Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disease that can be either
a congenital or early disease that occurs due to nervous system abnormalities. Since
autism arises from nervous system abnormalities, it affects the structure or functioning
of the brain. Accordingly, due to the abnormal electrical movements within the brain,
neurological problems such as seizures, involuntary movements, and loss of consciousness
may occur. Individuals who suffered from ASD face significant problems in social life,
school, or at work. Besides, individuals diagnosed with ASD have features such as
overwhelming memory, the ability to play music and sing. In ASD, the word “spectrum”
stands for a wide range of symptoms and to what extent these symptoms progress and
the degree of symptoms develop.[1] An infant or an adult with ASD can have varying social behavior and coping skills
issues. For example, they avoid eye contact and lack a particular facial expression.
They do not react to being named either they do not seem to hear individuals speaking
to them from time to time. They do not talk, speak late, or lose the ability to say
previously acquired words or sentences. They are resisting to hug and shake hands,
prefer to play alone, retreat to their world, not understanding how to use words or
sentences despite repeating word for word, repeating the same word continuously. With
their behavioral habits, an infant or adult with ASD can have multiple concerns. These
are repetitive movements such as swinging back and forth, turning around or clapping
hands, coordination problems, indifference to pain or temperature despite being unusually
sensitive to light, sound, or contact, abnormally focused or stuck on an object or
activity, refusing certain types of food altogether or eating only certain foods.
A child or adult with ASD may have different issues with repeated forms of behavior
such as serotypes and repeated motor movements, insistence on sameness, strict obedience
to schedule, limited and extreme interest, and sensory issues of less or more arousal.[2]
Etiology of Autism Spectrum Disorder
Environmental Factors
Environmental factors can cause ASD such as viral infections or drugs are taken during
pregnancy since the placenta is an imperfect barrier that limits what goes into the
fetus, and therefore, it partially protects the fetus. Materials or chemicals can
cross the placenta; small nonpolar molecules that do not easily dissolve in water
can cross the placenta easily, while large polar molecules can cross poorly.[3] Those chemicals increase DNA methylation, providing evidence of possible epigenetic
changes involved in ASD. Depending on the country, drugs have different kinds of testing
procedures, and various companies have tested and categorized drugs in regard to how
safe they are to be used during pregnancy.[4] There is a threshold and lower than the threshold effect, usually it is not expected
to have an anomaly for the fetus.[5] Also, gestation age is important to consider in case of exposure to teratogens.
The fetus gets affected by teratogens during organ development. For that reason, some
sources of teratogens may compromise the normal development of an organ. There is
also growing evidence that air pollution might be one of the factors causing autism.
Every chemical substance may be teratogenic as well as it will depend on how much
the mother consumes it.[6] The lifestyle of a pregnant woman is important. During pregnancy, if she is smoking,
using alcohol, this might cause several problems in the fetus. Adopting a healthy
diet is also important for the health of the fetus. The effects of those can occur
during postnatal or prenatal life, which means that if the mother has been exposed
to teratogens during pregnancy that will lead to anomalies in brain development or
several health problems of the fetus.[7] Parental age at conception may also be associated with an increased risk of autism.
Consequently, serious problems such as prematurity or oxygen deprivation may be faced.[8]
Genetic Factors
Autistic spectrum disorder is a complex disorder and multiple factors such as genetic
factors, epigenetic modifications, and environmental factors are involved in the development
of the autism disorder. Therefore, the inheritance pattern is not fully known.[9]
[10] ASD can be caused by a microdeletion of the 16p11.2 chromosome. Several genes have
been identified associated with autism, including the PTCHD1,[9]
[11]
HOX, CHD2, CHD8, FOXP2, SHANK3, and OXTR genes ([Table 1]).[12]
Table 1
Summary of autism disorder-related genes
|
Genes
|
Causes
|
|
PTCHD1
|
Mental development
|
|
HOX
|
Significant for brain development
|
|
CHD8
|
Deletion or inversion causes brain abnormalities
|
|
FOXP2
|
Developmental language and speech deficiencies
|
|
SHANK3
|
Neurotransmitter receptors and nerve cell communication
|
|
OXTR
|
Impact on face memory
|
The deletion and/or inversion of the CDH8 gene, which has located on the long arm of chromosome 16, can cause autism disorder.[13]
SHANK2 gene localized on the long arm of chromosome 22 and can cause autism disorder. Alterations
of the SHANK2 gene causes structural organization problems of neurotransmitter receptors and nerve
cell communication.[14]
FOXP2 is associated with developmental language and speech deficiencies.[15] Mutations on homeotic genes caused brain abnormalities.[16]
OXTR, known as oxytocin receptor, is a protein and acts as a receptor for the hormone
and neurotransmitter oxytocin. Mutations of the OXTR gene had an important impact on face memory. Low oxytocin and estrogen activation
do not inhibit the methylation of the oxytocin receptor and silencing contributes
to the enhanced amygdala and antisocial activity arousal intakes regulated by the
androgen receptor.[17]
SHANK proteins connect neurotransmitter receptors, ion channels, and other membrane
proteins to cytoskeleton actin and signaling proteins. They play a key role during
synapse formation and dendritic spine maturation,[18] and variations of the SHANK2 gene have been identified in individuals with ASD.[19] Several studies identified various candidate genes which they have a possible causal
role in ASD pathogenesis such as voltage-gated ion channels, scaffold proteins, cell
adhesion molecules, and synaptic architecture.[20] Mutations in CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1H, SCN1A, SCN2A, SCN3A, SCN7A, SNC8A, KCNMA1, KCND2, KCNJ10, KCNQ3, and KCNQ5 have been described in ASD.[20]
Epigenetic Factors
In addition to environmental factors, findings are suggesting another significant
factor causing autism may be genetics or epigenetic. Epigenetics are the heritable
or acquired changes in gene expression without modifications in the sequence of DNA.
