The Link between Common and Rare Forms of Autism

synapseAccording to recent research, rare forms of autism share a molecular signature with more common versions of the disorder. This finding is particularly intriguing to medical researchers, as it leads them to believe that autism is linked to a single genetic defect, also found in more complex forms of the disorder.

Researchers at the 2014 Society for Neuroscience annual meeting stated that a rare form of autism is linked to a duplication of the 15q11-13 chromosomal region, which is also duplicated in more common forms of autism.  Approximately 1 in 12,000 children carry the duplication, with about 41 percent of these individuals having autism.

Daniel Geschwind, lead researcher, analyzed patterns of gene expression in postmortem brains for 16 adults with idiopathic autism, meaning there was an unknown cause, along with the brains of 8 with autism and 15q11-14 duplications. According to their findings, the brains of those with idiopathic autism express lower levels of genes that play a role at neuronal junctions, or synapses, compared with controls. They were intrigued to find that the brains of those with the duplications showed the same trend, only to a more severe extent.

Geschwind, a professor of neurology, psychiatry, and human genetics at the University of California, Los Angeles, states, “It’s kind of remarkable. This is showing that a single gene disorder has the same pattern [as idiopathic forms of autism].”

Last month, two large studies that sequenced exomes, the parts of a genome that encode proteins, discovered that 50 “high-confidence” autism candidate genes are involved in two critical processes, neuronal connectivity and the control of gene expression. Geschwind states, “The proof is the replication. Although autism is very heterogeneous, we can capitalize on these findings to identify common molecular pathways.”

Geschwind and his team believe that autism, in all its forms, may develop from inherited genetic defects, causing dysfunctional synapses. In an attempt to correct the dysfunction, the brain sets off an inflammatory response, resulting in fewer active synapses, creating an imbalance between excitatory and inhibitory signaling, common to all those on the autism spectrum.

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Broccoli Improves Autistic Social and Verbal Behaviors

broccoli sproutSeveral weeks ago, a study was released that emphasized how the intake of certain vegetables can actually improve several symptoms of autism. Now, scientists are stating that a specific extract from broccoli sprouts may be used to curb these symptoms. This new study is a first step towards potentially providing effective treatment for those on the spectrum.

Johns Hopkins Hospital, in conjunction with Harvard, conducted a study over the course of 18 weeks, treating 40 autistic males. Twenty-six of these males took pills with sulforaphane, an extract from broccoli sprouts, with the remainder receiving a placebo. Dr. Paul Talalay, professor of pharmacology and molecular sciences at Johns Hopkins, study author, found that patients who took sulforaphane improved significantly. Almost half of the patients treated with the extract had “much improved” social interaction and verbal communication. Furthermore, more than half exhibited less erratic behaviors.

Upon completion of the series of taking the extract, the researchers found that the participants returned to their baseline levels for their symptoms within four weeks, signaling a need to continue with the extract to achieve the optimal benefits. Dr. Talalay states that although further research needs to be done to study how sulforaphane reacts in the body, their previous research suggests that the extract can cause the body to react as it would to a fever. Fevers are typically associated with temporary improvements in over a third of individuals with autism, so the researchers believe sulforaphane may work similarly.

Dr. Susan Hyman, chief of neurodevelopmental and behavioral pediatrics at the University of Rochester Medical Center, states, “The trial needs to be replicated and evaluated in larger and more age-diverse samples, but the data is certainly worth pursuing”. With the lack of effective treatments for individuals on the spectrum, the results of this study provide hopeful news. Sulforaphane is associated with very few side effects and is considered highly safe due to its natural origins. However, families should not administer sulforaphane to an individual on the spectrum without medical guidance.

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New App Aims to Create Individualized Treatment Plans for Children with ASD

children with tabletMore than ever, parents and educators of children with autism have been utilizing technology to help these children develop various skills. Now, researchers are finding that apps and touch-screen games can possibly allow scientists to tailor treatments for children on the spectrum.

