Stem Cell Therapy for Autism in Mint Hill, NC

All About Autism

Possible causes

Main article: Causes of autism

It had mostly long been presumed that there is a common cause at the genetic, cognitive, and neural levels for the social and non-social components of ASD's symptoms, described as a triad in the classic autism criteria.^[91] However, there is increasing suspicion that autism is instead a complex disorder whose core aspects have distinct causes that often co-occur.^[91][92] While it is unlikely that a single cause for ASD exists,^[92] many risk factors identified in the research literature may contribute to ASD development. These risk factors include genetics, prenatal and perinatal factors (meaning factors during pregnancy or very early infancy), neuroanatomical abnormalities, and environmental factors. It is possible to identify general factors, but much more difficult to pinpoint specific factors. Given the current state of knowledge, prediction can only be of a global nature and therefore requires the use of general markers.^[93]

Biological subgroups

Research into causes has been hampered by the inability to identify biologically meaningful subgroups within the autistic population^[94] and by the traditional boundaries between the disciplines of psychiatry, psychology, neurology and pediatrics.^[95] Newer technologies such as fMRI and diffusion tensor imaging can help identify biologically relevant phenotypes (observable traits) that can be viewed on brain scans, to help further neurogenetic studies of autism;^[96] one example is lowered activity in the fusiform face area of the brain, which is associated with impaired perception of people versus objects.^[97] It has been proposed to classify autism using genetics as well as behavior.^[98] (For more, see Brett Abrahams)

Genetics

Main article: Heritability of autism

See also: Missing heritability problem

Hundreds of different genes are implicated in susceptibility to developing autism,^[99] most of which alter the brain structure in a similar way

Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by rare mutations with major effects, or by rare multi-gene interactions of common genetic variants.^[100][101] Complexity arises due to interactions among multiple genes, the environment, and epigenetic factors which do not change DNA sequencing but are heritable and influence gene expression.^[102] Many genes have been associated with autism through sequencing the genomes of affected individuals and their parents.^[103] However, most of the mutations that increase autism risk have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to a single chromosome abnormality, and none of the genetic syndromes associated with ASD have been shown to selectively cause ASD.^[100] Numerous candidate genes have been located, with only small effects attributable to any particular gene.^[100] Most loci individually explain less than 1% of cases of autism.^[104] As of 2018, it appeared that between 74% and 93% of ASD risk is heritable.^[71] After an older child is diagnosed with ASD, 7% to 20% of subsequent children are likely to be as well.^[71] If parents have one autistic child, they have a 2% to 8% chance of having a second child who is autistic. If the autistic child is an identical twin, the other will be affected 36% to 95% of the time. A fraternal twin is affected up to 31% of the time.^{[medical citation needed]} The large number of autistic people with unaffected family members may result from spontaneous structural variation, such as deletions, duplications or inversions in genetic material during meiosis.^[105][106] Hence, a substantial fraction of autism cases may be traceable to genetic causes that are highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.^{[107][verification needed]}

As of 2018, understanding of genetic risk factors had shifted from a focus on a few alleles to an understanding that genetic involvement in ASD is probably diffuse, depending on a large number of variants, some of which are common and have a small effect, and some of which are rare and have a large effect. The most common gene disrupted with large effect rare variants appeared to be CHD8, but less than 0.5% of autistic people have such a mutation. The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8, which is a chromatin regulator enzyme that is essential during fetal development, CHD8 is an ATP dependent enzyme.^{[108][109][110]} The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to ADP.^[110] CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes. CHD8 negatively regulates Wnt signaling. Wnt signaling is important in the vertebrate early development and morphogenesis. It is believed that CHD8 also recruits the linker histone H1 and causes the repression of β-catenin and p53 target genes.^[108] The importance of CHD8 can be observed in studies where CHD8-knockout mice died after 5.5 embryonic days because of widespread p53 induced apoptosis. Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). CHD8 expression significantly increases during human mid-fetal development.^[108] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.^[109] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes.^[111] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.^[112] Recently CD8 has been associated to the regulation of long non-coding RNAs (lncRNAs),^[113] and the regulation of X chromosome inactivation (XCI) initiation, via regulation of Xist long non-coding RNA,^[ambiguous] the master regulator of XCI,^[ambiguous] though competitive binding to Xist regulatory regions.^[114]

Some ASD is associated with clearly genetic conditions, like fragile X syndrome; however, only around 2% of autistic people have fragile X.^[71] Hypotheses from evolutionary psychiatry suggest that these genes persist because they are linked to human inventiveness, intelligence or systemising.^[115][116]

Current research suggests that genes that increase susceptibility to ASD are ones that control protein synthesis in neuronal cells in response to cell needs, activity and adhesion of neuronal cells, synapse formation and remodeling, and excitatory to inhibitory neurotransmitter balance. Therefore, despite up to 1000 different genes thought to contribute to increased risk of ASD, all of them eventually affect normal neural development and connectivity between different functional areas of the brain in a similar manner that is characteristic of an ASD brain. Some of these genes are known to modulate production of the GABA neurotransmitter which is the main inhibitory neurotransmitter in the nervous system. These GABA-related genes are under-expressed in an ASD brain. On the other hand, genes controlling expression of glial and immune cells in the brain e.g. astrocytes and microglia, respectively, are over-expressed which correlates with increased number of glial and immune cells found in postmortem ASD brains. Some genes under investigation in ASD pathophysiology are those that affect the mTOR signaling pathway which supports cell growth and survival.^[117]

All these genetic variants contribute to the development of the autistic spectrum; however, it cannot be guaranteed that they are determinants for the development.^[118]

ASD may be under-diagnosed in women and girls due to an assumption that it is primarily a male condition,^[119] but genetic phenomena such as imprinting and X linkage have the ability to raise the frequency and severity of conditions in males, and theories have been put forward for a genetic reason why males are diagnosed more often, such as the imprinted brain hypothesis and the extreme male brain theory.^{[120][121][122]}