Autistic Kids Born Preterm or Post-Term Have More Severe Symptoms

For children with autism, being born several weeks early or several weeks late tends to increase the severity of their symptoms, according to new research out of Michigan State University.

Additionally, autistic children who were born either preterm or post-term are more likely to self-injure themselves compared with autistic children born on time, revealed the study by Tammy Movsas of MSU's Department of Epidemiology.

Though the study did not uncover why there is an increase in autistic symptoms, the reasons may be tied to some of the underlying causes of why a child is born preterm (prior to 37 weeks) or post-term (after 42 weeks) in the first place.

The research appears online in theJournal of Autism and Development Disorders.

Movsas, a postdoctoral epidemiology fellow in MSU's College of Human Medicine, said the study reveals there are many different manifestations of autism spectrum disorder, a collection of developmental disorders including both autism and Asperger syndrome. It also shows the length of the mother's pregnancy is one factor affecting the severity of the disorder.

While previous research has linked premature birth to higher rates of autism, this is one of the first studies to look at the severity of the disease among autistic children who had been born early, on time and late.

"We think about autism being caused by a combination of genetic and environmental factors," she said. "With preterm and post-term babies, there is something underlying that is altering the genetic expression of autism.

"The outside environment in which a preterm baby continues to mature is very different than the environment that the baby would have experienced in utero. This change in environment may be part of the reason why there is a difference in autistic severity in this set of infants."

Movsas added that for post-term babies, the longer exposure to hormones while a baby is in utero, the higher chance of placental malfunction and the increased rate of C-section and instrument-assisted births may play a role.

The study also found that babies born outside of normal gestational age (40 weeks) -- specifically very preterm babies -- showed an increase in stereotypical autistic mannerisms.

"Normal gestation age of birth seems to mitigate the severity of autism spectrum disorder symptoms, and the types of autistic traits tend to be different depending on age at birth," she said.

The study analyzed an online database compiled by Kennedy Krieger Institute at Johns Hopkins University of nearly 4,200 mothers -- with autistic children ages 4-21 -- between 2006 and 2010. It divided the data on births into four categories: very preterm (born prior to 34 weeks); preterm (34 to 37 weeks); standard (37 to 42 weeks); and post-term (born after 42 weeks)

The mothers filled out a pair of questionnaires regarding the symptoms of their autistic children, and the results revealed very preterm, preterm and post-term autistic children had significantly higher screening scores for autism spectrum disorder than autistic children born full term.

"The findings point to the fact that although autism has a strong genetic component, something about pregnancy or the perinatal period may affect how autism manifests," said Nigel Paneth, an MSU epidemiologist who worked with Movsas on the paper. "This adds to our earlier finding that prematurity is a major risk factor for autism spectrum disorder and may help us understand if anything can be done during early life to prevent or alleviate autism spectrum disorder."

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Mutations Linked to Autism Spectrum Disorders

Mutations in three new genes have been linked to autism, according to new studies including one with investigators at Mount Sinai School of Medicine. All three studies include lead investigators of the Autism Sequencing Consortium (ASC). The findings, in a trio of papers revealing new genetic targets in autism, are published in the April 4th online issue of the journal Nature. The studies provide new insights into important genetic changes and the many biological pathways that lead to autism spectrum disorders (ASD).

Gene mutations are glitches in DNA which can put you at risk for a particular disease. The genes with mutations identified in the studies -- CHD8, SNC2A, and KATNAL2 -- were discovered with a new state-of-the-art genomics technology known as exome sequencing, where all protein coding regions of the genome, called the exome, are analyzed. The researchers say that with further characterization of the genes and sequencing of genes in thousands of families, they will be able to develop novel therapeutics and preventive strategies for autism.

"We now have a good sense of the large number of genes involved in autism and have discovered about 10 percent of them," said Joseph Buxbaum, PhD, Director of the Seaver Autism Center and Professor of Psychiatry, Genetics and Genomic Sciences, and Neuroscience at Mount Sinai School of Medicine. "We need to study many more parents and their affected children if we are to uncover the genes important in ASD. As these genes are further characterized, this will lead to earlier diagnosis and novel drug development. This work is crucial for advancing autism treatment."

In the study, ASC researchers hypothesized that de novo mutations account for a substantial fraction of the risk for autism. De novo gene mutations are mutations that show up in affected children for the first time and result from mutations in the production of sperm or egg.

Founded by Dr. Buxbaum, the Autism Sequencing Consortium is an international group of autism genetics researchers that is working to identify additional genetic causes of autism through large-scale next-generation sequencing. The institutions involved in this study sequenced data from more than 500 families (both parents and the affected child), examining the protein-enriched areas of the genome.

"When the same mutations are found in multiple affected children and none are found in children without autism, we believe that we have identified mutations that collectively affect a higher proportion of individuals with autism," said Dr. Buxbaum. "Our studies revealed that the proteins encoded by the mutated genes interact with each other far more than expected, demonstrating significantly greater connectivity than would be expected."