A new game designed for tablets has been designed to evaluate implicit learning, which takes place without the learner being aware or being explicitly taught. Many of the skills that autistic children struggle with, such as language and social abilities, are learned implicitly. Implicit learning is becoming increasingly essential in understanding autism disorders, as well as critical in helping children develop important skills more effectively.

Rebecca Jones, postdoctoral researcher at Weill Cornell Medical College in New York, who presented the results of the study, states, “This is the age at which many children with autism are receiving behavioral intervention.” Studying this particular age group is essential, as behavioral interventions often involve implicit learning. In Jones’ initial study, 19 children between the ages of 3 to 7 were given a tablet to play a game based on popular cartoons. The primary object of the game was to tap the screen when they saw a specific character, in this case, SpongeBob Square Pants.

Approximately 75 percent of the time, a specific character, a squid, appeared on the screen right before SpongeBob’s appearance, while the remaining 25 percent featured a snail character prior to SpongeBob’s arrival. The researchers deemed these characters as clues to the children’s implicit learning abilities. They analyzed how fast the children were able to touch the screen when SpongeBob appeared.

As the game progressed, they found that the children subconsciously picked up on the fact that the squid character foreshadowed SpongeBob’s appearance. The researchers noticed that after a while, the children were slower to acknowledge SpongeBob when he appeared after the snail. Although they are not clear as to why this happened, Jones states, “the important thing is the difference between the low-probability and high-probability clues”.

The study suggests that moving from an implicit to explicit awareness may be critical in developing various methods of learning. This progression is particularly important for children on the spectrum, who often learn by more explicit methods, such as learning how to interact socially by being told repetitively, in detail, how to get along with others. Or rather, this study may be a signal for interventions to move children from explicit learning to more implicit, intuitive methods.

Researchers are still introducing the game to larger numbers of children with autism spectrum disorders, aiming to pinpoint the deficits in explicit learning, and where implicit learning can fill the void. Furthermore, they are seeing if the game can predict the effectiveness of three-month behavioral interventions for children on the spectrum. This approach can lead to “learning profiles” for the child, giving them therapies that will be most effective in their development.

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The Relationship Between Autism and the Cerebellum

Researchers recently presented the defects in a section of the cerebellum that is correlated to language problems in individuals with autism, highlighting the importance of examining this region of the brain to help understand the disorder.

Individuals with autism often have trouble responding to something they see, which is a process controlled by the cerebellum. The cerebellum receives inputs from sensory brain regions such as the visual cortex, sending out signals to the motor complex. Until recently, researchers did not focus on the cerebellum when trying to analyze the complexities of autism, however they are beginning to emphasize its importance.

Matt Mosconi, assistant professor of psychiatry at the University of Texas Southwestern in Dallas, went into detail about how individuals with autism have difficulty taking visual information and following through with an action, therefore resulting in the feeling of being anxious or overwhelmed. Mosconi and his team of researchers tested the ability of individuals translating visuals into actions by having participants to match and maintain the position of two lines on a screen by squeezing a sensor in their hand.

Researchers modulated the system so that the same amount of pressure can move the line by a lot or a little. Mosconi and his colleagues scanned the brains of 20 participants with autism and 23 controls, finding that different brain pathways are involved when the test is at its most or least sensitive. Overall, they discovered that individuals on the autism spectrum struggled to hold the bar still.

People with autism have weak responses in circuits connecting into and out of the cerebellum when the bar was only moving in subtle ways. When the sensor was highly sensitive, the participants showed hyperexcitiability in the sensory regions outside of the cerebellum. Mosconi states, “In a sense, they’re just more sensitive to any changes in the visual feedback in any direction”.

A separate team of researchers used brain scans to link defects in different regions of the cerebellum to language delay in autism. The team looked at 35 people with autism, 13 of whom have language delays, and 35 controls. The participants with autism have less gray matter, particularly in one subregion of the cerebellum called the right crus1. Participants who have both autism and language delays showed a decrease in gray matter in the left crus1.

