Tuesday, July 16, 2013

Combination of brain-attacking antibodies signals autism

Researchers at the University of California Davis found that mothers who have a certain combination of brain-attacking antibodies have a 99% chance of giving birth to a child with autism.

A significant portion of autism cases can be identified with nearly perfect accuracy before symptoms appear, possibly even before conception, according to research published Tuesday.
It found that 23 percent of children with autism spectrum disordershave mothers with a certain combination of antibodies in their blood. Mothers who have this combination are 99 percent likely to have autistic children, according to researchers at the University of California Davis.
A study led by Judy Van de Water of UC Davis finds that 23 percent of those with autism spectrum disorders have mothers with a specific combination of autoantibodies that attack seven proteins involved in fetal brain development.

Experts not involved with the work said it could represent a major advance if validated. The studies don’t deal with the great majority of other cases of the disorder; in which a variety of factors appear to be involved.Two studies based on the research were published in the open access journal Translational Psychiatry. One study, led by UC Davis researcher Judy Van de Water, is here. The second, led by her UC Davis colleague Melissa Bauman, is here. Open access means the complete studies are free to readers.
San Diego-based Pediatric Bioscience is developing a test for the autism-linked antibodies, said Jan D’Alvise, chief executive of the privately held company. The test is expected to be commercially available in late 2014.
The studies found that seven proteins active in fetal brains were targeted by the maternal antibodies, said Van de Water, an immunologist at UC Davis School of Medicine, who took part in both studies. Van de Water is also the chief scientific adviser to Pediatric Bioscience. Some maternal antibodies normally cross over through the placenta, guarding the developing baby against infection.
The main study, led by Van de Water, examined the maternal antibodies’ effects on the seven fetal brain proteins and correlated them with an autism or autism spectrum diagnosis in 246 children. Maternal antibodies were also examined in a control group of 149 normally developing children.
The study found certain combinations of antibodies that were found in 23 percent of mothers of autism spectrum disorder children, but in less than 1 percent of a control group of mothers who did not have ASD children.
The second study, led by colleague Melissa Bauman, examined the autism-linked antibodies’ effects in young rhesus monkeys. It found significant disruptions in the social behavior of these monkeys; monkeys not exposed to the antibodies did not experience the disruptions.
Pediatric Bioscience is developing the antibody test for two uses, D’Alvise said.
“One is a simple blood test that will tell women their risk of having an autistic child before they conceive,” D’Alvise said.
Prospective mothers who test positive could avoid the risk by using a surrogate mother who tests negative to carry the baby, she said.
Secondly, the test can also be taken by new mothers to assess autism risk in their infants, so those at risk can be treated promptly.
“It’s very hard to diagnose these kids early, and they benefit from interventional therapy, if you catch them early,” D’Alvise said.
About 1 in 88 children are diagnosed with autism spectrum disorder, according to the U.S. Centers for Disease Control and Prevention. At the mild end, those with Asperger’s syndrome experience significant difficulties in social interaction. At the severe end, classic autism includes delay in language development, repetitive behavior and intense fascination with certain objects or patterns.
While more work is needed before a test can be approved, Van de Water said the study results were solid, and she is confident in their accuracy. Further down the road, a preventive therapy might be possible, she said. Such a therapy would block the antibodies in the pregnant mothers, allowing normal development of the baby.
Maternal immune response dysfunction
The study represents “a great advance forward to explaining a substantial sub-set of cases of ASD,” said Cheryl Dissanayake, director of the Olga Tennison Autism Research Centre at La Trobe University, near Melbourne, Australia.
Dissanayake said by email that she had been aware of the research, and considers the rhesus monkey study to give more validity to Van de Water’s work.
“My own interest in dysregulated growth (both physical and brain growth) in a subset of cases is also modeled in the rhesus monkeys,” Dissanayake said. “These really are significant findings, although as always, more research is needed. I couldn’t recommend this work strongly enough.”
Eric Courchesne, a UCSD researcher studying the neurobiology of autism, was cautious in evaluating the results. He said the study covers an important area of research, identifying molecular markers in those with autism.
"The study suggests an important future study: Do mothers who already have an ASD child and these markers, have an increased risk of having another child with ASD?" Courchesne asked.
Elizabeth A. Thomas, a neuroscientist at The Scripps Research Institute, said the study results could be useful in assessing autism risk.
“These findings could have enormous potential to serve as a biomarker for disease risk in children, however, whether such a diagnostic test would have predictive value in assessing a woman’s risk of having a child with autism prior to conception, is less clear,” Thomas said. “This is because the samples were obtained from mothers of children at the time of the child’s diagnosis, not before pregnancy.”
The results make sense in light of what is already known about autism, Thomas said.
“Although autism spectrum disorders are highly heterogeneous, there is substantial evidence for maternal immune dysregulation during pregnancy and increased risk for autism, as well as other neuropsychiatric disorders, in offspring,” Thomas said. “However, exactly how maternal immune dysregulation is related to altered brain development and subsequent behavioral abnormalities is not clear.”
Identifying the seven target proteins represents “a critical advancement in the field,” Thomas said. “Because autism is known to have a strong genetic contribution, it would be important to see if any of these target proteins converge with the autism-associated genetic data that has been published in recent years.”
“Because several of the target proteins identified in this study are known to play important roles in neurodevelopment, it would be of interest to see if any of these maternal autoantibodies are associated with increased risk for other neuropsychiatric or neurodevelopmental disorders."
Monkey parallel
The studies builds on previous research by Van De Water and colleagues that found women with certain antibodies were at greater risk of having a child with autism than woman without the antibodies.
The study led by UC Davis researcher Bauman found a parallel in rhesus monkeys exposed to the autism-linked antibodies. These well-studied monkeys have their own complex social system, and the researchers looked for signs of disruption.
That study included three groups, one exposed to the maternal autism-linked antibodies, a second exposed to antibodies from human mothers whose children did not have autism, and a third group that did not receive any antibodies. Thus, the study had three groups, one test and two control.
Monkey offspring exposed to the autism-linked antibodies showed abnormal social behavior not displayed by the control offspring, the study said. This behavior included approaching unfamiliar monkeys, unusual for young rhesus monkeys.
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