**3. Environmental risk factors**

Fragile X syndrome [28]. However, fragile X mutations may be found in 7-8% idiopathic au‐ tism patients [77]. FMRP is a selective RNA-binding protein; it transports RNAs to dendrites and regulates local translation of synaptic mRNAs as a response to activation of metabotropic glutamate receptors. This protein is considered to have a role in synaptic plasticity and devel‐ opment of synaptic connections between neural cells. Impaired mRNA translation in the ab‐

Autism risk is higher than general population in neurofibromatosis, tuberosclerosis, or Cow‐ den Syndrome, a rare syndrome which is characterized by multiple tumor-like growths called hamartomas and affects the intellectual abilities. These diseases develop due to domi‐ nant mutations in tumor suppressor genes NF1, TSC1/TSC2, and PTEN. Mutations in these autism-associated genes affect synaptic protein level by impairing cellular translation. Alter‐

Angelman syndrome and Prader-Willi syndrome mainly develop due to genetic deletions in 15q11-q13 locus or disomy (condition where two copies of a chromosome comes from a sin‐ gle parent) belonging to a single parent [79]. Deficiencies in paternal genes cause Prader-Willi syndrome; Angelman Syndrome which is more commonly associated with autism may be caused by deletion or mutation in maternal ubiquitin protein ligase gene UBE3A or ATP10C [80, 81]. Other rare single gene defects associated with autism are found in Wil‐ liams Syndrome, Sotos Syndrome, hipomelanozis Ito, and Moebius Syndrome [82-85].

Since serotonin reuptake inhibitors have favourable effects on rituals and routines in autistic individuals and serotonin transporter gene has important role in serotonergic neurotrans‐ mission, serotonin transport gene has been investigated as candidate gene in autism. One of the polymorphisms examined in this gene is the one that is formed by long (L) and short (S) alleles owing to different number of insertion/deletion repeats of a 44-base-pair sequence in the transcriptional control region. Cook and his colleagues [86] reported a significant rela‐ tionship between autism and short allele while Klauck and his colleagues [87] revealed a significant relationship between autism and long allele. A subsequent study did not dupli‐ cate these findings [88]. A different polymorphism investigated at the serotonin transport gene is the variable number of tandem repeats (VNTR) polymorphism due to repeat of a 17 base-pair region at 2nd intron of the gene 9,10, and 12 times. This polymorphism could not be related to autism [89]. Evidence has been accumulated on the relationship of many sero‐ tonin genes, notably serotonin receptor (HTR) 1B, HTR2A, HTR3A, and HTR5A, with au‐

Glutamate is the main excitatory neurotransmitter associated with cognitive functions such as memory and learning. Autism has been hypothesized as a hypoglutamatergic disorder by virtue of neuroanatomic studies and the similarities glutamate antagonists generate in healthy persons [94]. It has been demonstrated in genome scanning studies that one of the candidate regions for autism is 6q21 region [95]. This region contains glutamate receptor 6 (GluR6) gene. A study by Jamain and his colleagues [96] found a significant relationship be‐ tween GluR6 gene and autism. It has been thought that GluR6 dysfunction may contribute the deterioration of communication and learning process in autism and any dysregulation of GluR expression may be related to an increase in the rate of epileptic disorder in autistic

sence of FMRP leads to an alteration in protein-synthesis-dependent plasticity [28, 78].

ations in protein level results in abnormal synaptic functions [28].

326 Recent Advances in Autism Spectrum Disorders - Volume I

tism [90-93].

In addition to effects of a number of genes of small effect, various environmental factors are believed to be responsible for susceptibility to autism. Development of autism seems to be dependent on interaction of susceptibility genes with each other and with the environment [110]. It has been claimed that among environmental factors related to autism are toxins (en‐ vironment-polluting matters, insecticides, thimerosal in vaccines, lead), viruses (prenatal ex‐ posure to influenza, rubella, and cytomegalovirus infections), and premature birth with premature retinopathy [111-115]. Although there has been a debate regarding the relation‐ ship of autism with thimerosal in measles, rubella, and mumps vaccines; further careful evaluation of data could not support the relationship between autism and vaccines [116, 117]. The relationship between exposure to Rh immune globulin, which contained the pres‐ ervative thimerosal until 2001 in the United States, and autism has also been investigated; however, no significant association has been revealed between exposure of antepartum RhIg preserved with thimerosal and an increase in risk of autistic disorder. The latter findings are in accordance with the consensus that exposure to ethymercury in thimerosal is not the cause of increased prevalence of autism [118].

Other factors related to intrauterine environment are maternal hypothyroxinemia [119], ma‐ ternal influenza [120], and high levels of sex hormone exposure related to infertility treat‐ ment [121].Thalidomide and anticonvulsant exposure in pregnancy is correlated to an increase in autism risk [122, 123]. Rasalam and his colleagues [124] showed that 8.9% of chil‐ dren exposed to sodium valproate in intrauterine life later develop autistic spectrum disor‐ ders such as autism or Asperger syndrome. Recently, Hadjikhani [125] have suggested that serotonin reuptake inhibitor use in pregnancy increases autism risk by causing hyperseroto‐ ninemia and indirectly affecting amygdala and oxytocin levels.

portant for social cognitive function. Therefore, it has been suggested that damage in orbito‐ frontal region may cause main deficits in autism that underlies inadequate responses to other people's mental status and that impairs self-organization of social-emotional behav‐ iours [137, 138]. Prenatal stress may impair brain development by many mechanisms includ‐ ing: a) fetal hypoxia due to reducing of uterine and placental circulation, b) impairment of hypothalamus-hypophysis-adrenal axis by stimulation of secretion of maternal stress hor‐ mones that can cross placenta, c) generation of pregnancy and birth complications, d) epige‐

Genetic and Environmental Factors in Autism

http://dx.doi.org/10.5772/53295

329

It has been reported that exposure of environmental stress factors at 21-32nd weeks with a prominent peak at 25-28th weeks is associated with an increase in possibility of development of autism [134]. When data regarding progressively worsening developmental process are considered [139], it has been argued that postnatal environmental exposures in genetically susceptible children may be etiologically important [140]. Expression and the impact of many genes is influenced by environmental factors. Thus, the effect of environmental factors in etiology of autism is believed to be indirect by influencing genetic functions [140, 141].

