Nearly four times more males are diagnosed with autism spectrum disorder (ASD) than females. Consequently, most basic and preclinical studies on ASD have focused on males.

ASD is typically diagnosed by deficits in social skills at an early age, together with stereotypic repetitive behaviors such as rocking back and forth, and impaired communication skills.

Female patients with ASD have remained understudied. The skewed ratios have also led to the positing of a female protective hypothesis (FPE) supported by the evidence that females diagnosed with ASD carry on average larger, more frequent and more harmful mutations than those found in males with ASD.

A new study in the journal Brain, “A neurogenetic analysis of female autism,” advocates caution in drawing conclusions regarding female ASD based on predominantly male studies. Understanding the basis of the sexually dimorphic expression of the disease is critical to developing a gender-specific understanding of the systems biology of the syndrome, the authors note.

Kevin Pelphrey, PhD
Scientists led by Kevin Pelphrey, PhD, at the University of Virginia School of Medicine, discovered that there is a significant difference in the genes that underpin autism in females and males [Dan Addison, UVA Communications]
The researchers integrated functional magnetic resonance imaging (fMRI) and genetic data in a gender-balanced sample of 45 ASD and 45 normal subjects ages 8–17 years, to probe into the female-specific risks of ASD.

Sociability, a multifaceted process that we often take for granted, includes intricate neural mechanisms that allow us to selectively attend to and process socially relevant cues over other stimuli in our environment. Being aware of biological motion—signals conveyed by the human face, eyes, hands, and body—is an important facet of sociability.

Therefore, the authors characterize female ASD brain response to human motion and compare them to analogous responses in normally developing female subjects. They find ASD females show reduced brain activity in sensorimotor, striatal, and frontal regions of the brain compared to typically developing females.

Of significance, the authors note, is that this difference between ASD and typically developing females does not resemble differences between ASD males and typically developing males, even though neural responses do not differ between female and male patients with ASD.

The authors also compare genetic data between 66 male and 61 female ASD patients and report females with ASD have larger rare copy number variants containing genes expressed in early life, between 10 days after conception to 2 years old.  This difference is primarily driven by copy number variants containing gene(s) expressed in striatum —a cluster of neurons under the cerebral cortex, in the basal ganglia of the forebrain, important in motor and reward systems.

Based on these findings, the authors conclude neurodevelopmental pathways in the striatum may contribute to risk in female ASD.

“This new study provides us with a roadmap for understanding how to better match current and future evidenced-based interventions to underlying brain and genetic profiles, so that we can get the right treatment to the right individual,” says lead investigator Kevin Pelphrey, PhD, from the University of Virginia School of Medicine and Brain Institute. “This advances our understanding of autism broadly by revealing that there may well be different causes for boys vs. girls; this helps us understanding the heterogeneity within and across genders.”

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