Parents of children with autism usually have a few unanswered questions like “how did my child develop autism?” “My child was hale and healthy and had even started to speak a few words. Then, what happened suddenly?” “Is autism acquired?” “Could it have been prevented?” “Is it genetic?” “Can the other children also have autism?”
Medical science does not have answers for many of these questions. Although the “why” may never be known. What is becoming clearer with ongoing research is, “what is the fundamental problem in the brains of the children with Autism”.
In autism, though the brain structure looks normal, there are functional abnormalities in speciﬁc regions of brain. This information, about the functioning of brain areas can be obtained from functional neuroimaging techniques like PET-CT scan and functional MRI scan of the brain. These imaging studies allow us to study the abnormal pattern of cortical activation in autism. These studies indicate that certain areas of the brain show reduced functioning like mesial temporal lobe (inner most part of the brain responsible for learning, understanding, memory, social interaction and abstract thinking), frontal lobe (the front part of the brain responsible for emotions and aggression) and cerebellum (responsible for balance, coordination, muscle tone and speech). Hence the dysfunction of these areas are responsible for problems seen in autism (1-5).
Positron Emission Tomography – Computed Tomography Scans showing areas of brain with reduced function
Research has also helped us to know that there isn’t one cause of autism but multiple risk factors that increase the risk of a child developing autism. Most cases of autism seem to be caused by a combination of autism risk genes and environmental factors influencing the early brain development. Over the last five years, scientists have identified anumber of rare gene changes or mutations which have been associated with autism. Other factors related to children with autism and their parents that may contribute to increase the risk of Autism have also been identified. Along with these certain environmental factors have also been included in the risk factors for Autism.
Below mentioned are a few probable causes of autism:
Patient and family related factors:
Gut microbiota affects the brain development and function. Various mice studies have indicated abnormal psychiatric symptoms in mice with abnormal gut microbiota. This theory has been extrapolated in Autism as well. There are two factors related to the gut that are postulated to be one of the causes in Autism. First, the abnormal micro bacterial population in the gut of the children and Second, the impaired carbohydrate metabolism by the intestinal cell lining. Many abnormalities in the intestinal cell lining like; ileo-colonic lymphoid nodular hyperplasia, enterocolitis, gastritis, and esophagitis have been noted in different studies. There is also disruption of enterocyte membrane with increase inflammation in the gut. The inflammatory markers like cytokines, immunoglobulins and lymphocyte profiles are altered in children with Autism. This leads to increased intestinal permeability, and deficient enzymatic activity. Studies have also shown strong correlation between the gastro-intestinal problems and severity of Autism.
Common GI disorders observed in children with Autism
Gastro-eosophageal reflux disorder (GERD)
Gluten/ Casein intolerance
1. Gastrointestinal flora and gastrointestinal status in children with autism-comparisons to typical children and correlation with autism severity. Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA BMC Gastroenterol. 2011 Mar 16; 11:22.
2. Normal gut microbiota modulates brain development and behavior. Heijtz, R. D., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., … Pettersson, S. (2011). Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3047–3052.
3. Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances. Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I., … Lipkin, W. I. (2011). PLoS ONE, 6(9), e24585.
4. Biological plausibility of the gut-brain axis in autism. Vasquez A. Ann N Y Acad Sci. 2017 Nov;1408(1):5-6
Genetics - Is autism heritable?
Genetic factors are thought to be one of the most significant causes for autism spectrum disorders. It was estimated that genetics could explain the occurrence of autism in over 90% of patients, however the studies later proved that this was an over estimate. In a twin study that was conducted it was found that many of the non-autistic co-twins had learning or social disabilities. Thus explaining the occurrence of autism, purely on the basis of genetics is a very complex task. As how, different genes interact with each other, how much penetrance (how deeply are they responsible for a certain feature or characteristics), what defect is there in the gene, environmental triggers, and many other factors finally decides, whether a child is or would be autistic or not.
A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult. There are several theories based on environmental factors that have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects, and others focus on the environment after birth, such as children’s diets.
Prenatal and perinatal risk factors could be one of the most important environmental triggers for autism. There are several prenatal risk factors which could cause autism, like advanced age of either parent, diabetes, bleeding, and use of psychiatric drugs in the mother during pregnancy. A child’s risk of developing autism has also been associated with the age of his or her parent at birth. The biological reasons for this are unknown: possible explanations include increased risk of pregnancy complications, increased risk of chromosomal abnormalities, spontaneous mutations, etc.
Autism is associated with some perinatal and obstetric conditions. A 2007 review of risk factors found associated obstetric conditions that included low birth weight and gestation duration, and hypoxia during child birth. This association does not demonstrate a causal relationship. As a result, an underlying cause could explain both autism and these associated conditions.
A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, vaccines, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies. The subject remains controversial and extensive further searches for environmental factors are underway.
Other maternal conditions:
Prenatal stress consisting of exposure to life events or environmental factors that distress an expectant mother, have been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. There have been animal studies which have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism.There also have been studies which report that prenatal high testosterone levels in the amniotic fluid and prenatal exposure to ultrasound waves have been fleetingly associated with autism, though no substantial evidence to support it has come through.
