Taking Antidepressants During Autism Greatly Increases Risk of Autism

Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Bérard of the University of Montreal and its affiliated CHU Sainte-Justine children's hospital revealed today. Prof. Bérard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies. "The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role," she explained. "Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs." Her findings were published today in JAMA Pediatrics.

Bérard and her colleagues worked with data from the Quebec Pregnancy Cohort and studied 145,456 children between the time of their conception up to age ten. In addition to information about the mother's use of antidepressants and the child's eventual diagnosis of autism, the data included a wealth of details that enabled the team to tease out the specific impact of the antidepressant drugs. For example, some people are genetically predisposed to autism (i.e., a family history of it.) Maternal age, and depression are known to be associated with the development of autism, as are certain socio-economic factors such as being exposed to poverty, and the team was able to take all of these into consideration. "We defined exposure to antidepressants as the mother having had one or more prescription for antidepressants filled during the second or third trimester of the pregnancy. This period was chosen as the infant's critical brain development occurs during this time," Prof. Bérard said. "Amongst all the children in the study, we then identified which children had been diagnosed with a form of autism by looking at hospital records indicating diagnosed childhood autism, atypical autism, Asperger's syndrome, or a pervasive developmental disorder. Finally, we looked for a statistical association between the two groups, and found a very significant one: an 87% increased risk." The results remained unchanged when only considering children who had been diagnosed by specialists such as psychiatrists and neurologists.

The findings are hugely important as six to ten percent of pregnant women are currently being treated for depression with antidepressants. In the current study, 1,054 children were diagnosed with autism (0.72% of the children in the study), on average at 4.5 years of age. Moreover, the prevalence of autism amongst children has increased from 4 in 10,000 children in 1966 to 100 in 10,000 today. While that increase can be attributed to both better detection and widening criteria for diagnosis, researchers believe that environmental factors are also playing a part. "It is biologically plausible that anti-depressants are causing autism if used at the time of brain development in the womb, as serotonin is involved in numerous pre- and postnatal developmental processes, including cell division, the migration of neuros, cell differentiation and synaptogenesis - the creation of links between brain cells," Prof. Bérard explained. "Some classes of anti-depressants work by inhibiting serotonin (SSRIs and some other antidepressant classes), which will have a negative impact on the ability of the brain to fully develop and adapt in-utero"

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That Wasn't Autism.

The headlines read “New study suggests autism can be outgrown”, or “outgrowing autism: a doctor’s surprise and wonder.” The stories are based on studies reporting that 7-9% of children with a documented early autistic syndrome disorder (ASD) have no symptoms of the disorder on follow-up later in childhood or adolescence. That is good news. The question is how to account for it.

Is it possible to simply “outgrow” autism? Was the initial diagnosis wrong? Did some interventions work? Or might there be other explanations for this welcome news?

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Hyperactivitation of UBE3A Gene Causes Autism

Last December, researchers identified more than 1,000 gene mutations in individuals with autism, but how these mutations increased risk for autism was unclear. Now, UNC School of Medicine researchers are the first to show how one of these mutations disables a molecular switch in one of these genes and causes autism.

Published today in the journal Cell, the research shows that an enzyme called UBE3A can be switched off when a phosphate molecule is tacked onto UBE3A. In neurons and during normal brain development, this switch can be turned off and on, leading to tight regulation of UBE3A. But a research team led by Mark Zylka, PhD, associate professor of cell biology and physiology, found that an autism-linked mutation destroys this regulatory switch. Destruction of the switch creates an enzyme that cannot be turned off. As a result, UBE3A becomes hyperactive and drives abnormal brain development and autism.

"Genetic studies are showing that there will be about 1,000 genes linked to autism. This means you could mutate any one of them and get the disorder. We found how one of these mutations works," said Zylka, senior author of the Cell paper and member of the UNC Neuroscience Center.

The work was done in human cell lines, as well as mouse models.

