Gender has been at the forefront of discussion in recent years. Amongst all the talk about social issues, is there a place for science? Can you be disadvantaged –or indeed advantaged –by your sex when it comes to disorders and disease?
Sexual dimorphism is the physiological and behavioural difference between sexes. It arises through natural selection due to the pressures of competitive mating, and examples can be seen across all gendered species.
Many disorders of the brain show sexual dimorphism. For example, depression is more common in women, whereas Parkinson’s is more common in men. Alternatively, the difference may lie in the symptoms or prognosis: women are more severely affected by stroke, whereas men face more extensive brain damage in multiple sclerosis.
Autism shows remarkable sexual dimorphism. It is generally acknowledged that four times as many boys are diagnosed than girls, although some studies have concluded this number to be as high as sixteen times.
The question is whether boys are genuinely more ‘prone’ to autism, or whether girls with autism are just not being diagnosed. Both ideas will be discussed here, followed by a pioneering study published earlier this year that has shed some light on the situation on a molecular level.
Although small improvements have been made in recent years, there lies a problem that the ‘female autism phenotype’ is incompatible with autism diagnostic criteria. Of course, every individual is different – some girls may match the stereotype – but in general the typical female presentation of autism is different.
Difficulties socialising, obsessions or obscure interests, and disruptive behaviour in school are behaviours that typically come to mind when hearing ‘autism’. But in girls, this is often not the case. Autistic girls are far more prone to and capable of ‘masking’ from a young age. ‘Masking’ is an effort to appear neurotypical through a combination of copy-catting and rule-making. Copy-catting can include imitating facial expressions and gestures made by peers, laughing when others do, or repeating phrases heard from friends. Rule-making is remembering to look people in the eye and counting to four before releasing or stepping slightly left ten paces before passing someone in the street. Formulating scripts for social interactions – from passing a friend in the street to picking up lunch in the canteen – is very common. These flowcharts for conversation are written, rehearsed and stored in vast memory banks.
Autistc girls are often described by their teachers as bright, conscientious, just sometimes a little quiet. Quiet because in a group situation where interactions dynamics are much more complex, it is impossible to create a rule that determines when to speak. Unless given a direct cue, it is easier to take a back seat – then no social rules will be inadvertently broken. A good performance at school means teachers and parents don’t suspect any underlying problems and hence miss the subtle clues.
These clues often emerge in retrospect from the ‘masking’ fog if a diagnosis is later given. In girls, the small details are crucial. Rather than the stereotypical obsessions with timetables, physics and trains, girls are more likely to have similar interests to their friends. But rather than holding tea parties, the toys are organised into categories. Rather than acting out family dinners, dolls houses are rearranged over and over. Apparent pickiness with food and clothes may be the result of sensory issues – the texture of certain foods, the feel of certain materials touching skin. Funny anecdotes about taking things literally may have deeper meaning. Looking back, the signs can seem endless but being so subtle, they are easily disregarded at the time.
A common theme in autistic girls is a Jekyll and Hyde behaviour split between school and home. At home, with less pressure to follow social rules, the chameleon act may wear thin. Mental exhaustion from navigating the outside world makes these girls prone to massive tantrums and arguments over what seems like nothing and attempts to intervene often make things worse. These will be written off again and again as an overreaction, parents unaware that their child is not simply having a tantrum, but an autistic meltdown.
‘Masking’ is carried on throughout life, with mounting pressure as girls reach high school and social interactions grow more complex. This discomfort is bottled up, putting autistic girls at a high risk of anxiety, depression and eating disorders. These diagnoses often further prevent people from recognising autism in girls, as any meltdowns will be written off as panic attacks associated with these other disorders.
As a spectrum, it is expected that individuals exhibit varying presentations of autism. However these deviations from textbook autism are reported on a population wide scale, not just in individual cases. This distinct female phenotype needs to be accounted for in diagnostic criteria so that girls struggling with autism can be picked up on from a younger age and given the support they require.
Clearly, many girls are going undiagnosed. But there remains a strong argument for the other side of the debate – “are boys more biologically prone to autism?”. Even when undiagnosed autistic girls are statistically accounted for, it remains the case that autism is more common in males. It would seem that there is a biological difference in neural systems that predisposes boys to autism.
