Etiology – causes of the disease

Mgr. Hana Celušáková, PhD.

What is the cause of autism?

Despite the many unanswered questions that our research center is also looking for, we can say with certainty that Autism Spectrum Disorders have a strong genetic basis. They are thought to arise from the interaction between an individual’s genetic profile and the environmental factors to which he or she has been exposed during the prenatal and perinatal periods.

Genetic factors

It has been known for long that ASD are probably the most genetically determined neurodevelopmental disease(s). It is assumed that the genetic causes of ASD are different; for a certain group of individuals, one mutation with a large effect is enough for the disease and vice versa, while the vast majority of cases are about the accumulation (increasing) effect of a large number of mutations with little effect in interaction environment (Bourgeron, 2015).

ASD are probably not a single disease, but rather a number of etiologically distinct conditions with different pathophysiological mechanisms of origin , that lead to similar behavioral manifestations (de la Torre-Ubieta, 2016).

In the last decade, genetic studies have been successful in identifying:

• several strong candidate genes,
• rare genetic variations, including inherited and de novo mutations, and
• copy number variations (CNVs) associated with autism (Lyall et al., 2017).

Although the genetic diversity between individuals with ASD is large, most responsible – mutated genes (epigenomes) affect the development of brain cells and their connections in prenatal life . Thus, these genes affect neuronal proliferation, migration, as well as synapse formation and plasticity, neural pathway and networking, connectivity, and function (Kiser, Rivero, & Lesch, 2015).  This can result in incorrect formation, placement and maturation of neurons and their connections in certain areas of the brain.

Syndrome and idiopathic autism

A distinction has been made in the relevant literature between syndrome autism and idiopathic autism. The term syndrome (or secondary) autism is used when the presence of a genetic syndrome is confirmed in a child and at the same time ASD manifestations are present. Autism syndrome is represented in only about 10% of ASD causes, the most important genetic syndromes associated with autism are:

• Rett syndrome,
• Fragile X chromosome
• Tuberous sclerosis.

Examination of autistic manifestations in individuals with syndromic and idiopathic autism has revealed significant differences between the developmental, behavioural, and cognitive profiles of these groups (Moss & Howlin, 2009).

Most genetic syndromes are accompanied by cognitive deficits. Individuals with more severe intellectual disorder can meet certain criteria for ASD only because they have not yet reached the level of development required to manifest expected types of social behaviour and play (Moss & Howlin, 2009). Similarly, some manifestations of narrowly defined and repetitive behaviour are non-specifically present in ASD as well as in mental deficits with other causes (Verplanken, 2018).

Environmental risk factors

As already mentioned, just as genes determine the origin and development of neurons and their connections, factors of the internal and external environment can modify this programmed development. Environmental risk factors can be divided into two main groups. The first group includes the impact of the prenatal and perinatal period, the second deals with the impact of the environment.

Influence of prenatal and perinatal period

In recent decades, risk factors during the prenatal and perinatal periods and their impact on increasing the child’s risk of developing ASD have been intensively studied.

Age of parents

A common research issue is the impact of higher age of parents on the risk of developing ASD. Meta-analyses have confirmed that the increasing age of both mother and father is independently associated with an increase in risk (Hultman, Sandin, Levine, Lichtenstein, & Reichenberg, 2011; Sandin et al., 2012). It is assumed that given the increasing risk of ASD with older fathers, there is a higher rate of de novo mutations and epigenetic changes. The mother is also at increased risk of genomic mutations, there is longer exposure to environmental factors, there is increasing likelihood of medication use, and increasing risk of complications during pregnancy and perinatal period (Idring et al., 2014).

The immune system

The transmission of immune substances produced by the mother during infection through the placenta to the child is an important adaptation mechanism that provides short-term immunity to the immunologically naive fetus. However, the maternal immune system mediates the transmission of antibodies regardless of specificity, and in addition to protective antibodies, pathologically important maternal autoantibodies can also occur, which affect the intrauterine development of the child’s brain and critically influence neurogenesis. Both infection during pregnancy and the occurrence of autoimmune diseasecan increase maternal autoantibody production.

Research shows an increased risk of ASD if a pregnant woman has been hospitalized for an infection, regardless of the trimester in which she became ill.