Most individuals with autism process language on the right side of their cortex, which interacts with the left side of the cerebellum. Catherine Stoodley, lead researcher and assistant professor of psychiatry at the American University states, “Within the cerebellum, you see different [circuit] loops depending on where you are.” She continues, “I think we’re getting more sophisticated in our take on the cerebellum and autism.”

In the future, researchers aim to use brain scans to analyze further links between the cerebellum and other parts of the brain. Studies are also trying to pin down the specific subregions of the cerebellum to understand their various functions.

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Treating GI Troubles May Improve Symptoms of Autism

probioticsAccording to several research studies, autism disorders are affected by activity in the gut. Stress and anxiety can create stomach pains, cramps, and spasms, and furthermore, create further issues within the brain. Although autism is an incredibly complex disorder, scientists have found promising clues within the digestive system. Research discovered that there is a significant difference in the bacteria found in the intestines of children with autism in comparison with that of their neurotypical peers.

Researchers at the California Institute of Technology have reported that not only is the gut bacteria in autistic individuals different, but it may actually contribute to the disorder and create some of the well-known symptoms. Although autism is primarily treated through behavioral therapies, new studies suggest that treatment can come in the form of live, “friendly” bacteria, such as probiotics. Paul Patterson, professor of biology at Caltech, states, “If you block the gastrointestinal problem, you can treat the behavioral symptoms”.

One of the primary health issues of children on the autism spectrum is gastrointestinal problems. Previous studies have estimated that upwards of 90 percent of autistic children suffer from a range of gastrointestinal troubles. Furthermore, according to the CDC, they are over 3.5 times more likely to experience chronic pain such as constipation in comparison to their neurotypical peers.

In order to examine why children on the spectrum may suffer from these troubles, researchers at Arizona State University analyzed the gut bacteria in a sample group of autistic children, as well as a control group. They found that the autistic children had many fewer types of bacteria, making the gut more vulnerable to attacks from disease-causing pathogens. Elaine Hsiao, postdoctoral researcher at Caltech, began to study how the gut microbiome may be responsible for autistic behaviors.

To test this, Hsiao and her team of researchers injected a mock virus into pregnant mice. These female mice went on to give birth to offspring with autistic symptoms, such as obsessive grooming, anxiety, and a sense of unawareness. These mice developed a “leaky gut”, in which gut bacteria trickled into the bloodstream and into the brain. As a result, the bacteria leak may have had a significant influence on behavior. Hsiao found that the blood of autistic mice contained 46 times more EPS, a molecule produced by gut bacteria, than in their control group. To treat this, Hsiao gave the affected mice B. fragilis, a probiotic to treat GI symptoms, in their food. Within five weeks, the levels of 4EPS in their blood had plummeted, and the gut microbiome began to resemble that of a healthy mouse. Their behavior also improved dramatically, as they were noted to be less anxious and more aware of their surroundings.

This study provides a great lead to further examine how probiotics may help autistic children with severe GI problems. A clinical trial will reveal if these positive results can apply to humans. Hsiao states, “It’s really impactful, this notion that by changing the bacteria, you could ameliorate what’s often considered an intractable disorder. It’s a really crazy notion and a big advance”.

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Certain Behaviors May Predict Autism in High-Risk Children

childrenYoung children with an autistic sibling are often at high-risk to develop the disorder as well. Recently, researchers have studied three distinct behavior profiles in toddlers with autistic siblings to predict an autism diagnosis at age 3.

Researchers studied 719 children with autistic siblings. According to previous studies, these younger siblings are nearly 20 times more likely to develop autism than those without a family member on the spectrum. The researchers analyzed different behavior profiles associated with autism, such as difficulty making eye contact, repetitive behaviors, and lack of communicative gestures. Their findings point to multiple developmental pathways to the disorder, meaning that autism cannot truly be identified by a single behavior.

Study leader Katarzyna Chawarska, associate professor of pediatrics at Yale, states that clinicians should pay special attention to the combinations of behaviors that her team studied in 18-month old children. She adds, “I think the best way of identifying these children is to look for combinations of markers, not a single marker.”