Because this one autism-linked UBE3A mutation was part of the Simons Simplex Collection - and Zylka previously had been funded through a Simons Foundation grant - he had access to the cells that were used to find this one mutation. When Jason Yi, PhD, a postdoctoral fellow in Zylka's lab, sequenced the genes from the cell samples - including cells from the child's parents - he found that the parents had no hyperactive UBE3A but the child did.

The child's regulatory switch was broken, causing UBE3A to be perpetually switched on.

"When this child's mutation was introduced into an animal model, we saw all these dendritic spines form on the neurons," said, Zylka, who is also a member of the Carolina Institute for Developmental Disabilities. "We thought this was a big deal because too many dendritic spines have been linked to autism."

Their findings thus pointed to hyperactivation of UBE3A as the likely cause of this child's autism.

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It is probably not the SOLE cause though.

Study of 5.7 Million Children Born Between 1985 to 2004 Confirms Parental Age and Autism Risk Link

The largest-ever multinational study of parental age and autism risk, funded by Autism Speaks, found increased autism rates among the children of teen moms and among children whose parents have relatively large gaps between their ages. The study also confirmed that older parents are at higher risk of having children with autism. The analysis included more than 5.7 million children in five countries.

[...]

Though we've seen research on autism and parental age before, this study is like no other," says co-author Michael Rosanoff, Autism Speaks' director of public health research. "By linking national health registries across five countries, we created the world's largest data set for research into autism's risk factors. The size allowed us to look at the relationship between parents' age and autism at a much higher resolution - under a microscope, if you will."

[...]

The study looked at autism rates among 5,766,794 children -- including more than 30,000 with autism -- in Denmark, Israel, Norway, Sweden and Western Australia. The children were born between 1985 and 2004, and the researchers followed up on their development until 2009, checking national health records for autism diagnoses.

Researchers identified and controlled for other age-related influences that might affect autism risk. When separating the influence of mother's versus father's age, they also adjusted for the potential influence of the other parent's age.

"After finding that paternal age, maternal age and parental-age gaps all influence autism risk independently, we calculated which aspect was most important," Dr. Sandin adds. "It turned out to be parental age, though age gaps also contribute significantly."

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Autism and a Ted Talk

Genes Associated With Autism Connected to Fetal Brain Development

Scientists at the University of California, San Diego School of Medicine have found that mutations that cause autism in children are connected to a pathway that regulates brain development. The research, led by Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry, is published in the February 18 issue of Neuron.

The researchers studied a set of well-known autism mutations called copy number variants or CNVs. They investigated when and where the genes were expressed during brain development. "One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods," said Iakoucheva.

Specifically, the scientists noted that one CNV located in a region of the genome known as 16p11.2, contained genes active during the late mid-fetal period. Ultimately, they identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is also mutated in children with autism.

[...]

Further experiments confirmed that CUL3 mutations disrupt interaction with KCTD13, suggesting that 16p11.2 CNV and CUL3 may act via the same RhoA pathway. RhoA levels influence head and body size in zebrafish, a model organism used by geneticists to investigate gene functions. Children with 16p11.2 CNV also have enlarged or decreased head sizes and suffer from obesity or are underweight. "Our model fits perfectly with what we observe in the patients," said Guan Ning Lin, PhD, a fellow in Iakoucheva's laboratory and co-first author with Roser Corominas, PhD.

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Autism-associated Mutation Shown to Have Strong, Negative Effects on Synapses

Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses

Authors:

Bemben et al

Abstract:

Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.

Canadians Unleash Robopocalypse on our Genomes...Starting With Studying Autism

In the decade since the genome was sequenced in 2003, scientists and doctors have struggled to answer an all-consuming question: Which DNA mutations cause disease?

A new computational technique developed at the University of Toronto may now be able to tell us.

A Canadian research team led by professor Brendan Frey has developed the first method for 'ranking' genetic mutations based on how living cells 'read' DNA, revealing how likely any given alteration is to cause disease. They used their method to discover unexpected genetic determinants of autism, hereditary cancers and spinal muscular atrophy, a leading genetic cause of infant mortality.