It has a different level of gene expression. Epigenetic alterations play an important
role and can change gene expression levels without changing genomic DNA. However,
they can change the gene expression level; there will be increased or decreased gene
expression. Four different mechanisms of epigenetic modifications are histone modifications,
DNA methylation, RNA interference, and RNA modifications. They play essential roles
at the level of gene expression and transcription. Although the chromatin shifts that
have just been addressed do not affect the DNA code, they can be carried on to the
subsequent generations of the cell. Epigenetic inheritance is also the inheritance
of characteristics inherited through pathways not specifically affecting the nucleotide
sequence. Epigenetic means individuals have alterations with inheritable parents.
They do not show Mendelian inheritance pattern. Therefore, it includes chromatin structure
instead is related to different packaging levels. Epigenetic pathways involving DNA
methylation, posttranslational modifications to histone proteins, and transcriptional
regulations that are central to neurodevelopmental processes in utero are likely to
be affected by maternal habits such as obesity, hunger, smoking, and alcohol.[21]
Histone Modifications
Histone modifications can help for the segmentation of the genome into domains of
different transcriptional potentials. Nucleosomal histones are subjected to a variety
of various modifications affecting the particular residues of amino acids in the histone
tails. Different chemical groups can be added; acetylation, monomethylation, dimethylation,
or trimethylation of lysine and phosphorylation of serine into the histone tails and
those modifications can attach histone tails covalently with the help of effective
proteins called bromodomains. Depending on the nature of the group, they affect the
level of DNA expression. Histone modification occurs through acetylation or methylation
of the histone tail. Histone tail acetylation allows the nucleosome to dissolve, releasing
the gene and altering the composition of the DNA. In comparison to acetylation, histone
tail methylation tightens the nucleosomes together, inactivates the gene, and leaves
DNA unapproachable for alteration. By adding the methyl group to cytosine, blocking
the transcription of those genes, methylation may also occur.[22] Histone acetylome-wide association study analyzed samples from the patients with
ASD and combined with the control brains that were exposed to H3K27 chromatin sequencing.[23] According to this acetylome study, cis regulatory elements were observed with a
high rate in patients with ASD. There was a link between genes and ion channels. This
was related to epilepsy and neuronal impulses. It was shown to be irregular during
ASD. In addition, reduced acetylation in ASD can be caused by conditions, for example,
chemokine signaling and histone deacetylase activity. They are corepressor that enhance
the activities of transcriptional repressors. HDAC removes the acetyl group on the
histone tail and changes chromatin configuration. Therefore, it contains a low level
of acetyl group so that gene expression does not occur because they are highly packaged.[21]
DNA Methylation
DNA methylation, the addition of methyl marks on the fifth carbon of cytosine, affects
the expression status of genes. DNA methylation is directly related to DNA expression
and transcription level. Methylation plays a role during the differentiation, regulation
of gene expression,[12] several disorders including cancer, imprinting disorders, Rett's syndrome, fragile
X syndrome, tuberous sclerosis, or Angelman's syndrome.[24]
UBE3A gene, located on chromosome 15q11–13, and mutations were observed in Angelman's syndrome.
