exclusively girls. Mental and social

development regresses - child, for example, no longer responds to her

parents and pulls away from social contact.

CHILDHOOD DISINTEGRATIVE DISORDER

Rare, mostly in boys, with onset between 3 and 4 years. It follows a

period of two years of apparently normal development. Loss of vocabulary

skills can be accompanied by a loss of bowel and bladder control,

seizures and low IQ.

HOW AUTISM COMPARES

Autism occurs much more frequently than other genetic childhood

disorders. Here are the rates of occurrence to live births.

AUTISM

1 in 150

TRANSLOCATIONAL DOWN SYNDROME

1 in 2,400

CYSTICFIBROSIS

1 in 3,200

NEUROFIBROMATOSIS

1 in 4,000

HEMOPHILIA

1 in 10,000

NOTE: Autism data include all autistic spectrum disorders.

SOURCES: NATIONAL AUTISM ASSOCIATION, NATIONAL INSTITUTE OF MENTAL

HEALTH; YALE UNIVERSITY DEVELOPMENTAL DISABILITIES CLINIC

1) " Since our sons were diagnosed we've never had a vacation. I can't

remember when either of us has gotten more than five hours of sleep.

It's exhausting. " - Gould, of Port Washington, on his autistic sons

Connor, 12, and , 16

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