7 minute read

X,Y, and Autism

AUTHOR: V. F.

The ABC of ASD

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Today, as much as 1% of the population carries the diagnosis of autism or autistic spectrum disorder (ASD), which is described by the American Psychiatric Association (APA) as “a neurodevelopmental syndrome characterized by difficulties with social reciprocity, social communication, flexibility, and sensory processing”.

Moreover, individuals with ASD have varying language skills, with the two extremities being completely absent speech and fluent language. This is where the term ”spectrum” comes into play: autism is a continuum of developmental and cognitive states often accompanied by comorbidities such as epilepsy and other physical and psychiatric abnormalities. Cognitive development may also vary dramatically, with all the possible conditions from profound intellectual disability to above-average intelligence. Thus, in the same way that no two snowflakes are identical, no two patients with ASD will show exactly the same phenotype. The extreme clinical heterogeneity of the disorder is probably one of the primary obstacles in understanding the pathophysiology and causes of autism. On top of this, sex and gender differences in the manifestation of the disorder further complicate the matter.

Genetics plays a major role in the development of ASD, but the impact of environmental factors cannot be understated. Even if some ASD-specific alleles have already been identified, the exact genotypic profile is still to be mapped. The only fact that is clear so far, is that the mode of inheritance is not Mendelian, with identical mutations potentially being associated with highly varying phenotypes. De novo mutations further play a significant role in the development of the disorder along with the identified inherited mutations.

Generally, the age of diagnosis for ASD is relatively high since, at the time of writing, the diagnosis is still set on a purely behavioral basis. On average, autistic people receive their diagnosis after the age of 3 or 4. This is, however, not always the case. As will be discussed later, one of the big challenges with female autism lies in the comparatively higher age of diagnosis than for males.

The Y chromosome

ASD is considered to be more prevalent among males compared to females, with the ratio being ca. 4.5:1 according to different sources. The cause for this difference is still quite poorly understood. Notwithstanding, several theories have been proposed, with the most common ones being the potential involvement of the X-chromosome in the etiology of the disorder, and the effects of hormonal influences and epigenetic modifications in utero.

The typical “male-like” or the most neutral phenotype that probably directly comes to one’s mind in association with the concept of ASD is the classical dyad: “difficulties in social communication and restricted and repetitive behavior, interests or activities”. What could be interesting on a side note is that atypical language development, historically associated with the diagnosis of ASD, has recently been removed from the criteria. Since the language skills vary so greatly between patients, it is now referred to as a co-occurring condition.

What sets us apart

So, one may wonder what makes autism in girls and women special. Another question that arises is if ASD has a true male prevalence or if bias in diagnostic criteria artificially shift the ratio. Moreover, should female autism be classified as a separate condition?

Many questions around this topic still remain unaddressed and the findings are extremely complex and quite inconsistent. The complex interplay between sex/ gender differences and autism and the male bias in the prevalence of the disorder has stimulated many research projects in recent years, ranging from clinical and neurobiological to etiological studies.

In light of the fact that ASD already is highly heterogeneous when it comes to genetic patterns, it might be difficult to distinguish a female-specific genetic characteristic in patients with ASD. Moreover, de novo mutations have been proposed to have a more substantial role in autism compared to inherited ones. An interesting phenomenon is the association of paternal age with increased risk of de novo mutations correlating with the increased risk of autism only in females, but not in males.

When it comes to phenotypic and behavioral representation, studies comparing male and female phenotypes have revealed a number of typical differences. Generally, females usually tend to have more comorbid neurological abnormalities, less RRBI (“restricted, repetitive patterns of behavior, interests, or activities”), together with an overall higher level of intellectual impairment. At the same time, females exhibit better expressive behaviours despite similar social difficulties and different manifestations of friendship-related behaviors.

There are a number of studies suggesting additional characteristic features that may be more associated with the female phenotype, such as pathological demand avoidance. Generally, females require a greater genetic load and more co-occurring conditions in order to reach the threshold for diagnosis compared to males, often referred to as the “female protective effect”. This is also when one of the main problems with female autism becomes significant: the diagnosis-setting is more complicated and therefore usually occurs later compared to males, with a high risk of the condition going completely unrecognized.

It should be noted that modern studies comparing the phenotypic differences between the sexes with ASD use the same diagnostic criteria and generally do not take into account the social gender differences. Therefore, they may lack sensitivity for the female ASD phenotype.

Thus, the results of these studies can not be considered completely reliable and to what extent the aforementioned differences may be a product of the male bias seen in ASD remains to be determined.

Diagnosing and understanding female autism

What could also be considered special with female autism is that even within this group, there are subgroups with highly varying traits. Female patients with classical male-like traits usually develop a cognitive delays which allow for a relatively early diagnosis and therefore early interventions.

However, the main diagnostic challenge lies in the subgroup of the higher functioning female patients with atypical, compensated, or camouflaged characteristics. These patients are more likely to be misrecognized, and tend to have a much older age of diagnosis om comparison to those with more male-like traits. Taking this fact into account, some studies suggest that the actual male:female ratio in the prevalence of ASD is lower than previously thought, within the interval of 2–5:1. Thus, even among the female population, ASD is a common, albeit under-recognized, problem.

This can also be seen from a different perspective. Some studies present the view that the comparatively older age of diagnosis in females is not the main problem per se. It is not that women are prone to be under-recognized, but rather that their need for a clinical diagnosis is less pronounced compared to males, or that this need arises at a later developmental stage. This could simply indicate that females with ASD generally tend to be more socially adaptable than males and manage without professional intervention for a longer time.

This is where the dilemma arises: to diagnose or not to diagnose? Where is the line between autistic and non-autistic in this case? On one hand, a later diagnosis can decrease the timeframe for getting effective intervention while the early identification of ASD may help to mitigate the risks associated with the disorder, for example by identifying the patient's special needs and providing appropriate interventions. At the same time, the lack of a diagnosis may help one escape stigma and promote a feeling of security and identity and thus improve the overall quality of life.

The late diagnosis is, in any case, a serious concern for the wellbeing of highfunctioning women with ASD. Many latediagnosed high-functioning female patients report acting “normal” throughout their life, and having to camouflage the autistic traits in social situations, something known as social mimicry. For the majority, health professionals had not noticed that their symptoms might be caused by ASD, as these symptoms had been masked by other co-occuring mental conditions, such as anxiety, depression, and eating disorders.

“Four to five years of depression and anxiety treatment…years of talking therapy…and not once did anyone suggest I had anything other than depression”, as one of the participants recall in the study by Mandy et al.

While timely identification and intervention of female ASD is important, one should also remember not to pathologize or stigmatize the women who, even possessing high-risk autistic traits, are able to manage on their own and/or do not meet the criteria for a clinical diagnosis or functional impairment.

The conclusions

So, what can be concluded from the existing studies is that the phenomenon of the late diagnosis of female autism can be explained both by the specific features of the female ASD phenotype and also the modern male-based diagnostic system.

Many questions about female autism and autism in general remain unanswered. While these issues and gender bias remain relevant, it is possible that different diagnostic criteria may arise for the two sexes in the future, so maybe we will then indeed once and for all draw a line between the male and female phenotypes?

Yet, one of the most important and obvious takeaways would be that autism is a continuous spectrum, rather than a binary condition and that the line between pathology and norm can be extremely thin, especially when it comes to female autistic traits.

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