Epigenetics of autism is the study of heritable changes in gene expression that do not alter the genetic code but may contribute to the development and variability of autism spectrum disorder (ASD). Autism tends to have a strong correlation with genetics along with other factors. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression, which includes mechanisms such as cytosine regulation and post-translational modifications of histones. The connection between epigenetics and autism is not fully known. Of the 215 genes contributing, to some extent in autism, 42 have been found to be involved in epigenetic modification of gene expression.
Diagnosis is based on observation of behavior and development. Many, especially girls and those who have fewer social difficulties, may have been misdiagnosed with other conditions. Males are diagnosed with autism four to five times more often than females. The reasons for this remain predominantly unclear, but current hypotheses include a higher testosterone level in utero, different presentations of characteristics in females (leading to misdiagnosis or underdiagnosis) compared to males, and gender bias. Clinical assessment of children can involve a variety of individuals, including the caregiver(s), the child, and a core team of professionals (pediatricians, child psychiatrists, speech-and-language therapists and clinical/educational psychologists). For adult diagnosis, clinicians identify neurodevelopmental history, behaviors, difficulties in communication, limited interests and problems in education, employment, and social relationships. Challenging behaviors may be assessed with functional analysis to identify the triggers causing them. The sex and gender disparity in autism diagnostics requires further research in terms of adding diagnosis specifiers as well as female-oriented examples, which may be masked through camouflaging behaviors. Camouflaging is defined as a coping mechanism used in social situations, consisting of individuals pretending to be other people without any communication difficulties. Because of camouflaging and other societal factors, autistic females are more likely to be diagnosed late or with a different mental health concern. In general, it is critical for people to understand that the female autism phenotype is less noticeable, especially when they present as "higher functioning" than other autistic people. Lastly, due to the imbalance in sexes participating in autism studies, the literature is potentially biased towards the ways that it presents in male individuals.
Autism is considered a lifelong condition and has no "cure." Many professionals, advocates, and people in the autistic community agree that a cure is not the answer and efforts should instead focus on methods to help autistic people have happier, healthier, and, if possible, independent lives. Support efforts include teaching social and behavioral skills, monitoring, factoring-in co-existing conditions, and guidance for the caregivers, family, educators, and employers. There is no specific medication for autism, however, drugs can be prescribed for other co-existing mental health conditions, such as anxiety. A study in 2019 found that the management of challenging behaviors was generally of low quality, with little support for long-term usage of psychotropic drugs, and concerns about their inappropriate prescription. Genetic research has improved the understanding of autism-related molecular pathways. Animal research has pointed to the reversibility of phenotypes but the studies are at an early stage.
Genetic and epigenetic overlap The etiology of Autism Spectrum Disorders (ASDs) is complex and involves the interaction of inherited genetic mutations and newly acquired epigenetic changes. Although epigenetic disorders may not be present per se, they serve as a “second hit” that serves to alter the expression of genetic predispositions. Environmental factors may serve to cause epigenetic changes that interact with common and rare copy number variants (CNVs) and single nucleotide variants (SNVs) in genes that are important for brain development and the formation of synapses, which may affect the degree of neurological and anatomical abnormalities that are present in ASDs.
Cortical hyperexcitability and autism One of the leading theories of a potential pathogenic process in autism is cortical hyperexcitability. Maintaining proper levels of cortical excitability is essential for many important cognitive functions, such as processing sensory information, communication between different regions of the brain, and neural plasticity. Hyperexcitability can disrupt these functions and thereby alter cognitive dynamism in important ways. For example, cortical hyperexcitability can affect how the duration of sensory stimuli are perceived. A common trait of autism is reduced somatosensory functioning, which has been linked to alterations in cortical hyperexcitability in autistic individuals. Cortical hyperexcitability can also alter how "old" and "new" stimuli are perceived by changing habituation and adaptation processes in the brain. Altered habituation processes have been linked to characteristic traits of autism, such as under-responsiveness to some stimuli and over-responsiveness to others.
There are many genetic and epigenetic factors that can contribute to increased excitability, but one of the mechanisms implicated in autism is alterations in GABAergic systems in the cortex. GABA is the main neurotransmitter implicated in inhibition in the cortex of mammalian brains; changes to this cortical inhibitory system can result in increased excitability. Alterations in this system have been associated not only with autism but also with several other psychiatric conditions, such as major depressive disorder (MDD) and schizophrenia.
