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This is an old revision of this page, as edited by Kelsidc (talk | contribs) at 18:38, 11 April 2022 (clarified which parts of the article are new/original). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

**note** new sections in this sandbox are cortical hyperexcitability and ASD, folate-methionine pathway enzymes, valproate exposure, HDACs and ASD, ASD and other disorders, and potential applications. None of these were present in the original wiki article on ASD. The intro paragraphs are edited/corrected and expanded versions of the current ASD page.

However, the cortical hyperexcitability and ASD section does incorporate sections from the original article (the sub-points about chromosome 15q-11-13), which was one of the parts of the article that we argued was very technical and difficult to understand. We attempt to put those sections into context by discussing the more general epigenetic model of ASD that this research supports and connecting it more clearly to ASD.

Epigenetics of Autism--Outline. People playing in this sandbox are: Kelsi Cox, Valentina, Ria, Christina

Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation.[1] Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation amongst how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms.[2] ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to be have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to effect gene expression. In particular, mechanisms such as cytosine regulation and post-translational modifications of histones. 42 out of the 215 genes causing ASD have been found to be involved in epigenetic modification of gene expression. [3]

Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye-contact and limitations in social situations, and with verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions.[4] Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities (e.g. to foods, noises, fabric textures, light), initiating and sustaining relationships, and maintaining jobs.[5][6]

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 ASD about four times more often than females.[6][7] The reasons for this are unclear, with suggestions including a higher testosterone level in utero, different presentation of symptoms in females (leading to misdiagnosis), and gender-bias.[8] The clinical assessment of children can involve caregivers, the child, and a core team of professionals (pediatricians, child psychiatrists, speech-and-language therapists and clinical/educational psychologists).[9][10] 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 it.[11]

ASD 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 people with ASD have happier, healthier, and, if possible, independent lives.[12] 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 ASD, 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.[13][14] Genetic research has improved the understanding of ASD-related molecular pathways. Animal research has pointed to the reversibility of phenotypes but the studies are at an early stage.[15]

Cortical hyperexcitability and ASD

One of the leading theories of the cause of ASD, in epigenetics and in biology more broadly, is cortical hyperexcitability. There are many genetic and epigenetic factors that can contribute to increased excitability, but one of the mechanisms implicated in ASD is alterations of GABAergic systems in the cortex.[6] GABA is the main neurotransmitter implicated in inhibition in the cortex of mammalian brains;[16] changes to this cortical inhibitory system can result in increased excitability.[6] Alterations in this system have been associated, not only with ASD, but also with several other psychiatric disorders, such as major depressive disorder (MDD) and schizophrenia.[17]

Alterations in the GABAergic system can occur through several epigenetic mechanisms, including modification of chromosome 15q11 to q13 regions and reduced levels of GABA signaling.[6][17] Cortical excitability can also be increased by modifications in the glutamatergic system.[6]

Chromosome 15q11-13 duplication and deletion

Chromosome 15q11-13 contain genes encoding subunits of GABA receptors, and both deletion and duplication of this region can lead to cortical hyperexcitability.[6] Duplications of 15q11-13 are associated with about 5% of patients with ASD[18] and about 1% of patients diagnosed with classical Autism.[19] 15q11-13 in humans contains a cluster of genetically imprinted genes important for normal neurodevelopment. Like other genetically imprinted genes, the parent of origin determines the phenotypes associated with 15q11-13 duplications.[20] "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.[21]

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 ASD.[6][21] 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 disorders.[21] The commonly duplicated region of chromosome 15 also includes paternally imprinted genes that can be considered candidates for ASD.

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[22] and multiple genetic studies have found significant evidence for association.[23] Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brain of AS, AUT and RTT patients.[24] Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).[25]

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.[26]

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.[27]

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 ASD patients. This effect seems to happen without MeCP2 directly binding to the promoters of UBE3A and GABRB3. (Mechanism unknown)[28] However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.[29]

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autism patients, has been shown to depend on MeCP2.[30] 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.[29]

Folate-methionine pathway enzymes

One current theory of the pathophysiology of ASD is the defective folate-methionine pathway enzymes.[31] Epigenetic changes can result in changed gene expression and a change in the folate levels can contribute to ASD. These changes to the epigenetic regulation interact with the pregnant person’s immune system activation and can result in an ASD phenotype in the fetus’ brain.[32]

The gene MTHFR codes for the enzyme methylenetetrahydrofolate reductase which is necessary for the synthesis of 5-methyl-tetrahydrofolate.[31] One important risk factor that has been identified for ASD is polymorphism in MTHFR. A meta-analysis demonstrated that polymorphism of the MTHFR C677T genotype is correlated with an ASD diagnosis in children from countries lacking food fortification.[33]

While MTHFR is a proposed genetic factor for ASD, there is limited clinical evidence from testing for MTHFR gene polymorphisms in the diagnostic setting.[34] 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 ASD diagnosis.[35]

Valproate exposure

If the fetus is exposed to the mood stabilizer drug valproate, the risk of ASD as well as other developmental abnormalities (decreased intrauterine growth, spina bifida, limb defects, craniofacial defects, etc.) is increased.[36] Valproate is an anticonvulsant drug commonly administered for generalized and partial seizures, but also for the treatment of migraines and bipolar mood disorder. Its mechanisms of action are varied, including enhanced GABA neurotransmission, modified inositol metabolism, and interaction with the ERK and Wnt/B-catenin signaling systems.[37] If taken while pregnant, the risk of ASD is 8.9% to 10.8%. When valproate and another antiepileptic drug are taken, the risk increases to 11.7%.[38][39] Compared to the general population, this risk of ASD is 16 times higher.[40]

Currently, there are two proposed epigenetic mechanisms for valproate increasing the risk in ASD: alteration in folate metabolism and HDAC inhibition. The inhibition of HDAC is correlated with overexpression of other genes.[41] Treatment of mice with valproate also increases hippocampal histone H3 acetylation.[42] Valproate not only modifies histones but is also linked to embryonic kidney cell demethylation.[43]

Current candidate genes relating to ASD in mice exposed to valproate in utero are NRXN1, NRXN2, NRXN3, NLGN1, NLGN2, and NLGN3. In the somatosensory cortex, CA1, dentate gyrus, and hippocampus, NLGN3 is significantly downregulated in mice treated with valproate.[44] While this evidence of NLGN3 downregulation due to valproate suggests a a potential relevant mechanism for ASD, further research is needed.