Their findings appear in today's issue of the leading journal Science.

Think of the human genome as a mysterious text, made up of three billion letters. "Over the past decade, a huge amount of effort has been invested into searching for mutations in the genome that cause disease, without a rational approach to understanding why they cause disease," says Frey, also a senior fellow at the Canadian Institute for Advanced Research. "This is because scientists didn't have the means to understand the text of the genome and how mutations in it can change the meaning of that text." Biologist Eric Lander of the Massachusetts Institute of Technology captured this puzzle in his famous quote: "Genome. Bought the book. Hard to read."

What was Frey's approach? We know that certain sections of the text, called exons, describe the proteins that are the building blocks of all living cells. What wasn't appreciated until recently is that other sections, called introns, contain instructions for how to cut and paste exons together, determining which proteins will be produced. This 'splicing' process is a crucial step in the cell's process of converting DNA into proteins, and its disruption is known to contribute to many diseases.

Most research into the genetic roots of disease has focused on mutations within exons, but increasingly scientists are finding that diseases can't be explained by these mutations. Frey's team took a completely different approach, examining changes to text that provides instructions for splicing, most of which is in introns.

Frey's team used a new technology called 'deep learning' to teach a computer system to scan a piece of DNA, read the genetic instructions that specify how to splice together sections that code for proteins, and determine which proteins will be produced.

Unlike other machine learning methods, deep learning can make sense of incredibly complex relationships, such as those found in living systems in biology and medicine. "The success of our project relied crucially on using the latest deep learning methods to analyze the most advanced experimental biology data," says Frey, whose team included members from University of Toronto's Faculty of Applied Science & Engineering, Faculty of Medicine and the Terrence Donnelly Centre for Cellular and Biomolecular Research, as well as Microsoft Research and the Cold Spring Harbor Laboratory. "My collaborators and our graduate students and postdoctoral fellows are world-leading experts in these areas."

Once they had taught their system how to read the text of the genome, Frey's team used it to search for mutations that cause splicing to go wrong. They found that their method correctly predicted 94 percent of the genetic culprits behind well-studied diseases such as spinal muscular atrophy and colorectal cancer, but more importantly, made accurate predictions for mutations that had never been seen before.

They then launched a huge effort to tackle a condition with complex genetic underpinnings: autism spectrum disorder. "With autism there are only a few dozen genes definitely known to be involved and these account for a small proportion of individuals with this condition," says Frey.

In collaboration with Dr. Stephen Scherer, senior scientist and director of The Centre for Applied Genomics at SickKids and the University of Toronto McLaughlin Centre, Frey's team compared mutations discovered in the whole genome sequences of children with autism, but not in controls. Following the traditional approach of studying protein-coding regions, they found no differences. However, when they used their deep learning system to rank mutations according to how much they change splicing, surprising patterns appeared.

"When we ranked mutations using our method, striking patterns emerged, revealing 39 novel genes having a potential role in autism susceptibility," Frey says.

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Mothers who do NOT Take Iron Supplements are 5x at Risk for Having Autistic Child, Older Mothers More

Mothers of children with autism are significantly less likely to report taking iron supplements before and during their pregnancies than the mothers of children who are developing normally, a study by researchers with the UC Davis MIND Institute has found.

Low iron intake was associated with a five-fold greater risk of autism in the child if the mother was 35 or older at the time of the child's birth or if she suffered from metabolic conditions such as obesity hypertension or diabetes.

The research is the first to examine the relationship between maternal iron intake and having a child with autism spectrum disorder, the authors said. The study, "Maternal intake of supplemental iron and risk for autism spectrum disorders," is published online today in the American Journal of Epidemiology.

"The association between lower maternal iron intake and increased ASD risk was strongest during breastfeeding, after adjustment for folic acid intake," said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences and a researcher affiliated with the MIND Institute.