Two other papers from groups participating in the Autism Sequencing Consortium are also featured in the same issue ofNature. Led by Matthew State, PhD, Yale School of Medicine, the first identified several highly disruptive mutations in genes associated with ASD. The results show that multiple variants on one gene identify risk factors for ASD. The second study led by Evan Eichler, PhD at the University of Washington discovered that certain mutations associated with ASD are mainly of paternal origin. Their findings also support previous research showing an increased risk of developing ASD in children of older fathers.

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Improvements in autism symptoms vary by child

A new study suggests that social and communication skills in some kids with autism may improve over time with therapy, but other kids will continue having problems functioning as they get older.

Not surprisingly, kids who had milder symptoms when they were first diagnosed tended to be doing better a few years later than those who started out with more severe autism.

But among close to 7,000 children followed by researchers, there was also a group of so-called "bloomers" who started out with lots of communication and social problems but made fast gains during their elementary-school years.

"There's a wide variety of children with different kinds of symptoms that fall within this (autism) umbrella," said Christine Fountain, the lead author of the study and an autism researcher at Columbia University in New York. "We were interested in how these symptoms play out over time."

The new findings, published Monday in Pediatrics, come just a few days after the Centers for Disease Control and Prevention released new data suggesting that one in 88 kids in the United States now has an autism spectrum disorder, which includes less-debilitating conditions such as Asperger's syndrome (see Reuters story of March 29, 2012).

Using data from California centers responsible for testing and treating kids with autism, Fountain and her colleagues tracked kids ages two to 14 who'd had at least four evaluations. During those approximately annual evaluations, staff recorded kids' symptoms of social and communication difficulties as well as their repetitive behaviors.

The researchers found that especially when it came to social and communication scores, most kids improved over time -- though some much faster than others.

White kids, and those whose parents were more educated, tended to have less severe autism symptoms during treatment. They were also more likely to be among the 10 percent or so of kids deemed bloomers, whose symptoms improved dramatically between ages three and 12.

Kids who had other intellectual disabilities along with autism weren't likely to have very large improvements.

"The conclusion is, if you have mental retardation as a co-occurring condition with autism, your prognosis is worse," said Johnny Matson, who studies autism spectrum disorders and intellectual disabilities at Louisiana State University in Baton Rouge.

That's not new, he said -- previous studies have shown that kids with autism and a normal IQ improve more from intensive therapy than those who have both autism and intellectual disabilities.

Unlike social and communication skills, repetitive behaviors didn't tend to improve or worsen much over time among the majority of kids in the study.

MOST KIDS WILL IMPROVE

The gaps in improvement based on parents' race and education are probably about access to good-quality treatment, according to Matson. The good news is, "those gaps are narrowing very rapidly," he told Reuters Health, because of laws requiring insurance companies to cover intensive treatment for all autistic kids.

Matson, who wasn't involved in the new study, had some doubts about the specific "symptom trajectories" the researchers used to separate kids, and said a lot of autism assessments aren't done correctly to begin with -- which makes interpreting changes over time difficult.

"I think all (kids with autism) are going to improve, it's just a matter of how much they're going to improve," Matson added. "I don't believe you can cure autism. Having said that, you can make it a lot better," especially if kids with autism continue to get therapy as they get older.

Still, another autism specialist not involved in the research said the different patterns in improvement -- or lack thereof -- jibe with his own experience.

"We deal with this problem every day, and we sense that there are different patterns or trajectories... in the kids as they develop," said Dr. Andrew Zimmerman, from the Lurie Center for Autism at Massachusetts General Hospital for Kids in Lexington.

"For some kids, you work very hard and you do a lot of therapy and nothing happens or very little, and then some kids seem to do really well," Zimmerman told Reuters Health.

Fountain said the findings suggest that providing equal access to the best autism treatment for minority and less well-off kids will be important going forward. Some states including California provide services to all kids with autism regardless of their ability to pay, she added, but others don't.

Kids' specific conditions and symptoms may play a role in their long-term improvement, but the treatment they get at certain points in development is also likely to be important, she added.

She and Matson said that parents of children with autism should be persistent in making sure their kids get the help they need, but agreed they can also be optimistic.

"There is a bit of a hopeful note in that we did find that most children get at least a little better over time," Fountain told Reuters Health.

Zimmerman agreed, adding that the idea of some kids being bloomers is especially exciting.

"There's a lot of hope here," he said.

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Study Might Explain Brain Overgrowth Seen in Autism

Researchers report that they have identified abnormalities in the DNA and RNA of cells in the prefrontal cortex of the brains of autistic children.