Chawarska and her colleagues analyzed data from a randomly selected subgroup of 565 toddlers, with siblings on the autism spectrum. At the age of 3, 122 of these children were diagnosed with autism, 138 showed signs of social and/or cognitive delays, and 305 were neurotypical. They analyzed the children through a diagnostic test called the Autism Diagnostic Observation Schedule, and classified the children into three groups (typical, atypical, and autistic) based on their scores for six items.

Their analysis discovered that three behavioral combinations are a strong signal for an autism diagnosis. The first profile describes children who have difficulty making eye contact and communicating through gestures. Children with the second profile have difficulty making eye contact but do not engage in imaginative play. The third profile consists of children with just a bit of trouble making eye contact, but that show repetitive behaviors.

In total, their algorithm flagged 57 percent of the children that were later diagnosed with autism. Their classification system was even more accurate at identifying typically developing siblings, indicating that the system is better at ruling out autism than fully detecting it. By studying combinations of behaviors, the algorithm improved the predictive value of a single behavior. For example, the study suggests that lack of eye contact alone is a poor indicator of autism. However, the presence of atypical eye contact in combination with nonverbal communication or lack of imaginative play can significantly increase the likelihood of autism.

Stelios Georgiades, assistant professor of psychiatry and behavioral neurosciences at McMaster University states, “By identifying the combination of symptoms and behaviors, we’re becoming more specific about what to look for”. The findings of this study suggest that siblings of children on the autism spectrum should undergo evaluations for the disorder periodically up to the age of 3. These evaluations can lead to an earlier diagnosis, allowing for earlier opportunities for therapies and optimal care.

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New Study Sheds Light on Genetic Mutation Linked to Autism

gene mutationA study utilizing mouse models has found new evidence towards how autism develops. The transgenic mouse model could lead to improvements in the diagnostic and treatment process for those on the autism spectrum.

Researchers at Vanderbilt University recently inserted a genetic variation into mice, creating a mutation which is commonly found in people with autism, ADHD, and bipolar disorder. This mutation affects the function of the dopamine transporter (DAT), a protein that regulates the brain’s supply of the neurotransmitter by removing excess dopamine from the synapse (the space between nerve cells).

The DAT mutation in individuals with autism causes the transporter to leak dopamine. Dr. Randy Blakely, senior author of the report, states, “[It’s like] a vacuum cleaner in reverse.” The mice with leaky DAT proteins have too much dopamine in and around their synapses, resulting in unusual behaviors. For example, they exhibited rapid, sudden movements, which they described as a “darting behavior”. While other mice were quiet and mostly unresponsive when researchers picked them up, those with the mutation were hyperactive, and as Dr. Blakely states, they would “take off”.

Dr. Blakely adds, “Early on, we could tell which ones carried the mutation by observing this response.” In addition, typical mice often explore their cages, while the mice with the mutation did not. Dr. Blakely states, “We wonder whether this may be a sign that the behavior is driven less by searching for clues to appropriate behavior versus acting on innate impulses.”

The effects of both amphetamine and methylphenidate (Ritalin) were also affected by the mutation. In neurotypical individuals and animals, the stimulants flood the synapse with dopamine, creating hyperactivity. However, when given to the mice with the mutation, the drugs quelled hyperactive and impulsive behaviors. As a result, Dr. Blakely and his team are contemplating how Ritalin may reduce the dopamine leak in children with autism and ADHD. He states, “These mice may give us much better clues as to how these drugs are acting.”

The darting mice have exposed specific behaviors that are directly linked to a specific mutation, as well as how Ritalin may suppress the behaviors to an extent. Dr. Blakely and his team are now focused on how to find the optimal treatments for other specific mutations.

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New Blood Test Shows Promise for Early ASD Diagnosis

blood test 2

For years, scientists have been focusing on finding better ways to diagnose autism disorders, and are hopeful to establish a method that will diagnose children at earlier ages. In the latest attempt, researchers at Stemina Biomarker Discovery in Madison, Wisconsin, and the Mind Institute at the University of California-Davis, have conducted an early-stage blood test that identified autism in children with a high level of accuracy.

