**Acknowledgements**

difference in susceptibility between genders. However, it is likely that many of the differences arise because of hyperexpression or hypoexpression of genes in pseudo autosomal regions that escape X inactivation, thereby being similarly expressed in men and women with a typical karyotype. The addition or loss of an X or Y chromosome, which leads to altered protein levels that are atypical or typical for both men and women, cannot explain the gender difference in ASD. However, some genes on the X chromosome are not in these regions and have no corresponding functional alleles on the Y chromosome, and escape X inactivation in some

Moreover, the *SRY* gene is mapped in a region on the Y chromosome and can also directly regulate the gene monoamine oxidase A (MAOA) that is located in the Xp11.3 region and encodes a key enzyme in the breakdown of catecholamines and other monoamines. SRY can directly affect transcription in the brain [159]. As individuals diagnosed with ASD are found with changes in catecholamine and metabolite levels in the dependent activity MAO-A and autism severity is associated with child and maternal MAO-A genotypes, the disruption of the synthesis of catecholamines may be modulated by the gender-specific *SRY* gene associated with ASD. Several genes on the Y chromosome are expressed in the brain. Since this leads to a specific expression of gender in the brain, these genes, some of which play a role in catecho‐ laminergic functions, are candidate genes for the increased susceptibility to ASD in males. An investigation of the role of these genes will possibly clarify the gender-specific mechanisms

underlying ASD and thus help in the understanding of the etiology of ASD [31, 125].

families, which are most representative of ASD in the general population [125].

give support to the patients and families in order to improve their quality of life.

Another factor that may contribute to the skewed gender ratio in ASD is parental age. Increased parental age is known to increase the risk of a child with ASD [45] and there are some indications that parental age affects the gender ratio of children diagnosed with ASD [125]. The male-female ratio dropped from 6.2:1 in under 30-year-old parents to 1.2:1 in parents older than 44 years old [8]. This finding may be related to the higher frequency of *de novo* mutations which are more common in older men and seem to play a minor role in the gender bias in the incidence of familial ASD. However, it is still not clear whether this effect is true for simplex

Thus, considering all that has been studied about ASD, it is difficult to conduct a comprehen‐ sive analysis about the etiologic complexity, without running the risk of over or under estimating some factors. On consulting the available literature on ASD, there is an impression that all can cause autism. The truth is that everything that affects the CNS system can interfere with mental health and this opens up a universe of possibilities. The gene expression, immune susceptibility and environmental stressors, even those that affect men more than women, need to be organized using a multidisciplinary approach in order to explain what actually happens in normal CNS development within the first three years of life. From there, the goal is to have a method of comprehensively analyzing each particular case to try to obtain specific treatment. While this is not available, it is interesting to investigate the most common risk factors and

circumstances [125].

334 Autism Spectrum Disorder - Recent Advances

**13. Conclusion**

This study was supported by grant nº2013/14919-6, São Paulo Research Foundation (FAPESP) and Faculdade de Medicina de São José do Rio Preto (BAP-FAMERP)
