سندرم های ژنتیکی، بیماری های مادری و عوامل پیش از تولد مرتبط با بیماری های طیف اوتیسم (ASD) Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD)

INTRODUCTION ASD is defined by the DSM 5 as a neurobehavioral disorder manifested by persistent deficits in social and communication interaction, deficits in developing, understanding and maintaining relationships, as well as abnormal and fixed interests and repetitive behavior (Kogan et al., 2009; American Psychiatric Association, 2013). Symptoms must be present at early childhood and interfere with daily function. ASD is 4 times more prevalent in males than in females, but in experimental animal models where ASD is induced by neuro-teratogens, there are little gender differences. Mental impairment is common among children with ASD, and a variety of learning and behavioral changes are also prominent in autistic animals. The etiology is diverse, largely unknown, and seems to be the result of genetic and environmental interaction (Kogan et al., 2009; Tchaconas and Adesman, 2013). Environmental exposures are increasingly being recognized as potential risk factors for ASD, and the possibility that the prenatal and perinatal environment affect fetal programming is an expanding direction for research. Prenatal environment include maternal use of medication, maternal infection and inflammations, and prenatal or perinatal exposure to various substances such as alcohol and heavy air pollution. Of special relevance are prematurity and maternal diabetes. Epidemiology The reported prevalence of autism has increased dramatically over time, from 4 to 5 cases per 10,000 in 1966 to ∼۱% today (Kogan et al., 2009; Tchaconas and Adesman, 2013). The increase is thought to result increased public awareness, changing diagnostic standards, earlier age of diagnosis, and development of treatment modes. It was also shown that many of the children and adults who were previously diagnosed as having mental retardation meet the DSM 4 and DSM 5 diagnostic criteria of ASD (Shattuck, 2006; Elsabbagh et al., 2012). Some increase, however, may result from “new” environmental causes such as pollution and changing life style. In the US, for example, the autism and developmental disabilities monitoring network (ADDM network) found in children aged 8 years in 2008 an increase from 1/150 in year 2000 to 1/88 in 2008 and in the 2010 monitoring the rate increased to 1/68 children (Autism Developmental Disabilities Monitoring Network Surveillance Year Principal Centers for Disease Prevention, 2012). In Israel, judging from the number of children who received childhood disability benefits by the Israeli Insurance Institute because of ASD, the cumulative incidence at 8 years of age at 2011 has increased 10-folds from 1991 and reached 0.49% with a ratio of males/females of about 5 (Raz et al., 2015b). The more recent global prevalence of autism was estimated to be 0.62% (Autism Developmental Disabilities Monitoring Network Surveillance Year Principal Centers for Disease Prevention, 2012; Elsabbagh et al., 2012). In spite of a wide variation in prevalence between the studies, the authors conclude that there is no evidence of a significant impact of ethnic or socioeconomic factors on the rate of ASD. It can be presumed that in developed countries the great progress in the diagnosis and treatment of ASD reached a relatively steady state at least in the last 10 years. However, both the incidence and prevalence of ASD continued to rise, implying that some of the increase results from a true increase in ASD rate. For example, in the UK in 1988–۹۲ the incidence was 0.40/10,000 person years and it raised to 2.98/10,000 person years in 2000–۲۰۰۱ (Smeeth et al., 2004) and an in the US an increase was reported in the same states in the US between 2000 and 2008 and a further increase between 2008 and 2010 (Fombonne, 2009; Autism Developmental Disabilities Monitoring Network Surveillance Year Principal Centers for Disease Prevention, 2012). An increased incidence was also reported in Israel (Davidovitch et al., 2013). If this is correct, it may largely result from prenatal environmental causes because genetic, ethnic, socioeconomic, and geographic factors did not change significantly during that time. Recent meta-analysis of seven studies including 1,140,210 children evaluated the association between inter-pregnancy interval and increased risk of ASD, and found OR of 1.9 for interval <12 months and 1.37 interval >5 years. Proposed mechanisms included folate deficiency, maternal stress, and sustained post-partum inflammation from previous pregnancy for short interval and infertility, unintended pregnancy, and inflammation for long one (Conde-Agudelo et al., 2016). Genetic predisposition was offered by Darbro et al. who found decreased risk of cancer among ASD patients. Despite increased prevalence of rare coding single-nucleotide variations in oncogenes they tend to develop fewer neoplasms. They hypothesized that the protective effect may be due to defects in cellular proliferation and aging (Darbro et al., 2016). The prenatal causes of ASD can be divided into environmental chemicals (i.e., drugs such as valproic acid, thalidomide, misoprostol; alcohol, cocaine, and toxic metals taken by the mother during pregnancy), exposure to particulate matter air pollution of up to 2.5 micron in diameter (PM2.5), maternal infections during pregnancy (i.e., rubella, CMV), maternal and fetal inflammation (Fox et al., 2012) and maternal diseases (i.e., diabetes mellitus), including autoimmune diseases (Brown et al., 2015) or allergic diseases such as asthma (Croen et al., 2005). In addition, perinatal factors such as perinatal asphyxia, IUGR, RDS, and others were also associated with an increase in the prevalence of ASD (Gardener et al., 2011). Numerous mechanisms for ASD have been offered, based also on experimental animal models. In addition to complex genetic susceptibility, epigenetic changes have also been proposed (Kogan et al., 2009). Other mechanisms are: immune dysregulation that include abnormal levels of cytokines and growth factors and various fetal and maternal antibodies to brain tissue (Rossignol and Frye, 2012). Additional proposed mechanisms are increased oxidative stress, mitochondrial dysfunction, abnormalities in brain serotonin, abnormal white matter connectivity, decrease number of Purkinje cells in the cerebellum, and neuronal migration defects (Billeci et al., 2012; Grabrucker, 2012; Rossignol and Frye, 2012). The purpose of the present review is to summarize the data describing genetic syndromes with ASD like behavior and the maternal diseases associated with increased prevalence of ASD. In addition, we summarize the antenatal injurious factors that are known to be related to the etiology and pathogenesis of ASD.