Also, studies showed that individuals who have three or too many copies of UBE3A have an increased risk for ASD. However, duplication on chromosome 15q11–13 leads
to repetitive self-grooming behavior. Glutamate delivery was suffered because of three
copies of the UBE3A gene. This neurotransmitter, which has been related to autism, is important for excitatory
signaling. UBE3A is the most common gene for hereditary causes of autism.[25] Rett's syndrome is related to different abnormalities and neural development. MECP2 gene, methylated cytosine-binding protein, plays a significant role in Rett's syndrome
and is also a central contributor to neurological disorders, stimulates and suppresses
transcription ([Table 2]).[26]
Table 2
Epigenetic alterations of autism spectrum disorder
|
Epigenetic factors
|
Causes
|
|
RNA methylation
|
Presumably deregulation of the regulatory transition between mRNA turnover and protein
synthesis. Alterations in the methylation lead to decreased methylation capability
and can also minimize RNA methylation.
|
|
IncRNAs
|
Differentially expressed IncRNAs are involved in the failure of neuronal connectivity
and synaptic functions. IncRNAs overlap with the imprinted loci. IncRNAs (e.g., MSNP1AS)
are associated with the risk of ASD IncRNA.
|
|
miRNAs
|
It controls genes involved in synaptic mechanisms, synaptic plasticity and memory,
neuronal morphology and functions. Linked with a variety of cell signal pathways.
For predictive or diagnosis of autism biomarkers, circulating serum and salivary miRNAs
holds promise into the future.
|
|
Inhibition of HDAC1
|
HDAC1 valproic acid inhibition and GSK3B lithium upregulate the Wnt transcription
inhibition and lead to macrocephalus.
|
|
Histone H3 phosphorylation
|
HMT LSD1, which prevents H3K4 demethylation for the stimulation of the androgen receptor
gene, contributes to AR gene activation loss, raises the amygdala's elevated arousal
consumption.
|
|
Epigenetic proteins
|
Decreased expression of DNA methyltransferase.
|
Recent studies showed that mutations of the epigenetic gene ASH1L were associated with ASD. Gao et al showed loss of ASH1L in the developing mouse
brain caused multiple developmental defects, core autistic-like behaviors, and impaired
cognitive memory.[25] ASH1L is a histone methyltransferase and mediates dimethylation of histone H3 lysine
36. Mutation studies showed that mutations of ASH1L were associated with ASD and/or
intellectual disability.[27]
[28]
Karayiorgou et al demonstrated differentially methylated sites in NR3C1, MTHFR, DRD4, 5-HTT, IGF2DMR, H19, and KCNQ1OT1 genes by using genome-wide DNA methylation in ASD patients.[29] Decreased level methylation of PRRT1 and TSPAN32 was observed in the cerebellum and temporal cortex of brains from 19 autism cases
and 21 controls.[30]
[31] Stenz et al demonstrated hypomethylation of ITGB2 (C3R), SPI1, TNF-α, C1Q, IRF8m, and C3 genes in brain tissue samples from 13 autism cases and 12 controls. They demonstrated
an adverse correlation between gene expression and DNA methylation within the individuals.[27] Hypomethylation of RRT1 and TSPAN32 genes were determined in the cerebellum and temporal cortex in the brains of ASD
patients.[32] In addition to this studies, loss of PRRT1 was reported to increase the number of
synapses and decrease synaptic strength that leads to synaptic dysfunction in ASD.[33]
Several other studies have also examined the altered pattern of DNA methylation of
other genes or evaluated the whole-genome methylation in ASD patients. All these studies
demonstrated the importance of epigenetic studies during the identification of ASD
pathophysiology. Altered methylation of neuronal regulation, synaptic signaling, and
immune system–related genes can be useful for the identification of ASD-related biomarkers.
The epigenetic, environmental, or genetic factors can cause ASD and advancement on
diagnostic tools can be used for the identification of epigenetic alterations such
as ASD-specific histone markers, regions between genes and noncoding RNAs in ASD.[21]
Conclusion
In conclusion, no definitive findings have yet been reached in the diagnosis of autism.
However, there is more than one factor that causes autism. Genetic factors are among
the studies that tried to identify the possible genetic background of autism. It has
been observed that more than one gene was related to autism. However, although these
findings are important, it should be considered that environmental and epigenetic
factors play an essential role in many diseases such as autism. Candidate gene studies
and alterations of epigenetic regulators highlight the importance of the interaction
between genetic and environmental factors on the etiology of ASD. Gene and environment
interactions are contributing to the increased prevalence of ASD. In that perspective,
epigenetic modifications and environment interaction hold promise for possible biomarkers
of autism. In line with these findings, many researchers have been researched to find
out possible biomarkers of autism and increase the quality of life of affected individuals,
reduce their symptoms, make them adapt to daily life, and increase and strengthen
their attitudes in human relations.
Overall, alterations in the status of DNA methylation in patients with ASD have been
discussed in this review article. Here, we described how DNA methylation patterns
and genetic alterations are related to the pathophysiology of ASD. We suggest that
our article shed light on future studies related to the possible biomarkers of autism.
