Asperger's Syndrome

The X Factor Explains Androgyny in Male Asperger’s

Un-erased maternal markers on the X may feminize male Asperger’s cases.

Posted Oct 24, 2014

C. Badcock
Source: C. Badcock

As a recent study points out, “The ‘extreme male brain’ theory suggests that autism spectrum disorder (ASD) is an extreme variant of male intelligence. However, somewhat paradoxically, many individuals with ASD display androgynous physical features regardless of gender.”

Photographs of face and body, as well as voice recordings, were obtained and assessed with respect to gender coherence, blindly and independently, by eight assessors. Psychiatric symptomatology, hormone levels, anthropometry, and the ratio of 2nd to 4th digit length (2D:4D, left) were measured in 50 adults with high-functioning ASD and 53 age- and gender-matched neurotypical controls. 

The relative length of fingers is fixed by 14 weeks' gestation, and reflects hormonal influences. In men, the ring finger (4D) tends to be longer than the index finger (2D), but this ratio tends to equality in women. Previous research found that a high ratio correlated with femininity, breast cancer, and high female/low male fecundity. A low ratio correlated with masculinity, left-handedness, musical ability, and autism. However, this study found that men in the ASD group "displayed higher (i.e. less masculine) 2D:4D ratios, but similar testosterone levels to controls."

The authors report that women with ASD had higher total and bioactive testosterone levels, less feminine facial features and a larger head circumference than female controls. Men in the ASD group were assessed as having less masculine body characteristics and voice quality, and androgynous facial features correlated strongly and positively with autistic traits measured with the Autism-Spectrum Quotient in the total sample.

The authors conclude that

Taken together, our results suggest that women with ASD have elevated serum testosterone levels and that, in several aspects, they display more masculine traits than women without ASD, and men with ASD display more feminine characteristics than men without ASD. Rather than being a disorder characterised by masculinisation in both genders, ASD thus seems to be a gender defiant disorder

Specifically, the authors comment that

Our results are compatible with the view that the androgen influence in ASD is enhanced in women but reduced in men. Moreover, in a study of children with ASD and gender identity disorder, almost all were male-to-female boys, but according to the early androgen impact hypothesis for ASD, the opposite should be expected. We thus modify the theory of Baron-Cohen, that autism should be regarded as the result of excessive masculinisation of the brain, by suggesting that it may rather be associated with androgynous features in both genders.

Once again, Baron-Cohen’s theory of autism seems to have taken a body blow. Indeed, these findings appear to confirm those of another recent study which suggest that paradoxically the extreme male brain theory applies more to females than to males!

As far as the imprinted brain theory is concerned, these provocative findings represent a further important line of evidence for the concept of epigenetic causes of Asperger’s syndrome originally put forward in 2008 by Julie R. Jones and others and independently proposed by me in a post of 2010.

Wikimedia Commons
Source: Wikimedia Commons

Along with 22 non-sex chromosomes (or autosomes, left) received from each parent, males get a Y sex chromosome from the father and an X from the mother, while females get an X from each parent. In order to avoid double-dosing of X gene products, most of the genes on one of a female’s two X chromosomes are inactivated. 

The X chromosome has about 1500 genes, of which at least 150 are related to intelligence and social, mind-reading, or empathic skills—what I would call mentalism. Identical female twins vary more on measures of social behavior and verbal ability compared to male identical twins thanks to differential X-inactivation of these key mentalistic genes—an epigenetic factor which contradicts the conventional wisdom that any differences between identical twins must be the result of non-genetic, environmental effects.

Maternal epigenetic markers on the X a woman passes to her children are normally erased, so that the X is epigenetically reset to zero. But this does not always happen. On the contrary, in my original post, I suggested that accidental retention of inactivation of key mentalistic genes on the X that a mother passes on to a son could explain both such a son’s mentalistic deficits and the predominance of male Asperger’s cases (daughters of course being in the main protected by having two Xs).

But as I pointed out in a later post, Jones and her colleagues raised a possibility I had not considered. This was that epigenetic markers retained from the mother on a son’s X chromosome could both up-regulate as well as down-regulate critical genes. At the time, I commented that the imprinted brain theory implied this might be more relevant to psychotic disorders than autistic ones, but consideration of the findings related to feminization in male Asperger’s cases has suggested a new possibility that readily explains the results reported.

Some autosomal genes are sex-specific, and at least 15% of X chromosome genes are expressed from both of a woman’s Xs, with an additional 10% of X genes being expressed variably in women. And because there are always twice as many X genes riding in female bodies by comparison to male ones, they are subject to female-benefitting selection twice as often as they are to selection that benefits males. Where the X chromosome is concerned, Mother Nature is a feminist! 

Accidentally retained maternal DNA markers on a son’s one and only X chromosome could trigger the expression of such genes in a son that would otherwise only normally be expressed in a daughter. Indeed, a telling precedent for this can be found in the case of the “anti-testis” X chromosome gene, DAX1, which challenges male development—successfully so if accidentally duplicated.

The imprinted brain theory predicts that enhanced expression of paternal and/or reduced expression of maternal genes predisposes to ASD. But because all fathers are male and all mothers are female, male and female sex chromosome genes are also implicated—in this case those on the X chromosome.

The finding that dysregulation of genes normally only expressed in females may also explain feminization of some male Asperger’s cases does not contradict the imprinted brain theory in the way that it does the extreme male brain theory of autism. On the contrary, feminization in some cases is an obvious implication of the proposition that epigenetic influences from the mother via her X chromosome may affect the expression of X genes in her sons in both directions. Of course, such feminizing outcomes would not be apparent in daughters—indeed, they might go some way to mitigating the masculinizing effects that this study confirms can often be found in high-functioning female autistics.

Finally, this idea would also explain why androgynous features are not found in all high-functioning male autistics. The reason would be that the genes in question would be affected randomly, so some males might escape the feminizing effects of retained maternal epigenetics but others might not. 

(With thanks to Dr Ian Johnson for bringing this issue to my attention.)