Alterations in the GABAergic system can occur through several epigenetic mechanisms, including modification of chromosome 15q11 to q13 regions which cause reduced levels of GABA signaling. Cortical excitability can also be increased by modifications in the glutamatergic system.
Chromosome 15q11-13 and GABA signaling Chromosome 15q11-13 contain genes encoding subunits of GABA receptors, and both deletion and duplication of this region can lead to cortical hyperexcitability. Duplications of 15q11-13 are associated with about 5% of autistic people and about 1% of people diagnosed with classical autism. 15q11-13 in humans contains a cluster of genetically imprinted genes related to neurodevelopment. Like other genetically imprinted genes, the parent of origin determines the phenotypes associated with 15q11-13 duplications. "Parent of origin effects" cause gene expression to occur only from one of the two copies of alleles that individuals receive from their parents. (For example, MKRN3 shows a parent of origin effect and is paternally imprinted. This means that only the MKRN3 allele received from the paternal side will be expressed.) Duplications in the maternal copy lead to a distinct condition that often includes autism.
Genes that are deficient in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, both of which are linked to high incidence of autism. Overexpression of maternally imprinted genes is predicted to cause autism, which focuses attention to the maternally expressed genes on 15q11-13, although it is still possible that alterations in the expression of both imprinted and bilallelically expressed genes contribute to these conditions. The commonly duplicated region of chromosome 15 also includes paternally imprinted genes that can be considered candidates for autism.
GABAA receptor genes on 15q11-13 Members of the GABA receptor family, especially GABRB3, are attractive candidate genes for Autism because of their function in the nervous system. GABRB3 null mice exhibit behaviors consistent with autism and multiple genetic studies have found significant evidence for association. Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brains of autistic people and people with Rett syndrome. Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).
Epigenetic regulation of gene expression in 15q11-13 Regulation of gene expression in the 15q11-13 is rather complex and involves a variety of mechanisms such as DNA methylation, non-coding and anti-sense RNA.
The imprinted genes of 15q11-13 are under the control of a common regulatory sequence, the imprinting control region (ICR). The ICR is a differentially methylated CpG island at the 5' end of SNRPN. It is heavily methylated on the silent maternal allele and unmethylated on the active paternal allele.
MeCP2, which is a candidate gene for Rett syndrome, has been shown to affect regulation of expression in 15q11-13. Altered (decreased) expression of UBE3A and GABRB3 is observed in MeCP2 deficient mice and autistic people. This effect seems to happen without MeCP2 directly binding to the promoters of UBE3A and GABRB3. (Mechanism unknown) However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.
Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autistic people, has been shown to depend on MeCP2. Combined, these data suggest a role for MeCP2 in the regulation of imprinted and biallelic genes in 15q11-13. However, evidently, it does not play a role in the maintenance of imprinting.
Folate-methionine pathway enzymes One current theory of the pathophysiology of autism is that it arises from a deficit in the folate-methionine pathway. Folate donates methyl groups to convert homocysteine into methionine, which is the precursor of S-adenosylmethionine. S-adenosylmethionine is the methyl group donor responsible for DNA and histone methylation. Epigenetic changes can result in changed gene expression of pathway enzymes resulting in a change in folate levels which can contribute to autism. These changes to the epigenetic regulation interact with the pregnant woman's immune system activation and can result in an autism phenotype in the fetus' brain. To add, low levels of folate in the pregnant woman are correlated with DNA hypomethylation in the fetus.
The gene MTHFR codes for the enzyme methylenetetrahydrofolate reductase which is necessary for the synthesis of 5-methyl-tetrahydrofolate, a biologically active form of folate One important factor that has been identified for autism is polymorphism in MTHFR. A meta-analysis demonstrated that polymorphism of the MTHFR C677T genotype is correlated with an autism diagnosis in children from countries lacking food fortification.
While MTHFR is a proposed genetic factor for autism, there is limited clinical evidence from testing for MTHFR gene polymorphisms in the diagnostic setting. The reason for these complications may be due to other modifiers of the folate metabolism pathway or other genes included in the pathway. Additionally, the levels of homocysteine (HCy) seem to result in an increased utility of the folate metabolism pathway as a predictor for autism diagnosis.
Pharmacological inducers and glial cells