Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, repeated behaviors, and restricted interests. While early signs of ASD include poor eye contact, no gesturing by 12 months, and loss of language/social skills, it is generally diagnosed anywhere from 18 months to 2 years of age (Hodges 2020). However, late diagnosis is prevalent in girls because females are less likely to present overt symptoms, and more likely to mask symptoms due to gender biases and socialization, meaning the average age of diagnosis is closer to 4 years of age (Tanner 2020). Currently, the World Health Organization estimates that international prevalence of ASD is 0.76%, but this is not perfectly accurate due to discrepancies in access to healthcare and social stigma: Caucasian children are more consistently identified with ASD than black or Hispanic children (Hodges 2020). Further, while studies suggest that intervention before 3 years of age has the greatest impact and the AAP recommends that screening for autism should be performed around 2 years of age in all children, the U.S. Preventive Services Task Force in 2016 found that there is not enough evidence to assess the benefits and harms of screening ASD in asymptomatic children, and found that the possibility of helping more children with ASD and reducing late in life diagnosis did not outweigh the possibility of false positive and the misuse of resources. In the past, ASD was made up of multiple distinct disorders—autism, pervasive developmental, and Aspergers—but the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) in 2013 combined them into one umbrella, autism spectrum disorder (Chahin 2020). While there are no clear biomarkers for ASD at this time, it can still be reliably identified based on a number of behavioral tests, and studies are underway to find common neurological markers of ASD. Current screening tests include: various questionnaires, rated on a five point scale, assessments for verbal comprehension, perceptual reasoning, working memory, and processing speed, tests for nonverbal intelligence—symbolic memory, cube design, spatial memory, analogic reasoning, object memory, and mazes—language and vocabulary evaluations, and interviews with psychologists who specialize in the disorder (Chahin 2020).

In children, ASD presents with the following symptoms: deficits in social communication, difficulty with eye contact and accelerated head circumference in the first year of life. Later in life, symptoms such as restricted interests, repetitive behaviors, gastrointestinal symptoms, and executive dysfunction appear (O’Hearn 2008). ASD exists on a spectrum. Some individuals are low-functioning—with language difficulties, lower than average intelligence, and strong sensory issues—while some individuals are high functioning—they can mask symptoms and adjust quickly, but have trouble applying their knowledge in everyday life and adjusting to social situations. Common symptoms from across the spectrum include: poor eye contact, speaking in an abnormal tone/rhythm, repeating phrases or words, hand flapping, unaware of others emotions, difficulty recognizing nonverbal and implicit cues, developing specific rituals and becoming disturbed if the rituals are disrupted, fixating on objects or activities, and having specific food preferences (Mayo Clinic). As of right now, causative factors vary and are not fully understood, but a few common ones stand out. Maternal exposure to toxic substances remains a strong indicator of ASD in children. Specifically, prenatal exposure during fetal development to specific environmental factors or substances have been reported to increase risk of ASD, including: thalidomide, valproic acid, certain prescription medications (opioids and anti-seizure medications), infections (rubella or influenza), environmental pollutants, or nutrient deficiencies (folic acid) (Qin 2024). Furthermore, advanced maternal and paternal age are both associated with increased risk of having a child with ASD, which is a possible explanation for increased ASD diagnosis in the 21st century—couples are having children later in life. Even infants born prematurely have a higher risk of ASD (Hodges 2020). All of these factors combined may increase ASD risk by affecting fetal brain development and nervous system maturation.

The question then arises how exactly the nervous system of individuals with ASD differs from the nervous systems of neurotypical individuals. The first area of difference is in genetics. A number of specific genetic syndromes—fragile X syndrome (a repeat expansion on the FMR1 gene), tuberous sclerosis (mutations in the TSC1/TSC2 genes), 15q11-q13 duplication syndrome (maternal duplication of a region of Chromosome 15), and Rett syndrome (mutations in the MECP2 gene)—have all been found to be associated with higher risk of ASD. These conditions, often caused by a mutation in a single gene, lead to significant differences in brain development and function, thus increasing the probability of an ASD phenotype. Analysis of large-sample genome-wide association studies have found several consistently identified genes associated with higher ASD risk—chromosomal regions 3p21, 5p14, 7q35, and 20p12, which contain genes like CNTN4, CNTNAP2, and NRXN1, all of which are crucial to synaptic adhesion and neurotransmission (Qin 2024). Many of these genetic defects associated with ASD encode regulatory proteins such as transcription factors, or proteins relevant at the neuronal synapse, where the neurons communicate with one another (Hodges 2020). The second area of difference is in brain architecture and connectivity. Studies point to possible alterations in the brainstem, cerebellum, and in the limbic structures: the hippocampus, amygdala, septal nuclei, and anterior cingulate cortex. In general, cells in the limbic structures are smaller and more densely packed in autistic brains, and neurons in the hippocampus of autistic individuals also display reduced dendrite complexity (Lord 2000). This reduced dendrite complexity most likely connects to problems found with cortical layer formation and neuronal differentiation (Hodges 2020). Apart from alterations to limbic structures, studies also indicate that the white and gray matter volumes of autistic individuals were enlarged in the most in the frontal and prefrontal regions, slightly in the temporal and parietal regions, and were normative in the occipital cortex. Despite these observed differences, autistic circuitry has comparable functional connectivity to control brains, meaning that the abnormalities selectively affect higher order behaviors—such as executive function and social processing—while sparing basic processes that are not as dependent on widely distributed circuitry (O’Hearn 2008).

