Autism’s Female Protective Effect
Males have a 2-3 times greater risk of autism spectrum disorder (ASD) compared to females, even after accounting for the role of ascertainment or diagnostic bias (Halladay et al., 2015). A female protective effect (FPE) or increased susceptibility of males to genetic disruption of the brain compared to females is a possible explanation of this difference. This theory predicts that females diagnosed with ASD of the same severity have a higher mutational burden (i.e., the number of mutations within the genetic autism spectrum) than males in terms of the presence and severity of genetic risk factors.
In support of the FPE model, Jacquemont et al. found that females with ASD have a greater accumulation of mutations than males with ASD, even after controlling for sex differences in cognition in ASD patients (Jacquemont et al., 2014). Additionally, Palmer et al. identified a higher risk of ASD for siblings of female patients than of male patients and a higher risk of ASD for male siblings of ASD patients than for female siblings. This augments the FPE hypothesis, which would offer a comprehensive explanation: Females require a greater mutational burden to be diagnosed with ASD, therefore, the parents of females with ASD carry more genetic risk factors than the parents of males with ASD. Thus, siblings of affected females are more likely to develop ASD. Additionally, male siblings of ASD patients are more likely to develop ASD than females due to their increased susceptibility to genetic risk factors.
There are several reasons why girls with ASD might not be diagnosed correctly. Firstly, FPE may prevent diagnosis of females; i.e., females would be less likely to cross the diagnostic threshold. This could be due to outlying genetic differences, brain connectivity (The Economist, 2014), or other factors. However, there is evidence for differential diagnosis that is not explained by difference in the prevalence of ASD (Halladay, 2015).
Secondly, there may be a different presentation of symptoms in females, i.e., sexual dimorphism. This is supported by the fact that some symptoms are less severe or present less frequently in females, like lack of functional social behavior and the presence of repetitive behaviors (Halladay, 2015). This would mean that many females with ASD are not diagnosed because they do not fit the male-oriented standard for diagnosis.
Additionally, to diagnose females and males with ASD requires different baselines of comparison due to inherent biological and social sex differences (Halladay, 2015). These include sexual dimorphism in language development, memory, cognitive flexibility and other factors as well as differential social expectations (Halladay, 2015). Many females with ASD may be undiagnosed because, while they present with symptoms far from the female baseline, the symptoms are close enough to the male baseline that they go undetected.
Lastly, differential diagnosis could be partially the result of stereotyping. A bias toward viewing girls as more social than boys could blind clinicians from symptoms of autism that females display.
Acknowledgments
I thank Prof. Maryellen Ruvolo, my professor for HEB 1600 at Harvard, for her feedback on an early version of this paper.
References
Halladay, A. K., Bishop, S., Constantino, J. N., Daniels, A. M., Koenig, K., Palmer, K., ... & Taylor, J. L. (2015). Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Molecular autism, 6(1), 36.
Jacquemont, S., Coe, B. P., Hersch, M., Duyzend, M. H., Krumm, N., Bergmann, S., ... & Eichler, E. E. (2014). A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. The American Journal of Human Genetics, 94(3), 415-425.
[The Economist] "Autism: Why it's not "Rain Woman"." The Economist, 1 Mar. 2014.
Photo Credits (in order of appearance)
1. KarelinLestrange/Pixabay, 2. Sukinah_1407/Pixabay, 3. NickelBabe/Pixabay.
Tags
#AutismSpectrumDisorder, #Autism, #NeuroDevelopmentalDisorder, #MentalDisorder, #FemaleProtectiveEffect, #SexualDimorphism, #Neuroscience, #Genetics