In line with studies aimed to understand the neurobiology of autism, the presence of altera‐ tions in regional brain anatomy and functional neuronal communicative network has been currently proved. The main role among factors underlying abnormal brain development be‐ longs to genetic factors. Evidence regarding that autism is a primarily genetic disorder is progressively increasing. Although environmental factors alone can explain a few cases, they are believed to increase autism risk by interacting with genetic susceptibility. Although data collected so far contribute to the ever-increasing body of knowledge about neurobiolo‐ gy of autism, they do not influence diagnosis and treatment of autism. Use of these data is aimed in future in differentiation of autism from other neurodevelopmental disorders and

1 Ankara Pediatric & Pediatric Hematology Oncology Training and Research Hospital,

2 Gazi University Medical Faculty, Child and Adolescent Psychiatry Department, Ankara,

netic effects on expression of stress response-related genes [137].

**4. Conclusion**

**Author details**

Turkey

Esra Guney1\* and Elvan Iseri2

in diagnostic and therapeutic processes.

\*Address all correspondence to: dresraguney@gmail.com

Child and Adolescent Psychiatry Department, Ankara, Turkey

In many studies, the pre-perinatal complication rates in autistic disorder have been studied and a higher pregnancy-related complication rate has been demonstrated in autistic children [126, 127]. In a recent meta-analysis [128], the most strong risk factors for autism were ad‐ vanced maternal and paternal age, maternal gestational hemorrhage, gestational diabetes, ma‐ ternal prenatal drug use (particularly psychoactive drugs), and birth in a foreign country following immigration of mother. Both advanced maternal and paternal age are associated with autism. The underlying mechanism is unclear. Maternal age may be related to autism due to increased risk of chromosomal abnormalities in ova of increased age or because of unstable trinucleotide repeats [128]. The relationship between paternal age and autism is considered to result from imprinted genes (genes showing different expression patterns depending on the parent it originates), de novo spontaneous mutations that accumulate with advancing age in spermatagonia, or confounder effects of sociocultural environmental factors [129]. Another po‐ tential risk factor for autism is maternal birth abroad [130]. It has been suggested that this factor may result from absence of immunization that mother would develop against widespread in‐ fectious agents of the country in which she gives birth. Another possible explanation is about the potential role of maternal stress because of immigration [131]. A more detailed investiga‐ tion on the relationship between mother immigration and autism is needed. It has been demon‐ strated in some studies that gestational hemorrhage increases autism risk by causing fetal hypoxia [130]. Among other factors considered to cause hypoxia and associated with increased autism risk in some studies are fetal distress, maternal hypertension, prolonged labor, cord complications, low Apgar score, and cesarean section [132]. Gestational diabetes is another risk factor, with unknown biologic mechanism [128].

Some studies demonstrated that prenatal stress increases autism risk [133, 134]. However, due to limitations that these studies are based on retrospective expressions of mothers and these mothers are generally susceptible for experiencing stressful life events outside preg‐ nancy period, these studies need to be supported by further studies. Spontaneous abortions, pre-perinatal complications, congenital anomalies, and neurologic/immunologic abnormali‐ ties are among the negative impacts of prenatal stress. Prenatal stress also has various nega‐ tive effects on brain development such as a delay in myelinization, an increase in sensitivity of amygdala to glucocorticoids, and abnormal development in dopaminergic system [135-137]. Autistic disorder is associated with a functional derangement in brain areas relat‐ ed to social cognitive functions in which amygdala and orbitofrontal cortex plays an impor‐ tant role. Orbitofrontal cortex is susceptible to effects of prenatal stress especially in the middle of gestation. Normal functioning of orbitofrontal cortex - amygdala axis is very im‐ portant for social cognitive function. Therefore, it has been suggested that damage in orbito‐ frontal region may cause main deficits in autism that underlies inadequate responses to other people's mental status and that impairs self-organization of social-emotional behav‐ iours [137, 138]. Prenatal stress may impair brain development by many mechanisms includ‐ ing: a) fetal hypoxia due to reducing of uterine and placental circulation, b) impairment of hypothalamus-hypophysis-adrenal axis by stimulation of secretion of maternal stress hor‐ mones that can cross placenta, c) generation of pregnancy and birth complications, d) epige‐ netic effects on expression of stress response-related genes [137].

It has been reported that exposure of environmental stress factors at 21-32nd weeks with a prominent peak at 25-28th weeks is associated with an increase in possibility of development of autism [134]. When data regarding progressively worsening developmental process are considered [139], it has been argued that postnatal environmental exposures in genetically susceptible children may be etiologically important [140]. Expression and the impact of many genes is influenced by environmental factors. Thus, the effect of environmental factors in etiology of autism is believed to be indirect by influencing genetic functions [140, 141].