An increased incidence of autoimmune diseases has also been demonstrated in parents of children with ASD, in mothers especially:

• type I diabetes
• idiopathic thrombocytopenia,
• purpura,
• myasthenia gravis,
• rheumatic fever,
• celiac disease

although the incidence of these diseases in the study sample was relatively small (Atladóttir et al., 2009; Keil et al., 2010).

Medication, smoking, drugs and nutrition during pregnancy

Like antibodies, some drugs can cross the child’s placenta and blood-brain barrier. Studies have shown that antiepileptics (valproic acid) and antiasthmatics (especially B2AR) given during pregnancy increase the risk of ASD. The relationship between smoking or alcohol consumed during pregnancy and ASD has not been established. Several studies have shown an association between an increased risk of ASD and obesity in pregnancy or a sharp increase in weight during pregnancy, but these studies have many methodological shortcomings (Rivera, Christiansen, & Sullivan, 2015).

Low gestational age, low and high birth weight, childbirth section

Many studies have confirmed an increased risk of ASD in preterm infants, with the risk increasing with lower gestational age at delivery, the need for postpartum lung ventilation, and intracranial hemorrhage (Joseph et al., 2017; Kuzniewicz et al., 2014). The risk of ASD also increased in children born smaller to their gestational age (less than the 5th percentile) by the 34th week of pregnancy; in contrast, in between 39th and 41st week of pregnancy, 16% risk increase for ADS was recorded for children larger to their gestational age (above 90th percentile) (Moore, Kneitel, Walker, Gilbert, & Xing, 2012). Sectional birth has been associated with a moderate increase in odds ratio, but given the rising trend of sectional births, which is around 30% in developed countries including Slovakia, it can have a significant impact on society (Curran et al., 2015).

Environment

In the last ten years, several studies have shown the negative effects of increased exposure to air pollution during pregnancy and the child’s first year of life. In particular, exposure to elevated concentrations of polycyclic aromatic hydrocarbons, small dust particles (PM2.5) and nitrogen oxides increases the risk of ASD (Volk, Lurmann, Penfold, Hertz-Picciotto, & McConnell, 2013; Weisskopf, Kioumourtzoglou, & Roberts, 2015).

The role of inflammation and disorders of immune mechanisms in the development of ASD

According to current hypotheses, the cause – or at least one of the factors – involved in the development of ASD is inflammation and impaired immune system function. ASD are more common in families where a member suffers from an autoimmune disease (e.g., lupus erythematosus, thyroiditis), asthma, or allergies. Research has shown that the presence of impaired immunity in the family poses a higher risk of ASD, especially in male children.

Studies show that the immune system significantly interferes with the development of the nervous system and brain functions, especially through cytokines – substances involved in immune responses. If the future mother is affected by a viral or bacterial infection during pregnancy, the immune system is activated, and the body responds by producing pro-inflammatory cytokines. These are transmitted through the placenta into the child’s body and disrupt the process of formation and maturation of nerve cells, as well as the formation of their interconnections – synapses. The transfer of substances to the fetal brain is aided by immaturity and increased permeability of the blood-brain barrier, which should protect the brain from unwanted substances. The existence of specific antibodies against the brain structures of the child’s brain has also been demonstrated. Impaired brain development with behavioral manifestations is an effect of these immune molecules during some (yet not specified) phases.

It has been found that some children, who have been diagnosed with ASD during their lifetime, have had elevated levels of multiple cytokines at birth compared to control children. These results suggest that impaired immune function is present in children with ASD even before ASD is diagnosed, and may be thought to be involved in the development of an autistic disorder..

Activation of the mother’s immune system can trigger impaired function of the child’s immune system, which persists throughout life. It can manifest itself in a number of different ways, for example in the form of increased levels of pro-inflammatory substances, allergies, or insufficient immunity.

Deviations in immune functions could also be a link between genetic and environmental risk factors for ASD, as disruption of immune processes can be the result of immune-related gene disorders, but can also be caused by environmental factors. For example, the effects of heavy metals or a lack of certain vitamins can cause changes in the baby’s intestinal microbiota. Subsequently, the altered microbiota may adversely affect the functioning of baby’s immune system.

Although many findings point to the role of impaired immune processes in the development of ASD, the exact mechanism of action has not yet been elucidated.

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