Histone deacetylases (HDACs) and ASD

The association of HDACs to ASD is demonstrated through the valproic acid (VPA) model. VPA is a weak HDAC inhibitor used clinically as an anticonvulsant. The VPA model discerns the potential pathogenesis and mechanisms of action of ASD in animal models. HDAC inhibition is the most understood. In animal models, mice prenatally exposed to VPA had transient hyperacetylation of histones H3 and H4, decreased HDACs, and developed ASD-like symptoms.[45] However, mice prenatally exposed to valpromide, analogous to VPA but not an HDAC inhibitor, did not experience transient hyperacetylation of histones H3 and H4 and did not develop ASD-like symptoms.[46] An important thing to note is the time of exposure to VPA. In the animal models, the significant effects of VPA in causing ASD-like symptoms was demonstrated mainly in rats exposed to VPA on gestation day 12.5, not in other gestation days like day 9, 14.5, etc.[45] [46] The ASD-like symptoms of mice included decreased distressed pup calls, decreased social exploration, decreased social behaviors, increased stereotypic locomotor, decreased acoustic prepulse inhibition, and increased sensitivity to non painful stimuli.[46]

The same association is replicated in clinical studies. Children prenatally exposed to VPA or with fetal valproate syndrome (FVS) have a higher prevalence of ASD. FVS is a rare condition in children that happens due to VPA exposure during the first trimester of pregnancy.[46]

Postnatal exposure to HDAC inhibition has opposite effects. Romidepsin and MS-275, both HDAC inhibitors, improve the preference and interaction times of SHANK 3 deficient mice. Trichostatin A (TSA) is another example of an HDAC inhibitor. It results in increased histone acetylation at the oxytocin and vasopressin receptors of the nucleus accumbens (NA) in female voles, increasing pair bonding. In a small clinical trial, beta hydroxybutyrate, a product of the ketogenic diet and inhibitor of class 1 HDAC, has shown promise in improving the social behavior and skills in children with ASD.[45]

ASD and Other Disorders

SHANK 3

SHANK proteins are scaffolding proteins at glutamatergic synapses crucial for synaptic development. The disruption of SHANK genes is associated with neurocognitive impairments and disorders. The disruptions, either from mutations or deletions, are associated with disorders such as Phelan-McDermid syndrome (PMS), schizophrenia, and ASD. SHANK 3 is the most studied gene from the SHANK gene family. Several studies have found that disruptions to SHANK 3 cause more severe cognitive impairments than disruptions to SHANK 1 or 2. These findings suggest that the SHANK gene that is disrupted may determine the severity of the cognitive impairments.[47]

A study on two mutant mice lines, one line with an ASD-linked SHANK 3 mutation on exon 21 and the other with a schizophrenia-linked SHANK 3 mutation on exon 21, found differences in the synaptic and behavioral impairments caused by disruptions to SHANK 3. The ASD-linked mutation results in a complete loss of SHANK 3 (like a deletion) and impaired striatal synaptic transmission. The schizophrenia-linked mutation results in a truncated SHANK 3 protein and severe synaptic impairments in the prefrontal cortex.[47]

Other studies suggest that SHANK3 knockout mice display behavioral phenotypes of ASD. These mice display self-injurious grooming, anxiety, and social deficits. Restoration of SHANK 3 in adult mice improved social deficits and self-grooming behaviors. These findings indicate the potential therapeutic effect of restoring SHANK 3. SHANK 3 restoration may alleviate some symptoms of ASD. In addition, modulators and proteins associated with SHANK 3 are potential therapeutic targets for ASD. However, the effects of targeting modulators differ depending on the specific SHANK 3 disruption. For instance, studies have shown that increasing mGluR5 activity improved self grooming and behavioral deficits. Yet, other studies have shown the opposite effect. This demonstrates that the therapeutic effects are dependent on specific SHANK 3 mutation.[47]

Potential applications of epigenetic research to treatment of ASD

Folate pathways have been studied to be potential predictors of ASD. A few genetic polymorphisms such as folate hydrolase 1 and hydroxymethyltransferase 1 along with hyperhomocysteinemia were used as risk factors to develop an artificial neural network (ANN). Studies showed that this model was around 63.8% accurate in predicting ASD risk, implying a moderate association between genetic polymorphisms of the folate pathway and autism risk. [35]

New References (already added in text; rewritten here so we can keep track)

Neural Hyperexcitability in Autism Spectrum Disorders https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664056/

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies https://pubmed.ncbi.nlm.nih.gov/27145016/

GABA and glutamate in the human brain https://pubmed.ncbi.nlm.nih.gov/12467378/

Genetics and epigenetics of autism: A Review[48]

"Epigenetics of Autism Spectrum Disorder: Histone Deacetylases[45]

Epigenetics and autism[49]

The valproic acid- induced rodent model of Autism[46]

SHANK proteins: roles at the synapse and in autism spectrum disorder[47]

REVIEW ARTICLE: Autism Spectrum Disorders and Epigenetics (Grafodatskaya et al., 2010)

References

Genetics and epigenetics of autism: A Review[48]

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