The authors of the current study in 2011 were the first to report associations between supplemental folic acid and reduced risk for autism spectrum disorder, a finding later replicated in larger scale investigations.

"Further, the risk associated with low maternal iron intake was much greater when the mother was also older and had metabolic conditions during her pregnancy."

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*cough*older mothers*cough*

Autism: What we Know...and Don't

Autism is Tied to Parental Age, Especially Maternal Age

Older parents are more likely to have a child who develops an autism spectrum disorder (ASD) than are younger parents. A recent study from researchers from the Drexel University School of Public Health in Philadelphia and Karolinska Institute in Sweden provides more insight into how the risk associated with parental age varies between mothers' and fathers' ages, and found that the risk of having a child with both ASD and intellectual disability is larger for older parents.

In the study, published in the February 2014 issue of the International Journal of Epidemiology, researchers report that fathers' and mothers advancing ages have different impacts on their child's risk. The rise in ASD risk with parental age was greater for older mothers as compared to older fathers.

"The open question at hand really is, what biological mechanisms underlie these age effects?" said Brian K. Lee, PhD, an assistant professor in the Drexel University School of Public Health and research fellow of the A.J. Drexel Autism Institute, and senior author of the study. The observed differences in risk based on mothers' and fathers' ages point to a need to continue investigating underlying mechanisms of ASD that may be influenced by a mother's age, Lee said, even though much recent discussion has focused on fathers' and even grandfathers' ages.

The risk of having a child with ASD had a more complicated relationship to age in women than in men – whose risk of fathering a child with ASD increased linearly with age across their lifespan. Among women giving birth before the age of 30, the risk of ASD in the child showed no association with age -- it was simply very low. But for babies born to mothers aged 30 and older, the chance of developing ASD rose rapidly with the mother's age.

Lee noted that the non-linear maternal age effect that is relatively stronger than the paternal age effect on ASD risk has been observed in previous studies, but has not received much attention.

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Autism is Inherited From Mom

When it comes to developmental disorders of the brain, men and women are not created equal.

Decades of research have shown that males are at far greater risk for neurodevelopmental disorders such as autism spectrum disorder (ASD) than females. Boys, on average, are five times more likely to have autism than girls . What causes this disparity has largely remained unknown.

Now scientists have uncovered compelling genetic evidence to explain why the biological scales aren’t balanced.

According to a team of geneticists in the U.S. and Switzerland, it all boils down to what’s called the “female protective model.” This suggests that girls have a higher tolerance for harmful genetic mutations and therefore require a larger number of them than boys to reach the diagnostic threshold of a developmental disorder. With identical genetic mutations, then, a boy could show symptoms of ASD while a girl could show none.

But because the female mutation threshold is higher, when girls are diagnosed with ASD, they tend to fall on the more severe end of the spectrum.

Researchers believe the same dynamic could explain why more boys are diagnosed with ADHD, intellectual disabilities and schizophrenia. The findings were published Thursday in the American Journal of Human Genetics.

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Autism Detected, Correcly Diagnosed at 2 Months of Age

Children with autism make less eye contact than others of the same age, an indicator that is used to diagnose the developmental disorder after the age of two years. But a paper published today in Nature reports that infants as young as two months can display signs of this condition, the earliest detection of autism symptoms yet.

If the small study can be replicated in a larger population, it might provide a way of diagnosing autism in infants so that therapies can begin early, says Warren Jones, research director at the Marcus Autism Center in Atlanta, Georgia.

Jones and colleague Ami Klin studied 110 infants from birth — 59 of whom had an increased risk of being diagnosed with autism because they had a sibling with the disorder, and 51 of whom were at lower risk. One in every 88 children has an autism spectrum disorder (ASD), according to the most recent survey by the US Centers for Disease Control and Prevention in Atlanta.

At ten regular intervals over the course of two years, the researchers in the new study showed infants video images of their careers and used eye-tracking equipment and software to track where the babies gazed.