For the study, the researchers at Stemina analyzed blood samples from 82 children ranging in age from 4 to 6 years old, with 52 of the children having autism disorders, and 30 without. The team of researchers analyzed metabolites in the blood, trying to establish which molecules may signal autism. This study separates itself from previous research, as most blood-based biomarker studies have tried to distinguish any defects by examining gene expression.

Stemina has also conducted a study in partnership with UC-Davis involving nearly 300 patients, as well as a 210-patient study in conjunction with the Arkansas Children’s Hospital Research Institute. However, the results of these studies have yet to be published, as the test is “still at least three years and one larger-scale study away from commercialization”, according to Elizabeth Donley, co-founder and CEO of Stemina.

Stemina uses metabolomics technology to perform toxicity tests on compounds for drug developers and consumer products. A blood test for autism would be the company’s first diagnostic product. Diagnosing the disorder as early as possible is critical, as studies have shown that early treatment is incredibly beneficial to the child, building their cognitive and social skills. The primary challenge in creating an earlier diagnosis for autism is that the standard diagnosis is based on a series of behavioral testing, as opposed to a biological test.

Donley states that her company’s test is going to be advantageous, as it studies the metabolites instead of gene expression, providing a “readout of the organism’s current state in real time.” She continues, “Gene expression will also be important, but we don’t believe it will be as predictive.” Although Stemina’s test does not provide answers to the process of how a child becomes autistic, it can provide strong evidence of what is different about that child, leading to an earlier diagnosis. She states, “That’s where we think the promise is of this particular test and approach.”

The test results demonstrate the differences in the metabolism of children with ASD, which distinguishes them from neurotypical children. Stemina was able to distinguish autism through their blood test with 81 percent accuracy, with their subsequent studies showing equal levels of accuracy. “We are very pleased with the result of this first study because it demonstrates that differences in the metabolism of children with ASD are profound enough to distinguish them from typically developing children,” Donley states. She continues, “This will allow us to understand the individual metabolism of children with ASD in a way we never could before, leading to earlier diagnosis and individualized treatment.” Stemina now plans to conduct its own clinical study involving over 1,500 children, and has a target date of late 2017 to launch their blood test.

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Scientists Create an Opportunity for Personalized Treatments for ASD


Autism has always been considered a very complex disorder, affecting each individual quite differently. Scientists have recently found that over 500 genetic variants can increase the risk for autism, although they are still trying to establish just how they contribute to the repetitive behaviors and social difficulties associated with the disorder. Today, scientists are trying to configure the root of autism by collecting cells from individual autistic children and turning them into neurons that they can analyze.

Alysson Muotri, neuroscientist at the University of California, San Diego, and her colleagues have collected cells from the skin, blood, and teeth of autistic children, and turned them into neurons in their lab. By studying their electrical properties, the scientists aim to find out what may be wrong on an individual patient basis, and therefore create ways to treat it. She states, “If we sequence two people with very similar symptoms, what we see is they don’t necessarily have mutations in the same genes.” She continues, “This is not one disease, there are probably several diseases under the umbrella of autism.”

This strategy, which many scientists are picking up on, is based on the Nobel Prize-winning discovery that mature cells can be returned to an immature state, where they have the potential to grow into many different types of cells, including neurons. These intermediate cells are called induced pluripotent stem cells, or iPS cells.

Muotri and colleagues recently studied an 8-year old boy with autism. When one of his baby teeth fell out, the team focused on isolated cells from the dental pulp, turned these into iPS cells, and turned the iPS cells into neurons. Upon analyzing the neurons under a microscope, they noticed several things wrong. They had fewer branches and fewer synapses than neurons made the same way from people without autism. The researchers saw what they thought might be a clue to these abnormalities in the boy’s genome, which is a TRPC6 mutation that disrupts a specific gene. Following up, the researchers treated the neurons by using a drug called hyperforin. The results were promising, as the appearance and firing activity of the neurons became more normal. Based on their findings, Muotri and her team believe that the TRPC6 mutation is highly responsible in the development of the boy’s autism. She states, “TYPC6 is one of the genes that’s affected. [But] I think it’s not the only one.”

