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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.

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.[3] 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.[4][5]

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.[5][6] 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.[7] 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).[8][9] 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.[10]

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.[11] 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.[12][13] 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.[14]

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.[5] GABA is the main neurotransmitter implicated in inhibition in the cortex of mammalian brains;[15] changes to this cortical inhibitory system can result in increased excitability.[5] Alterations in this system have been associated, not only with ASD, but also with several other pysiciatric disorders, such as major depressive disorder (MDD) and schizophrenia.[16]

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.[5][16] Cortical excitability can also be increased by modifications in the glutamatergic system.[5]

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.[5] Duplications of 15q11-13 are associated with about 5% of patients with ASD[17] and about 1% of patients diagnosed with classical Autism.[18] 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.[19] "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.[20]

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.[5][20] 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.[20] 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[21] and multiple genetic studies have found significant evidence for association.[22] Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brain of AS, AUT and RTT patients.[23] Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).[24]

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.[25]

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.[26]

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)[27] However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.[28]

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autism patients, has been shown to depend on MeCP2.[29] 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.[28]

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.[30] 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. [31]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.[30] [31]To add, 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.[31]

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.[31]

Post natal 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.  TSA, also an HDAC inhibitor,  increases 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.[30]

Potential Applications of Epigenetic Research to Treatment of ASD

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[32]

"Epigenetics of Autism Spectrum Disorder: Histone Deacetylases[30]

Epigenetics and autism[33]

The valproic acid- induced rodent model of Autism[31]

References

Genetics and epigenetics of autism: A Review[32]

