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Sep 3 2015
A study of about 800 children with autism found gender differences in a core feature of the disorder, as well as in the youngsters’ brain structures.


The study also found that brain differences between boys and girls with autism help explain this discrepancy.

The study, published online Sept. 3 in Molecular Autism, gives the best evidence to date that boys and girls exhibit the developmental disorder differently.

“We wanted to know which specific clinical manifestations of autism show significant gender differences, and whether patterns in the brain’s gray matter could explain behavioral differences,” said the study’s senior author, Vinod Menon, PhD, professor of psychiatry and behavioral sciences. Knowledge of the difference could help clinicians better recognize and treat autism in both sexes, he added. “Understanding this is really quite crucial clinically.” 
 
“We found strong evidence for gender differences in autism,” said postdoctoral scholar Kaustubh Supekar, PhD, the study’s lead author. The researchers used two large, public databases to examine nearly 800 children with high-functioning forms of autism in the United States, he said.

Repetitive and restricted behavior is perhaps the most widely recognized of the three core features of autism. It can show up as a child’s preoccupation with a narrow interest, inflexibility about routines or repetitive motions such as hand-flapping. The other core features of autism are social and communication deficits.

More boys with high-functioning autism
Among children diagnosed with the high-functioning form of autism, boys outnumber girls by four to one. Scientists were interested in comparing the expression of core features of the disorder between sexes because they have long suspected girls with autism may display symptoms differently, causing them to be underdiagnosed or making it harder for them to get the most appropriate treatment.

Vinod Menon

“Autism has primarily been studied from the viewpoint of boys with the disorder,” said Menon, who holds the Rachael L. and Walter F. Nichols, MD, Professorship. “Understanding gender differences can help in identifying the behavioral skills that are most important to remediate in girls vis-a-vis boys.”
The study examined the severity of autism symptoms in 128 girls and 614 boys registered with the National Database for Autism Research. The children ranged in age from 7 to 13, had IQ scores above 70, and had been evaluated with standard tests for autistic behavior. The boys and girls were matched for age, and had the same average IQ. Girls and boys had similar scores for social behavior and communication. Girls and boys had similar scores for social behavior and communication. But girls had lower (more normal) scores on a standard measurement of repetitive and restricted behaviors.
The researchers then examined data from the Autism Brain Imaging Data Exchange that included structural MRI brain scans of 25 boys with autism, 25 girls with autism, 19 typically developing boys and 19 typically developing girls. The individuals among the groups were matched for age and IQ. The researchers again found that girls and boys did not differ on social behavior and communication skills, but that girls had less-severe repetitive and restricted behaviors. “This replication provides the strongest evidence to date for gender differences in a core phenotypic feature of autism,” Menon said.

Brain-structure differences
The brain-scan analysis revealed several gender differences in brain structure between typically developing boys and girls, consistent with the findings of earlier studies.
Children with autism, however, had a dissimilar set of gender differences in their brains — specifically, in the motor cortex, supplementary motor area and a portion of the cerebellum. These regions affect motor function and planning of motor activity. The researchers noted that many repetitive behaviors, such as hand-flapping, have a motor component. The study demonstrated that patterns of gray matter in these motor regions could accurately distinguish girls from boys with autism, Supekar said. The researchers found that parts of the motor system that contributed to individual scores for repetitive and restricted behaviors were different in boys and girls.

“Girls and boys with autism differ in their clinical and neurobiological characteristics, and their brains are patterned in ways that contribute differently to behavioral impairments,” Menon said.
“The discovery of gender differences in both behavioral and brain measures suggests that clinicians may want to focus diagnosis and treatments for autistic girls differently than boys,” Supekar added.

By Erin Digitale
Erin Digitale is the pediatrics science writer for the medical school’s Office of Communication & Public Affairs. Email her at digitale@stanford.edu
Jessica Wright
27 July 2015     


Girls with autism are nearly three times as likely as boys with the disorder to have severe epilepsy that responds poorly to medication.

