Autism

Characteristics of Autism

Autism is a spectrum disorder, which means a child’s symptoms can present in a wide variety of combinations, from mild to severe. Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children, features of subjects with ASD include compromised social communication and interaction, coupled with repetitive and unusual sensory-motor behaviors.

Complications and Causes of Autism

ASD is associated with a variety of symptoms, such as intellectual disability, speech difficulties, language development delay and various cognitive impairments, including executive function difficulties, such as planning and organization, repetitive stereotypic behavior, and theory of mind deficits. Another characteristic of ASD is the frequent occurrence of comorbidities such as epilepsy, sleeping, and gastrointestinal dysfunction, and immunological disturbances.

Typically, ASD may be divided into syndromic and non-syndromic (or idiopathic). Despite the differences, both syndromic and idiopathic autism are characterized by disrupted brain synaptic connectivity. Whole-exome sequencing (WES) studies have proved that the genetic architecture of ASD involves the interplay of common and rare variants and their impact on hundreds of genes. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently that mediate post-translational lysine methylation/demethylation modifications of histones.

Fig.1 ASD genes in synaptic networks. (De, 2014)

Major Developmental Pathways Affected in Autism

A number of signaling pathways are differentially perturbed in ASD. Dysregulation of neurodevelopmental pathways, such as Wnt, Hedgehog and Retinoic acid are highly associated with the development of this syndrome via disrupted neurogenesis. Other signaling cascades, such as PI3K/AKT/mTORC1 and ERK1/2, important regulators of cell survival and energy homeostasis, display mutations that maintain pathways inappropriately active. Inflammatory responses in the brain and periphery are aberrantly active in ASD patients. It appears that local and systemic inflammatory responses dysregulation may lead to neural function misbalances, which are altered in neuronal plasticity and connectivity, therefore causing changes in social and cognitive skills.

Fig.2 Association of autism with the enhancement of the signaling pathway. (Baranova, 2021)

Treatment of Autism

Treatment and management of ASD are highly individualized, focusing on educational and behavioral therapies. Approved therapies aim at reducing aggression and repetitive behavior. An increment on disabling symptoms may require harsher treatment, including pharmacological interventions, the atypical antipsychotics risperidone and aripiprazole are the only two molecules approved for ASD treatment so far. However, serious concerns with side effects from the long-term treatment with these dopamine receptor antagonists have led to the introduction of selective serotonin reuptake inhibitors (SSRIs). However, up to now, there is no effective drug for treating autism. The main goal in the future is to identify targets by exploring ASD signaling pathways and then develop new drugs.

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References

1. De Rubeis, S.; et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014, 515(7526): 209-215.
2. Baranova, J.; et al. Autism spectrum disorder: signaling pathways and prospective therapeutic targets. Cellular and molecular neurobiology. 2021, 41: 619-649.