michele31
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Michele
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Researchers: New understanding of autism is near
Researchers: New understanding of autism is near
BY DELTHIA RICKS
[email protected]
August 14, 2007
Attorney David 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, Bryan, 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. Bryan 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 Bryan 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 Michael 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 James Watson, 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. Bryan 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 James 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, Jonathan 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, John 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. John Pomeroy, director of the John 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."- David Gould, of Port Washington, on his autistic sons Connor, 12, and Bryan, 16
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