The findings, published 26 June in Autism Research, add a twist to one of the biggest conundrums in autism: its 4-to-1 ratio of boys to girls. Research suggests that girls are somehow protected from autism-linked mutations. The new study hints that these mutations also lead to treatment-resistant epilepsy.

Roughly 25 percent of people with autism have epilepsy, compared with about 1 percent of the general population. In the new study, researchers found that women who have both autism and epilepsy tend to have milder autism symptoms, but more severe seizures, than do men with the disorder. The finding suggests that whatever protects women from autism does not shield them from epilepsy.

“It’s really intriguing,” says lead researcher Karen Blackmon, assistant professor of neurology at New York University.

Previous studies have shown that epilepsy affects more girls than boys with autism. The new findings serve as a warning to doctors that epilepsy in these girls may also be especially difficult to treat.

Doctors “should be prepared to try multiple medications and realize the medications might fail at the first try,” says Shafali Jeste, assistant professor of psychiatry at the University of California, Los Angeles, who was not involved in the study.
Seizure skew:

Blackmon and her colleagues followed 125 individuals with autism who sought treatment for epilepsy. The participants ranged in age from 2 to 35 years.

Of the 97 boys and men, 24 percent showed no response to two epilepsy drugs. By contrast, 46 percent of the 28 girls and women did not respond. They also have milder autism symptoms than the males do, according to parent questionnaires.


The researchers excluded people with known genetic syndromes linked to epilepsy, such as tuberous sclerosis. But some participants may carry variants tied to both autism and treatment-resistant epilepsy, such as a duplication of the chromosomal region 15q11.13 — which can lead to fatal seizures.

The study’s findings may be a result of the girls and women in the study carrying a disproportionate number of these severe mutations, says Elliott Sherr, professor of neurology at the University of California, San Francisco, who was not involved with the study. That would skew the results to suggest that more girls than boys in general have treatment-resistant epilepsy, for example.

Still, the work sheds new light on the long-observed overlap between autism and epilepsy. “We know very little about the subgroup of individuals with [both] autism and epilepsy,” says Christine Nordahl, assistant professor of psychiatry at the University of California, Davis, who was not involved in the study. “This study is a great first step in exploring sex differences in this subgroup.”

The researchers also used magnetic resonance imaging to explore the possible neurological underpinnings of girls’ susceptibility to intractable seizures.

They found that women who have both autism and epilepsy are more likely than men with both disorders to have mild abnormalities such as cortical dysplasias, in which some neurons in the top layer of the brain fail to migrate to the correct place. Roughly 42 percent of females in the study have unusual brain scans, compared with just 19 percent of males. These abnormalities track with treatment-resistant epilepsy in both genders.

Cortical dysplasias are linked to epilepsy, but some of the other abnormalities seen in the study are minor and may not be harmful. Blackmon and her colleagues are finding better ways to detect cortical dysplasias and plan to look for them across a large database of brain scans. The prevalence of these abnormalities may start to explain the connection between autism and severe epilepsy in girls, Blackmon says.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.
References:
1: Blackmon K. et al. Autism Res. Epub ahead of print (2015) PubMed
 

Alexandra Sifferlin
 May 12, 2015 


The reasons why girls are less often diagnosed may be both biological and social

Autism, already a mysterious disorder, is even more puzzling when it comes to gender differences. For every girl diagnosed with autism, four boys are diagnosed, a disparity researchers don’t yet fully understand.

In a new study published in the journal Molecular Autism, researchers from the UC Davis MIND Institute tried to figure out a reason why. They looked at 112 boys and 27 girls with autism between ages 3 and 5 years old, as well as a control sample of 53 boys and 29 girls without autism. Using a process called diffusion-tensor imaging, the researchers looked at the corpus callosum — the largest neural fiber bundle in the brain — in the young kids. Prior research has shown differences in that area of the brain among people with autism.

They found that the organization of these fibers was different in boys compared with girls, especially in the frontal lobes, which play a role in executive functions. “The sample size is still limited, but this work adds to growing body of work suggesting boys and girls with autism have different underlying neuroanatomical differences,” said study author Christine Wu Nordahl, an assistant professor in the UC Davis Department of Psychiatry and Behavioral Sciences, in an email.