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Autism Strongly Correlated to Genes Related to Linguistic Impairment, OCD, etc

Lorenzo Miodus-Santini an 11-year-old sixth-grader from Princeton, who was classified as autistic at only 13 months old, was never a big talker. As an infant he didn't babble or coo. When he was a toddler beginning to speak, he would learn one word but forget another.

His older brother, Christian, a 15-year-old high school sophomore, shared some similar characteristics – difficulty with reading, processing words and speaking clearly. Doctors said he had language impairments but was not autistic.

New research published online today in the American Journal of Psychiatry, by scientists at Rutgers University and The Research Institute at Nationwide Children's Hospital in Ohio, reveals that there is a genetic link connecting family members with autism like Lorenzo Miodus-Santini to those like his brother, Christian, who have specific language impairment characterized by speech and language difficulties that can't be explained by cognitive or physical problems.

The research project leader Linda Brzustowicz, Rutgers professor and chair of the Department of Genetics, in the School of Arts and Sciences, says that genes in a narrow region of two chromosomes (15q23-26 and 16p12) responsible for oral and written language impairments can result in similar behavioral characteristics with one family member developing autism and the other having only language difficulties.

Specific language impairment is one of the most common learning disabilities, affecting an estimated 7 percent of children. It is not considered to be an autism spectrum disorder. Autism effects one in 88 children nationally – with nearly five times as many boys than girls diagnosed – about half of whom have some degree of language impairment.

"In this group of families we are trying to find genetic factors that might connect them," says Brzustowicz, who collaborated on the study with Christopher W. Bartell, principal investigator in the Battelle Center for Mathematical Medicine at Nationwide Children's Hospital. "This research is important because it is hard to understand autism until we find the genes that might be involved."

While scientists don't believe that there is one single gene that causes autism but rather a number of genes that increase the risk, Brzustowicz and her team of researchers are working to identify genetic patterns in these families in order to help gain a better understanding of the mechanisms that lead to autism, a developmental brain disorder that appears in the first three years of life.

In the Rutgers autism study, 79 families – mostly from New Jersey and Pennsylvania – with one child with autism and at least one with specific language impairment underwent extensive in-home testing. Besides taking blood samples for genetic testing, family members including parents, children, and grandparents and in some cases even uncles, aunts and cousins underwent a battery of tests to assess grammar, vocabulary and language processing.

"Our results indicate that there are shared patterns of DNA and visible behavioral characteristics across our group of study families," says Judy Flax, an associate research professor working on the study with Brzustowicz.

In addition to the language findings, researchers also found strong evidence of a genetic link in the areas of obsessive-compulsive, repetitive behaviors and social interaction skills, other symptoms associated with autism.

Brzustowicz says the next step will be to sequence the whole genome of those who participated in the study in order to compare the families to see if scientists can pinpoint any specific genes or mutations that are common to all.

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I think they ought to include parental ages of the children.  It would be MORE than illuminating.

First Genetic Test for Austism

A team of Australian researchers, led by University of Melbourne has developed a genetic test that is able to predict the risk of developing Autism Spectrum Disorder, ASD.

Lead researcher Professor Stan Skafidas, Director of the Centre for Neural Engineering at the University of Melbourne said the test could be used to assess the risk for developing the disorder.

"This test could assist in the early detection of the condition in babies and children and help in the early management of those who become diagnosed," he said.

"It would be particularly relevant for families who have a history of Autism or related conditions such as Asperger's Syndrome," he said.

Autism affects around one in 150 births and is characterized by abnormal social interaction, impaired communication and repetitive behaviours.

The test correctly predicted ASD with more than 70 per cent accuracy in people of central European descent. Ongoing validation tests are continuing including the development of accurate testing for other ethnic groups.

Clinical neuropsychologist, Dr Renee Testa from the University of Melbourne and Monash University, said the test would allow clinicians to provide early interventions that may reduce behavioural and cognitive difficulties that children and adults with ASD experience.

