Autism is one of the most genetically influenced neuropsychiatric disorders. However, its detailed genetic basis is far from being clear. Genome-wide association studies have revealed a number of candidate genes, mostly related to synaptogenesis and various neuroendocrine pathways. In our study we have focused on oxytocin (OT), oxytocin receptor (OXTR), GABA receptor gamma 3 (GABRG3), neuroligin (NLGN4X), and reelin (RELN). After signed consent, 90 autistic boys and 85 healthy controls were enrolled in the study. Polymorphisms of OT (rs2740204), OXTR (rs2228485), GABRG3 (rs28431127), and NLGN4X (rs5916338) were analyzed using restriction fragment length polymorphism. (GGC)n STR polymorphism in the 5' UTR of the RELN gene was genotyped using fragment analysis. The only significant association in autistic boys in Slovakia was found with higher number of GGC repeats in the RELN gene (P=0.001) potentially explaining lower RELN levels in blood and brain of autistic patients.

Autism spectrum disorders (ASDs) are neurodevelopment disorders which are characterized by impairments in the following core domains: social interaction, language development, verbal/nonverbal communication, and repetitive and restricted behaviors. The androgen theory of autism proposes that autism spectrum disorders develop in part due to elevated fetal testosterone levels, which correlate with a number of autistic traits. The present study evaluates androgen and estrogen levels in saliva as well as polymorphisms in genes for androgen receptor (AR), 5-alpha reductase (SRD5A2), and estrogen receptor alpha (ESR1) in the Slovak population of prepubertal (under 10 years) and pubertal (over 10 years) children with autism spectrum disorders. The examined prepubertal patients with autism, pubertal patients with autism, and prepubertal patients with Asperger syndrome had significantly increased levels of salivary testosterone (P Ͻ 0.05, P Ͻ 0.01, and P Ͻ 0.05, respectively) in comparison with control subjects. We found a lower number of (CAG) n repeats in the AR gene in boys with Asperger syndrome (P Ͻ 0.001). Autistic boys had an increased frequency of the T allele in the SRD5A2 gene in comparison with the control group. The frequencies of T and C alleles in ESR1 gene were comparable in all assessed groups. The modulating influence of studying genotypes on the effect of testosterone could provide insight into the pathogenesis of autism spectrum disorders.

Spatial abilities are known to be related to testosterone levels in men. Polymorphisms of genes related to androgen metabolism, however, have not been previously analyzed in association with spatial abilities. Our study analyzes genetic polymorphisms of androgen receptor (AR), aromatase (CYP19), and 5-alpha reductase (SRD5A2) in relation to mental rotation and spatial visualization in prepubertal intellectually gifted boys. DNA samples of 36 boys with an average age of 10.0 ± 0.7 years and an IQ higher than 130 were isolated from buccal cells in saliva. DNA was subsequently used for amplification by PCR. The CYP19 C1558-T polymorphism and SRD5A2 A49T polymorphism were determined by RFLP analysis, and the AR (CAG)n polymorphism was determined by fragment analysis. Salivary testosterone levels were measured with radioimmunoassay. Spatial abilities (mental rotation and spatial visualization) were assessed using standard psychometric tests. AR and CYP19 polymorphisms were not associated with spatial abilities. Heterozygotes in A49T polymorphisms (AT) of SRD5A2 had significantly better results in both mental rotation and spatial visualization tests compared to AA homozygotes. TT homozygotes were not found. The T allele of A49T polymorphism of the SRD5A2 was reported to have a 5-fold increased activity in comparison to the A allele. AT heterozygotes outscored AA homozygotes in tests of spatial performance. Since dihydrotestosterone – the product of 5-alpha reductase catalyzed reaction – has a higher affinity to AR, this might indicate a potential molecular mechanism for the influence of SRD5A2 polymorphism on spatial abilities in intellectually gifted prepubertal boys.

Fetal testosterone significantly influences the brain development. It affects number of neurons and conformation of dendritic spines within the sexual dimorphic preoptic area in the hypothalamus. Excessive testosterone levels in utero possibly contribute to the masculinization of the brain. Evidences of these facts are plausible in the anatomic field as well as behavioral effects both in rat models and in humans. Rats exposed to excessive testosterone doses in utero show masculinized brain anatomy and behavior, such as better spatial visualization performance typical for males. In humans, congenital adrenal hyperplasia that causes elevated androgen level possibly results in masculinized behavior observed in these individuals. There are reasons for the theory of the connection existence between testosterone influence on the brain functions and the pathogenesis of neurodevelopmental disorders. In this review, pathogenesis of autism, the most genetic neurodevelopmental disease is discussed. Autism is a disease with broad genetic heterogeneity and polygenic inheritance. Autism associated genes are localized throughout the genome, with the chromosome 7q most frequently involved. One of these genes encodes reelin protein that is crucial for neuronal migration in the developing brain. The connection between androgens, neuronal migration and neurodevelopmental disorder pathophysiology is also discussed.