In other preliminary research presented at the International Meeting for Autism Research, or IMFAR, in Salt Lake City, the study authors showed that when girls and boys with autism are compared with typically developing boys and girls, the behavioral differences between girls with autism and the female controls are greater than the differences among the boys. Nordahl says this suggests that girls can be more severely affected than boys.

A study earlier this year by a separate group found notable differences in symptoms between autistic boys and girls, which could be one of the reasons autism in girls sometimes goes unnoticed or is diagnosed late. Girls generally display less obvious behavioral symptoms at a young age compared with boys, the researchers found.

One of the reasons females with autism are less understood than males is that most research studies do not have equal numbers of boys and girls, says Nordahl. “This is not surprising, given that there are so many more males with autism than females,” she says. “We need to do a better job of trying to recruit females with autism into our studies so that we can fully explore differences between males and females with autism.”

Nordahl says understanding gender differences in autism affects how kids are diagnosed, as well as how they are treated. Understanding what biological differences may be at work can ultimately lead to a better understanding of autism and the best interventions for treatment.

Public Release: 12-May-2015

Male toddlers with autism have significant structural differences in their brains compared to females with the condition, according to research published in the open access journal Molecular Autism.

The journal is publishing a special series of articles looking at the links between sex/gender and autism, which reveal additional insights into the role of prenatal sex hormones and the 'female protective effect'.

Autism spectrum conditions are more common in males than in females, with a 2 or 3:1 male to female bias in prevalence consistently found in studies. Why this is the case is still not fully understood.

Guest editor Meng-Chuan Lai from the Autism Research Centre, University of Cambridge, UK, said: "Autism has always been perceived as a condition that occurs more often in males, which means that females are usually underrepresented in research studies. This means there's a risk that the scientific and clinical literature provides a partial, male-based understanding of autism.

"But autism is clearly not a 'male condition'. Delineating the role that sex and gender play in the characteristics of autism, across multiple levels, may inform both our ability to identify the condition and lead to a greater understanding of its developmental psychology and biology."1

Sex/gender differences in the brain

Researchers from the MIND Institute at University of California, Davis, USA, found sex differences in children with autism when looking at the organization of fibers in the corpus callosum, the largest bundle of nerve fibers in the brain.2

The study included 139 three-to-five year olds with autism (112 male/27 female) and 82 typically developing children (53 male/29 female). Using MRI, the researchers studied the pattern of nerve fibers projecting from the corpus callosum to different regions of the brain.

There were clear sex differences in the results. While both males and females with autism had alterations in regions of the corpus callosum connected to the frontal lobe, the pattern of alterations differed between the sexes.

In particular, males with autism had smaller callosal regions connecting to the orbitofrontal cortex, which is involved in emotional processing and reward-related decision-making. In contrast, females with autism had smaller callosal regions connecting to the anterior frontal cortex, which is involved in higher order 'executive function' such as planning.

The study suggests that males and females with autism should be evaluated separately and not assumed to share the same pattern of atypical brain structure. The study also suggests that differences in the corpus callosum are established early in development, before three years of age.

Genes and prenatal sex hormones

In another study, researchers from the George Washington University, USA, found sex differences in the levels of the gene 'RORA' in the brain. RORA regulates many genes linked to autism, including a gene that influences prenatal testosterone levels, a known risk factor for autism.3

The team showed that RORA protein levels are higher in the brains of typically developing females compared to typically developing males, providing females with a buffer against RORA deficiency. RORA deficiency has previously been proposed as one factor that may make males more vulnerable to autism.

Female protective effect

Two papers in this new thematic series of the journal shed light on the 'female protective effect' -- the theory that there is a mechanism protecting the developing female brain from autism.

Researchers from University of California, Los Angeles, USA, investigated the risk of autism in males and females in over 1,000 families, and the rate at which autism re-occurred in siblings.4

The results demonstrated the expected higher rates of autism in males compared to females, but also showed a significantly greater risk of autism for siblings of females with autism, compared to siblings of males with autism.