"Early identification of risk means we can provide interventions to improve overall functioning for those affected, including families," she said.

A genetic cause has been long sought with many genes implicated in the condition, but no single gene has been adequate for determining risk.

Using US data from 3,346 individuals with ASD and 4,165 of their relatives from Autism Genetic Resource Exchange (AGRE) and Simons Foundation Autism Research Initiative (SFARI), the researchers identified 237 genetic markers (SNPs) in 146 genes and related cellular pathways that either contribute to or protect an individual from developing ASD.

Senior author Professor Christos Pantelis of the Melbourne Neuropsychiatry Centre at the University of Melbourne and Melbourne Health said the discovery of the combination of contributing and protective gene markers and their interaction had helped to develop a very promising predictive ASD test.

The test is based on measuring both genetic markers of risk and protection for ASD. The risk markers increase the score on the genetic test, while the protective markers decrease the score. The higher the overall score, the higher the individual risk.

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70% is pretty good but needs improvement.  The fact that they have a genetic test with that much accuracy is a big hint on what the real causes are rather than people's wishful thinking.

Autism: An X Chromosome Linked Trait?

New research from the Centre for Addiction and Mental Health (CAMH) and The Hospital for Sick Children (SickKids), both in Toronto, Canada provides further clues as to why Autism Spectrum Disorder (ASD) affects four times more males than females. The scientists discovered that males who carry specific alterations of DNA on the sole X-chromosome they carry are at high risk of developing ASD. The research is published in the September 15 issue of Science Translational Medicine.

ASD is a neurological disorder that affects brain functioning, resulting in challenges with communication and social interaction, unusual patterns of behaviour, and often, intellectual deficits. ASD affects one in every 120 children and a startling one in 70 boys. Though all of the causes of ASD are not yet known, research has increasingly pointed towards genetic factors,. In recent years, several genes involved in ASD have successfully been identified.

The research team was led by Dr. John B. Vincent, Senior Scientist and head of CAMH's Molecular Neuropsychiatry and Development Laboratory and Dr. Stephen Scherer, Senior Scientist and Director of The Centre for Applied Genomics at SickKids, and Director of the McLaughlin Centre at the University of Toronto. The scientists analyzed the gene sequences of 2,000 individuals with ASD, along with others with an intellectual disability, and compared the results to thousands of population controls. They found that about one per cent of boys with ASD had mutations in the PTCHD1 gene on the X-chromosome. Similar mutations were not found in thousands of male controls. Also, sisters carrying the same mutation are seemingly unaffected.

"We believe that the PTCHD1 gene has a role in a neurobiological pathway that delivers information to cells during brain development – this specific mutation may disrupt crucial developmental processes, contributing to the onset of autism." said Dr. Vincent. "Our discovery will facilitate early detection, which will, in turn, increase the likelihood of successful interventions."

"The male gender bias in autism has intrigued us for years and now we have an indicator that starts to explain why this may be," says Dr. Scherer. "Boys are boys because they inherit one X-chromosome from their mother and one Y-chromosome from their father. If a boy's X-chromosome is missing the PTCHD1 gene or other nearby DNA sequences, they will be at high risk of developing ASD or intellectual disability. Girls are different in that, even if they are missing one PTCHD1 gene, by nature they always carry a second X-chromosome, shielding them from ASD." Scherer adds, "While these women are protected, autism could appear in future generations of boys in their families."

There was a relatively recent study that found that autism was more common in affluent caucasian families with older parents. It went rather contrary to the environmental causes hypothesis. If I have time (HA!) I'll find and put a link to that one.

It makes me wonder if this can be directly linked to postponing having kids: we already know of increased rates of other issues such as down's and whatnot. Perhaps the damage is being caused by meiosis potentially going slightly off tracks in (some) older women. As more women postpone their fertility, the number of autistic children rises and will continue to do for generations afterwards because their daughters might be carriers of the damaged regions on their inherited X chromosomes.

I can't imagine that this will be a popular study result or my hypothesis either.