User:Kelsidc/Epigenetics of autism

Autism spectrum disorder (ASD)

Autism spectrum disorder (ASD) includes autism, Asperger disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. 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. 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. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations.

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. 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.

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. 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. 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). 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.

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. 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. 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.

Causes

While the exact cause of ASD has remained somewhat of a mystery, it appears to be genetic in origin. Most data supports a polygenic, epistatic model, meaning that the disorder is caused by two or more genes and that those genes are interacting in a complex manner. Several genes, between two and fifteen in number, have been identified and could potentially contribute to disease susceptibility. However, an exact determination of the cause of ASD has yet to be discovered and there is likely not one single genetic cause of any particular set of disorders. This led many researchers to believe that epigenetic mechanisms, such as genomic imprinting or epimutations, may play a major role in ASD.

Epigenetics

Epigenetic mechanisms can contribute to disease phenotypes. Two examples of epigenetic modifications are DNA cytosine methylation and post-translational modifications to histones. These mechanisms help to regulate gene expression without changing the DNA sequence. They can be influenced by exposure to environmental factors and may be heritable from parents. Rett syndrome and Fragile X syndrome (FXS) are single gene disorders related to ASD with overlapping symptoms, including deficient neurological development, language and communication impairment, difficulties in social interactions, and stereotyped or repetitive hand gestures. It is not uncommon for an individual to be diagnosed with both ASD and Rett syndrome and/or FXS. Epigenetic regulatory mechanisms play a central role in pathogenesis of these two disorders. Rett syndrome is caused by a mutation in the gene that encodes methyl-CpG-binding protein (MeCP2), one of the key epigenetic regulators of gene expression. MeCP2 binds methylated cytosine residues in DNA and interacts with complexes that remodel chromatin into repressive structures. On the other hand, FXS is caused by mutations that are both genetic and epigenetic. Expansion of the CGG repeat in the 5’-untranslated region of the FMR1 genes leads to increased susceptibility of epigenetic silencing which can result in a loss of gene expression.

Another potential contributor to ASD epigenetic regulation of gene expression is genomic imprinting. In this instance, the epigenetic modification(s) causes the offspring to express the maternal copy of a gene or the paternal copy of a gene, but not both. The imprinted gene is silenced through epigenetic mechanisms. Candidate genes and susceptibility alleles for autism are identified using a combination of techniques, including genome-wide and targeted analyses of allele sharing in sib-pairs, using association studies and transmission disequilibrium testing (TDT) of functional and/or positional candidate genes and examination of novel and recurrent cytogenetic aberrations. Results from numerous studies have identified several genomic regions known to be subject to imprinting, candidate genes, and gene-environment interactions. Particularly, chromosomes 15q and 7q appear to be epigenetic hotspots in contributing to ASD. Also, genes on the X chromosome may play an important role, as in Rett Syndrome.