The researchers say this supports the 'female protective effect' hypothesis because females with autism carry greater genetic load predisposing them to develop the condition, compared to males. This could cause them to overcome the 'female protective effect', although this interpretation of their results awaits testing at the molecular level.

This greater genetic predisposition may run in families and means that siblings of females with autism are more likely to present autism.

A final study, led by University of California, San Francisco, Washington University in St Louis and Yale School of Medicine, USA, analyzed genetic data from over 4,500 families affected by autism. Their work found that no single gene is associated with the female protective effect. The authors conclude that the mechanism of this protection remains unknown, but that multiple genes could play a role.5

Joseph Buxbaum, Co-editor in Chief of the journal Molecular Autism, said: "We are excited to be publishing such high quality, novel research on the important and previously neglected topic of the roles that sex and gender play in understanding autism."

Simon Baron-Cohen, Co-editor in Chief of the journal, added: "A focus on sex and gender in autism research should help improve the clinical identification of females who may have autism that has gone undiagnosed.

"Research into this topic may also help us understand the complex mix of sex-linked genetic, hormonal, and social factors that contribute to individual differences in social and language development and flexible adaptation to change, as well as autism itself."

 
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Sex differences take center stage in autism special issue
Paul Raeburn
29 May 2015

One of the most consistent findings in autism, and perhaps the most perplexing, is that it affects about four boys for every girl. This sex bias has become a hot topic in autism research — so much so that Molecular Autism devoted its entire May issue to it.

One of the papers in the issue ruled out the suspicion that there is a single gene responsible for the so-called ‘female protective effect’ — the apparent resistance of girls to mutations that cause autism.

Previous studies have suggested that the protective effect might be traceable to a single genetic location on the X chromosome. Alas, nothing in autism is simple. In the new study, researchers analyzed two large genetic databases of girls with and without autism and found no evidence for such a DNA hotspot.

This finding does not mark the end of the search, however. The protective effect likely stems from a collection of genes rather than a single one, the researchers say, and efforts to find those genes will continue.

A second study in the special issue centers on the thick bundle of nerve fibers that connects the brain’s two hemispheres. Previous studies have shown that this bundle, called the corpus callosum, develops differently in children with autism, losing some of its structural integrity over time. The new study uncovers some intriguing sex differences in preschool children.

Researchers used a scanning method called diffusion tensor imaging to compare the corpus callosum in 112 boys and 27 girls with autism, and 53 boys and 29 girls without the disorder, all aged 3 to 5 years. They found discrepancies between boys and girls with autism in both the structure and the organization of the nerve bundle.

Compared with the controls, boys and girls with autism show different patterns of fibers projecting to the brain’s frontal lobe. In boys with autism, the portion of the fibers connecting to the orbitofrontal cortex, a region involved in decision-making, is smaller than in typically developing boys. But the researchers saw no difference here between girls with and without autism. In girls with autism, however, a smaller section of the fiber bundle connects to an adjacent region, the anterior frontal cortex, than in typically developing girls.

It’s unclear how these differences might affect the workings of the brain, but the researchers speculate that they could contribute to the apparent resistance of girls to autism.

A third paper in the issue garners more support for the female protective effect. It found that children with older sisters on the spectrum are more likely to receive an autism diagnosis than are children whose older brothers are affected.

Together, the studies highlight several gender differences in autism that are ripe for further study. If researchers could find the responsible genes, for example, they might be able to use that knowledge to develop new treatments or even a way to help prevent autism.

Editor’s note: To kindle even more interest in this area, we are planning a special report of our own on gender differences in autism. Look for it in a few months.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. 
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On 11 March, David Skuse and William Mandy presented evidence to support the notion that the tools available for diagnosing girls with autism show an inherent gender bias. They also shared interviews with a former patient to provide specific examples of the ideas they discussed. Tania Marshall is referred to by the researchers as a valuable resource



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