Current therapies for autism vary, but there is no curative treatment. Because autism is a neurodevelopmental disability, some treatment options are for the mother rather than child: prenatal supplements of folic acid in patients exposed to antiepileptic drugs, for example (Hodges 2020). For autistic individuals, recommended treatment involves various therapies—speech, sensory integration, and auditory—or pharmacological agents that improve behavioral symptoms—neurotransmitter reuptake inhibitors, tricyclic antidepressants, anticonvulsants, atypical antipsychotics, or acetylcholinesterase inhibitors (Kumar 2012). There are a few areas of research I believe warrant more exploration and attention in search of new cures or therapies. First, research into the pathophysiology of MECP2 (methyl-CpG binding protein 2 gene) mutations, since decreased MECP2 expression leads to failure to suppress expression of genes regulated by methylation. The FMR1 gene, whose full mutation leads to Fragile X syndrome, could also use more research, since understanding of the mechanism by which reduced FMR1 expression leads to social-communicative problems has overlap with autism. The most promising area of research is into the maternal duplication of gene 15q11-q13, which has been most frequently found in large autism gene samples: 0-3% of the time. This is the region where no maternal expression of UBE3A (ubiquitin binding enzyme 3A) and no maternal expression lead to Angelman and Prader-Willi syndrome respectively—both associated with different mental disabilities. It is possible that duplication of 15q11-q13 has distant effects such as UBE3A overexpression, and treating this duplication could be a possible avenue of therapy for autism (Lord 2000). Ultimately, however, autism is simply another mental disorder, and there is nothing truly wrong with those who have it.

Bibliography

Chahin, S. S., Apple, R. W., Kuo, K. H., & Dickson, C. A. (2020). Autism spectrum disorder: psychological and functional assessment, and behavioral treatment approaches. Translational Pediatrics, 9(S1), S66–S75. https://doi.org/10.21037/tp.2019.11.06

Hodges, H., Fealko, C., & Soares, N. (2020). Autism spectrum disorder: Definition, epidemiology, causes, and clinical evaluation. Translational Pediatrics, 9(1), 55–65. https://doi.org/10.21037/tp.2019.09.09

Kumar, B., Prakash, A., Sewal, R. K., Medhi, B., & Modi, M. (2012). Drug therapy in autism: a present and future perspective. Pharmacological Reports, 64(6), 1291–1304. https://doi.org/10.1016/s1734-1140(12)70927-1

Lord, C., Cook, E. H., Leventhal, B. L., & Amaral, D. G. (2000). Autism Spectrum Disorders. Neuron, 28(2), 355–363. https://doi.org/10.1016/s0896-6273(00)00115-x

Mayo Clinic. (2018, January 6). Autism Spectrum Disorder. Mayo Clinic; Mayo Foundation for Medical Education and Research. https://www.mayoclinic.org/diseases-conditions/autism-spectrum-disorder/symptoms-causes/syc-20352928

O’Hearn, K., Asato, M., Ordaz, S., & Luna, B. (2008). Neurodevelopment and executive function in autism. Development and Psychopathology, 20(4), 1103–1132. https://doi.org/10.1017/s0954579408000527

Qin, L., Wang, H., Ning, W., Cui, M., & Wang, Q. (2024). New advances in the diagnosis and treatment of autism spectrum disorders. European Journal of Medical Research, 29(1). https://doi.org/10.1186/s40001-024-01916-2

Tanner, A., & Dounavi, K. (2020). The Emergence of Autism Symptoms Prior to 18 Months of Age: A Systematic Literature Review. Journal of Autism and Developmental Disorders, 51(3). https://doi.org/10.1007/s10803-020-04618-w