The findings may help to explain the underlying mechanism for the brain "overgrowth" that prior reports have documented in autistic children. Those studies have found that the brains of young children with autism are larger than the brains of non-autistic children, particularly in the prefrontal cortex. The prefrontal cortex is key to complex thoughts and behaviors, including language, social behavior and decision-making.

This growth abnormality likely contributes significantly to the social, communication, and emotional deficits common among people with autism, the researchers said.

In the new study, researchers analyzed tissue from the prefrontal cortexes of 33 postmortem brain samples from autistic and non-autistic people aged 2 to 56.

In addition to DNA differences known as copy number variations, researchers also did genome-wide RNA profiling and found differences in RNA between the autistic and non-autistic brains. RNA (ribonucleic acid) plays crucial roles within cells, serving as an intermediary between DNA, the blueprints for genetic information, and the production of proteins that carry out a vast array of vital activities in cells.

The RNA abnormalities appear to be involved with genes that code for proteins regulating cellular growth, the researchers said.

"What we found was the networks that are supposed to regulate the genesis of brain cells and develop them were abnormal. The networks that were supposed to regulate DNA repair were turned down. And the networks supposed to regulate neuron removal and survival were abnormal," said study author Eric Courchesne, director of the Autism Center of Excellence at the University of California, San Diego (UCSD) School of Medicine.

The study is published in the March 22 issue of PLoS Genetics.

How might these differences fit into the autistic picture?

Preliminary research by the UCSD team found that an excessive amount of neurons, or brain cells, might account for the overgrowth. While typically developing kids had about 0.88 billion neurons in the prefrontal cortex, autistic children had about 1.57 billion.

According to the researchers, the copy number variations along with the RNA abnormalities may disrupt the cell cycle and may explain the underlying mechanism driving the overgrowth.

"We found DNA defects, or copy number variations, in a variety of genes that regulate cell production and cell survival," Courchesne said. "To us, that suggests the explanation for why there are an abnormal number of neurons in the prefrontal cortex. Those genes fall into networks that control the number of neurons generated and the number that survive in prenatal life."

Researchers also noted that the RNA differences vary, depending on the age of the brain, with children and adults having different RNA profiles.

Courchesne said that the way the brain responds to that overgrowth of neurons -- in other words, what's happening in those repair pathways -- may help to explain why people with autism may have different trajectories, with some seeming to regress and others continuing to learn new skills throughout their lifetime.

"In adulthood, we see individuals that continue to improve, and continue to gain more and more skills and abilities," Courchesne said. "Then there are others that don't show that continued, ongoing improvement or show the opposite. My best guess is the trajectory has less to do with the original cause of the autism, than with an individual's specific composition of genes, or the available genes to remodel the brain."

Robert Ring, vice president for translational research at Autism Speaks, said researchers offer up a provocative and plausible theory. However, he noted that while brain overgrowth is well-established, only one, small study has shown that the explanation for it is too many neurons.

"What's valuable about the approach this group has taken is that they've gone directly to the tissue of interest, and have asked, 'Is there any evidence there are abnormalities in the expression of genes that correlate with the neuro-anatomic or cellular findings that have been reported?'" Ring said.

"What they're reporting is there is indeed some evidence that particular pathways might be disregulated in the autistic brain vs. the control brain, and some of these pathways, when you look at their function, may be a plausible explanation for the increased growth and increased cell number."

The study, Ring added, offers up new clues for researchers to pursue, but nothing is proven. "There is an enormous amount of work needed to confirm this," he said.

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Evidence Found for the Genetic Basis of Autism: Models of Autism Show That Gene Copy Number Controls Brain Structure and Behavior

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered that one of the most common genetic alterations in autism -- deletion of a 27-gene cluster on chromosome 16 -- causes autism-like features. By generating mouse models of autism using a technique known as chromosome engineering, CSHL Professor Alea Mills and colleagues provide the first functional evidence that inheriting fewer copies of these genes leads to features resembling those used to diagnose children with autism.

"Children normally inherit one copy of a gene from each parent. We had the tools to see whether copy number changes found in kids with autism were causing the syndrome," explains Mills. In 2007, Professor Michael Wigler, also at CSHL, revealed that some children with autism have a small deletion on chromosome 16, affecting 27 genes in a region of our genomes referred to as 16p11.2. The deletion -- which causes children to inherit only a single copy of the 27-gene cluster -- is one of the most common copy number variations (CNVs) associated with autism.

"The idea that this deletion might be causing autism was exciting," says Mills. "So we asked whether clipping out the same set of genes in mice would have any effect."

"Mice with the deletion acted completely different from normal mice," explains Guy Horev, a Postdoctoral Fellow in the Mills laboratory and first author of the study. These mice had a number of behaviors characteristic of autism: hyperactivity, difficulty adapting to a new environment, sleeping deficits, and restricted, repetitive behaviors.

Read more: http://www.sciencedaily.com/releases/2011/10/111003151819