These complexities highlight the difficulty of getting to the root of autism development. Ricardo Dolmetsch, global head of neuroscience at Novartis Institutes for Biomedical Research, states, “There’s the issue of are you absolutely sure that a mutation is causative,” Dolmetsch said. “It’s hard to know unless you find it multiple times.” Dolmetsch has been using iPS cells to study autism for some time, and believes that the approach will help bring to light some of the possible causes of certain forms of autism. He believes that autism is caused by multiple gene mutations, as opposed to one major mutation. He adds, “iPS cells will be important to understand how these mutations interact.”

A major reason to study iPS cells is to hopefully develop more targeted treatments. These cells can help scientists identify different categories of autism with different underlying causes. Neurons and other cells derived from iPS cells could also be used in high-throughput drug screens to identify new drug candidates. One optimistic scenario is to have personalized medicine for autism, in which doctors use a patient’s genome and neurons derived from iPS cells to make a diagnosis and select the most effective drugs for that particular patient. Drugs could even be tested on the patient’s own neurons before being prescribed.

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The Link between Oxytocin Levels in Blood and Cerebrospinal Fluid

In recent years, scientists have been assessing levels of oxytocin in the brain, a hormone responsible for various social behaviors. Researchers have now found direct evidence that blood oxytocin levels in children are strongly linked to levels of oxytocin in cerebrospinal fluid, which surrounds the brain. 

Researchers at Stanford University School of Medicine have found that low levels of oxytocin in blood as well as cerebrospinal fluid (CSF) are strongly correlated to levels of high anxiety. Anxiety is highly common in individuals of all ages on the autism spectrum. Dr. Karen Parker, assistant professor of psychiatry and behavioral sciences, states, “So many psychiatric disorders involve disruptions to social functioning”. She continues, “This study helps scientifically validate the use of measuring oxytocin in the blood, and suggests that oxytocin may be a biomarker of anxiety. It raises the possibility that oxytocin could be considered as a therapeutic target across a variety of psychiatric disorders.”

In order to collect CSF, patients must undergo an invasive lumbar puncture procedure. Therefore, Dr. Parker and her team studied a group of volunteers who needed lumbar punctures for medical reasons. Their group consisted of 27 individuals, ranging in age from 4 to 64. Researchers tested the oxytocin levels in the CSF, as well as collected blood samples during the time the CSF was obtained. They were questioned about their levels of anxiety (with parents answering the questionnaire on behalf of the children enrolled in the study).

Dr. Dean Carson, postdoctoral scholar in psychiatry and behavioral sciences, states, “The fact that we measured blood and CSF at the same time shows for the first time that there’s a tight relationship between those two components and anxiety”. As a result, Dr. Carson and Dr. Parker wanted to know if oxytocin could treat anxiety in children with autism. Dr. Carson states, “Our belief is that there are oxytocin responders and nonresponders. Being able to have objective measures of psychiatric [disorders] will really enhance early diagnosis and measures of treatment outcomes.”

Dr. Eric Hollander, Director of the Compulsive, Impulsive and Autism Spectrum Disorder Program at Albert Einstein College of Medicine/Montefiore Medical Center, and Chairman of the ICare4Autism Advisory Council, has been studying oxytocin and its impact on individuals with autism for over 10 years. According to studies conducted by Dr. Hollander and his colleagues, oxytocin infusion in adults with autism resulted in the retention of social cognition memories, as well as improved social cognition (such as recognizing emotions, enhancing empathy, and decreasing social stress). Oxytocin stimulates receptors in the regions of the brains that involve social affiliation, like the amygdala and the thalamus. Therefore, low levels of oxytocin would indicate a higher susceptibility to social stress and anxiety.

“I was amazed by how beautiful the data looked,” Dr. Parker noted, stating that the correlations between oxytocin and anxiety were surprisingly strong for a small study, and provide interesting leads for future research. “I think it opened up a lot more doors.” With social anxiety affecting up to 90% of children with autism, children may truly benefit from levels of oxytocin therapy.

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