The extreme male brain theory is a controversial one. Championed by Simon Baron-Cohen, it is the idea that neurotypical male and female brains function differently. Males are better at systemising (analysing the variables of a system and working out the rules that govern them) whereas females are better at empathising (understanding that mental states exist out with self and understanding what it could be. This involves imagination). People have the capacity for both, but one system will be more dominant.
Imagine a scale with systemising at one end and empathising at the other. Typical males will sit slightly towards systemising, and females slightly towards empathising. Baron-Cohen’s idea is that autism is an extreme version of the systemising male brain, sitting much closer to the systemising end of the scale with empathising becoming very weak. Many believe that this scale explains why more boys have autism. Autism is a neurodevelopmental disorder – the differences in brain circuitry that give the autistic phenotype arise due to abnormalities during the development of the brain during pregnancy. In most cases of autism, there are many, many small changes in the developmental process that add up to give the autistic phenotype. The theory goes that in boys, because the ‘typically’ male brain lies closer to the systemising end of the scale anyway, fewer abnormal events during development are required in order to push the brain to the extreme end of the spectrum – autism.
There is also some genetic evidence to support the idea that autism is at the male end of the brain spectrum. By comparing patterns of autism gene expression with neurotypical males and females, the autism expression pattern was seen to bear much more similarity to the typical male expression.
The extreme male brain theory is a logical one, and there is certainly a lot of support for it, but it is important to remember how many confounding variables there are in gender studies like these. Determining how much of the brain differences are innate, and what has been programmed by society is near impossible. However, this year some solid biological evidence for gender differences on the molecular level have been uncovered that begins to explain the sexual dimorphism seen in autism.
The widespread effects of neurological conditions – from schizophrenia to depression and OCD – on brain networks and ultimately behaviour all originate from small changes at the molecular level. The brain is a very delicate and balanced system. Researchers at the University of New Hampshire investigated whether the gender split lies at this molecular level. Their study has indeed revealed gender biased proteins.
First, some background on DNA. DNA is a string of thousands of genes, each one encoding the building instructions for a protein. Proteins are the tiny molecules that work together to perform all biological processes from energy production and immune functions, to cell communication and development. Small changes in the structure of a protein can change the way it functions; hence different variants of genes mean people turn out differently. Once these proteins have been made, their activity must be regulated – this is another step in what makes us all different. By adding a small phosphate molecule to a protein, it can be activated or inactivated. This process – phosphorylation – is key to regulating the activity of a protein.
The researchers investigated an enzyme called AC3 which is involved in the phosphorylation of proteins in neurons. AC3 has previously been associated with autism as well as other neurological conditions like depression, so it was a good target to begin looking at phosphorylation’s role in autism.
By knocking out AC3, the researchers could determine which proteins in the brain were being phosphorylated as a result of AC3 activity. The phosphorylation of proteins in the brain was then compared between males and females – this is something that has never been done before. The leap in the dark paid off, as AC3 was found to act differently in males and females by phosphorylating different proteins, therefore giving different patterns of regulation. 204 proteins were more tightly regulated in females and 31% of these were associated with autism.
This is a good explanation as to why autism is less likely to develop in females. If the autism-related proteins are more tightly regulated, they are less likely to get out of control and produce autistic behaviours. It is small changes at the molecular level that produce overall changes in activity at system level in the brain, so it may also begin to explain the behavioural differences seen between autistic males and females.
As discussed earlier, sexual dimorphisms such as this arise due to natural selection. Therefore, there must have been an evolutionary advantage to this gender difference. The researchers proposed that it could be due to the historical need for males to have extreme focus in tasks such as hunting, whereas females needed to be good at multitasking. To protect female brains from gaining the autism-like single-mindedness that would be useful in males, female proteins underwent more phosphorylation.
Of course, this is an initial study on animal models so further investigation is needed, but in the past there has been good translation of animal research to humans in autism studies, so the scientists are optimistic. As this new branch of autism research develops, there is a possibility that it will lead to a new pharmacological treatment to ease the lives of those at the extreme end of the autism spectrum. Furthermore, as this provides some scientific validation for the gender differences in autism, hopefully there will more imminently be improved awareness of the female autism phenotype so that fewer girls will slip through the net.
This post was written by Ailie McWhinnie and edited by Miles Martin.