  1. ^ "WHO releases new International Classification of Diseases (ICD 11)". www.who.int. Retrieved 2022-03-28.
  2. ^ American Psychiatric Association; American Psychiatric Association; DSM-5 Task Force (2017). Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA: American Psychiatric Association. ISBN 978-0-89042-554-1. OCLC 1042815534.{{cite book}}: CS1 maint: numeric names: authors list (link)
  3. ^ CDC (2020-03-13). "Screening and Diagnosis | Autism Spectrum Disorder (ASD) | NCBDDD". Centers for Disease Control and Prevention. Retrieved 2022-03-28.
  4. ^ "Key priorities for implementation | Autism spectrum disorder in adults: diagnosis and management | Guidance | NICE". www.nice.org.uk. Retrieved 2022-03-28.
  5. ^ a b c d e f g h Comer, Ronald J (1999). Fundamentals of abnormal psychology. New York: Worth Publishers. ISBN 978-0-7167-3314-0. OCLC 40716666.
  6. ^ "10 Facts about Autism Spectrum Disorder (ASD)". www.acf.hhs.gov. Retrieved 2022-03-28.
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  11. ^ "Autism spectrum disorder - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2022-03-28.
  12. ^ Prescribing of psychotropic drugs to people with learning disabilities and/or autism by general practitioners in England (PDF). Public Health England. 2015. OCLC 995055327.
  13. ^ LeClerc, Sheena; Easley, Deidra (June 2015). "Pharmacological Therapies for Autism Spectrum Disorder: A Review". Pharmacy and Therapeutics. 40 (6): 389–397. ISSN 1052-1372. PMC 4450669. PMID 26045648.
  14. ^ Sztainberg, Yehezkel; Zoghbi, Huda Y. (November 2016). "Lessons learned from studying syndromic autism spectrum disorders". Nature Neuroscience. 19 (11): 1408–1417. doi:10.1038/nn.4420. ISSN 1546-1726.
  15. ^ Petroff, Ognen A. C. (2002-12). "GABA and glutamate in the human brain". The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry. 8 (6): 562–573. doi:10.1177/1073858402238515. ISSN 1073-8584. PMID 12467378. {{cite journal}}: Check date values in: |date= (help)
  16. ^ a b Schür, Remmelt R.; Draisma, Luc W. R.; Wijnen, Jannie P.; Boks, Marco P.; Koevoets, Martijn G. J. C.; Joëls, Marian; Klomp, Dennis W.; Kahn, René S.; Vinkers, Christiaan H. (2016-09). "Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies". Human Brain Mapping. 37 (9): 3337–3352. doi:10.1002/hbm.23244. ISSN 1097-0193. PMC 6867515. PMID 27145016. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Schanen N. C. (2006). "Epigenetics of autism spectrum disorders". Human Molecular Genetics. 15: R138 – R150. doi:10.1093/hmg/ddl213. PMID 16987877.
  18. ^ Samaco, R. C.; Hogart, A. & LaSalle, J. M. (2005). "Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3". Human Molecular Genetics. 14 (4): 483–492. doi:10.1093/hmg/ddi045. PMC 1224722. PMID 15615769.
  19. ^ Cook, E.H., Jr.; Lindgren, V.; Leventhal, B.L.; Courchesne, R.; Lincoln, A.; Shulman, C.; Lord, C. & Courchesne, E. (1997). "Autism or atypical autism in maternally but not paternally derived proximal 15q duplication". American Journal of Human Genetics. 60 (4): 928–934. PMC 1712464. PMID 9106540.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ a b c Hogart, A. (2009). "Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alteration in gene expression not predicted from copy number". Journal of Medical Genetics. 46 (2): 86–93. doi:10.1136/jmg.2008.061580. PMC 2634820. PMID 18835857.
  21. ^ Klose, R.J. & Bird, A.P. (2006). "Genomic DNA methylation: the mark and its mediators". Trends in Biochemical Sciences. 31 (2): 89–97. doi:10.1016/j.tibs.2005.12.008. PMID 16403636.
  22. ^ Kriaucionis, S. & Bird, A. (2003). "DNA methylation and Rett syndrome". Human Molecular Genetics. 12 (2): R221 – R227. doi:10.1093/hmg/ddg286. PMID 12928486.
  23. ^ Pickles, A.; Bolton, P.; Macdonald, H.; Bailey, A.; Le Couteur, A.; Sim, C.H. & Rutter, M. (1995). "Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism". American Journal of Human Genetics. 57 (3): 717–726. PMC 1801262. PMID 7668301.
  24. ^ Ma, D.Q.; Whitehead, P.L.; Menold, M.M.; Martin, E.R.; Ashley-Koch, A.E.; Mei, H.; Ritchie, M.D.; Delong, G.R.; Abramson, R.K.; Wright, H.H.; et al. (2005). "Identification of significant association and gene – gene interaction of GABA receptor subunit genes in autism". American Journal of Human Genetics. 77 (3): 377–388. doi:10.1086/433195. PMC 1226204. PMID 16080114.
  25. ^ Nicholls, R.D. & Knepper, J.L. (2001). "Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes". Annu. Rev. Genom. Hum. Genet. 2: 153–175. doi:10.1146/annurev.genom.2.1.153. PMID 11701647.
  26. ^ Hogart, A.; et al. (Feb 2009). "Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number". Journal of Medical Genetics. 46 (2): 86–93. doi:10.1136/jmg.2008.061580. PMC 2634820. PMID 18835857.
  27. ^ Pickles, A.; Bolton, P.; Macdonald, H.; Bailey, A.; Le Couteur, A.; Sim, C.H. & Rutter, M. (1995). "Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism". American Journal of Human Genetics. 57 (3): 717–726. PMC 1801262. PMID 7668301.
  28. ^ a b Samaco, R. C.; Hogart, A. & LaSalle, J. M. (2005). "Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3". Human Molecular Genetics. 14 (4): 483–492. doi:10.1093/hmg/ddi045. PMC 1224722. PMID 15615769.
  29. ^ Hogart, A.; et al. (2007). "15q11-13 gabaa receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism spectrum disorders". Human Molecular Genetics. 16 (6): 691–703. doi:10.1093/hmg/ddm014. PMC 1934608. PMID 17339270.
  30. ^ a b c d Tseng, Chieh-En Jane; McDougle, Christopher J.; Hooker, Jacob M.; Zürcher, Nicole R. (2021-12). "Epigenetics of Autism Spectrum Disorder: Histone Deacetylases". Biological Psychiatry: S0006322321018321. doi:10.1016/j.biopsych.2021.11.021. {{cite journal}}: Check date values in: |date= (help)
  31. ^ a b c d e Nicolini, Chiara; Fahnestock, Margaret (2018-01). "The valproic acid-induced rodent model of autism". Experimental Neurology. 299: 217–227. doi:10.1016/j.expneurol.2017.04.017. {{cite journal}}: Check date values in: |date= (help)
  32. ^ a b Waye, Mary M. Y.; Cheng, Ho Yu (2018-04). "Genetics and epigenetics of autism: A Review: Genetics and epigenetics of autism". Psychiatry and Clinical Neurosciences. 72 (4): 228–244. doi:10.1111/pcn.12606. {{cite journal}}: Check date values in: |date= (help)
  33. ^ Mbadiwe, Tafari; Millis, Richard M. (2013). "Epigenetics and Autism". Autism Research and Treatment. 2013: 1–9. doi:10.1155/2013/826156. ISSN 2090-1925. PMC 3787640. PMID 24151554.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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