Understanding Gender Bias in Autism
M. Chiara Manzini, PhD
George Washington University Institute for Neuroscience
Manzini MC. Understanding gender bias in autism [published online April 26, 2019]. Neurology Consultant.
Serendipity often leads to the most interesting discoveries in science. As my colleagues and I were working on identifying genes that affect learning and memory, we discovered mutations in humans’ CC2D1A gene in individuals affected by intellectual disabilities, autism spectrum disorder, and seizures. By removing the gene in a mouse, we sought to understand how the loss of CC2D1A would affect brain development and behavior.
We discovered a striking difference between male and female mice when CC2D1A was removed. While the male mice had cognitive deficits, social deficits, hyperactivity, and anxiety, the female mice only had mild learning issues. The mice seemed to mirror the sex difference in autism diagnosis in humans—boys are diagnosed with autism at a 4 to 1 rate compared with girls, and 10 to 1 for high-functioning autism—which piqued our interest in looking at the mechanisms for sex bias in autism.
Through our research, we hope to understand the molecular causes behind the gender differences and how they are established. By determining the mechanisms involved, we might be able to discover something druggable in a pathway that we can use to first rescue the mouse as a pre-clinical model, and then go into patients to help alter the imbalance.
However, a main barrier to treating patients will be deciding whether to do so individually or in groups. Hundreds of genes that cause autism have been discovered, and in most cases, it is an individual mutation that causes the disease in a particular patient. This generates a big conundrum in the field: Do we treat each patient individually, or can we develop categories where we can group patients with the same general molecular dysfunction and treat those groups? It might be impossible to go after each individual genetic mutation, especially for the very rare ones.
The Importance of Thinking About Gender
While not all our questions have been answered, there is already a clinical takeaway from our ongoing research: Think very carefully about gender.
Individuals of each gender may respond differently to medication. Men and women may also have different presentations of their psychiatric and neurological disorders due to the regulation of different circuits and molecules in both genders, which is something that our model, as well as other animal models in the field, has demonstrated.
On top of the molecular differences that cause a gender bias in presentation, we also have to consider the diagnostic bias that societal norms have helped create. For example, autism was initially described mostly in boys, and so all the diagnostic criteria and tools that are being used were designed for boys. In general, society expects girls to be more social and so women with autism will have learned to mask their social deficits early on, leading them to present differently than boys with autism.
I have heard stories of physicians telling women they do not have autism because the patients make eye contact. However, that may be because the patients were trained to make eye contact and be social, since that is how society expects girls to act.
This kind of interaction can undermine patient trust and is what also causes autism to be diagnosed later in life—and sometimes not at all—in women. (And age bias is another factor that can affect autism diagnosis, with many in clinical practice sometimes forgetting that there are adults and aging individuals with autism.)
Gender bias in prevalence is not only present in autism, but also in other neurological and psychiatric disorders. For example, intellectual disabilities and Tourette syndrome are more prevalent in boys, while depression, Alzheimer disease, and multiple sclerosis are more prevalent in women. The origin for sex biases for these different conditions could actually be similar, and their connection—and how it will affect drug development—is continuously being researched.
I urge neurologists to keep abreast of research on sex differences in neurological disorders at all stages of a patient’s life because there may be information coming up from the neurodevelopmental disorders that may be important for the neurodegenerative disorders, and vice versa.
M. Chiara Manzini, PhD, is an assistant professor of pharmacology and physiology at the George Washington University Institute for Neuroscience in Washington, DC.
Zamarbide M, Mossa A, Munoz-Llancao P, Wilkinson MK, Pond HL, Oaks AW, Manzini MC. Male-specific cAMP signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability. Biol Pscyhiatry. 2019;85(9):760-768. https://doi.org/10.1016/j.biopsych.2018.12.013.