Diabetes in the mother during pregnancy is a significant risk factor for autism apart from that obesity and hypertension during pregnancy are also associated risk factors. How they contribute to development of autism though is still not clear.
Thyroid deficiencies in the first 8-12 weeks have been postulated to produce changes of autism. Thyroxine deficiencies can be caused by inadequate iodine in the diet, improper absorption or possible environmental agents such as flavonoids in food, tobacco smoke, and most herbicides. However, this hypothesis has not been proven yet.
Recently it has been noticed that certain traits of the father of the child may also contribute as a risk factor for autism.
Paternal Age: Studies have suggested that advance paternal age is a risk factor for Autism. The risk of children developing autism increases 3 folds in fathers above the age of 45 years as compared fathers with the age of 24 years. Not only advanced age but also younger age can contribute to child developing autism. A study has suggested fathers with the age less than 20 years also have higher risk of their child developing autism. This risk carries forward over generations, a study suggests if fathers age if above 50 years, not only their children but their grandchildren also have a higher risk of developing autism.
Environmental factors play a role in increasing risk of Autism. With urbanization and industrialization we are exposed to chemical pollutants in air, water, soil and therefore even the food we eat. With advent of technology we are exposed to more and more electromagnetic radiations. These elements are presumed to contribute to increased risk of Autism.
Electromagnetic radiations can alter bio-electric activity of the brain, increase blood brain barrier permeability and induce epigenetic modifications. This can potentially alter brain development and damage the brain cells. Wireless radiations can potentially contribute to neuroinflammation. Exposure to wireless radiations during pregnancy may affect the fetus. Children exposed to wireless radiations early in the childhood may also experience harmful effects of the radiation. These radiations are presumed to interfere with the ability of human body to excrete heavy metals. This can lead to heavy metal accumulation inside cells and cause toxicity. Reducing the exposure to wireless radiation has shown reduction in the symptoms of Autism in some instnaces. Although the evidence for the causative effect of these radiations is very minimal at the moment, it warrants further investigation.
Mercury poisoning has been thought to be one of the causes of autism. Mercury binds to Cystein-Thiol which can damage brain cells. Glutathione prevents mercury binding to Cystein-Thiol group. Glutathione levels in children with autism are significantly reduced as compared to normal individual, in addition mercury cannot be excreted effectively in children with Autism. Therefore, mercury exposure can lead to toxicity in these children. Mercury toxicity can cause immune deficits, sensory deficits, motor deficits and behavioural abnormalities; all of these present in children with autism. However, this cause has not been very well validated. A meta-analysis published in 2007 concluded that there was no link between mercury and autism.
Lead levels as less as 10 μg/dl can cause aberrant learning and defective neurobehaviour in Autism. High levels of lead can cause permanent brain dysfuction, impaired cognition and learning, behavioural disorders, attention deficit, affected communication and social funcitoning.
Alluminium is a neurotoxin and a strong immune adjuvant, its neurotoxicity could be attributed to its impact of inducing oxidative stress and liberating DNAase which is a significant DNA damage inducer.
The MMR vaccine theory of autism is one of the most extensively debated theories regarding the origins of autism. There are different concerns regarding vaccination and its relationship with autism. Primary concern being the Measels – Mumps – Rubella (MMR) Vaccine itself causing autism, second one of the preservatives used in different vaccines causing autism and third simultaneous administration of multiple vaccines can overwhelm the immune system that leads to immune compromise causing autism.
There was a finding presented by a British Gastroenterologist in Dr. Andrew Wakefield who presented a case series of 8 children with Autism who were diagnosed of Autism 1 month after receiving the MMR vaccine (8). The findings in the paper however were refuted by many other scientists due to lack of control group, inability to disprove the coincidental occurrence of autism in these children. There were approximately 40000 children receiving the vaccine every year in the UK and the prevalence of autism was 1 in 2000 children in 1998. Therefore, it was very likely that this could be an coincidental finding. This paper was later retracted by Lancet.
Twenty epidemiological studies thereafter from different countries with large enough population to detect even a minor effect of vaccines on autism have been conducted, all of these studies don’t show any relation between vaccination and risk for Autism. (9)The Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the U.K. National Health Service have all concluded that there is no evidence of a link between the MMR vaccine and autism. As diseases like measles can cause severe disabilities and death, the risk of a child’s death or disability due to not vaccinating a child is significantly larger than presumed risk of child developing Autism.
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2. Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Annals of neurology. 1999 Mar 1;45(3):287-95.
3. Schifter T, Hoffman JM, Hatten JR HP, Hanson MW, Coleman RE, DeLong GR. Neuroimaging in infantile autism. Journal of Child Neurology. 1994 Apr;9(2):155-61.
4. Mountz JM, Tolbert LC, Lill DW, Katholi CR, Liu HG. Functional deficits in autistic disorder: characterization by technetium-99m-HMPAO and SPECT. Journal of Nuclear Medicine. 1995 Jul 1;36(7):1156-62.
5. Zürcher NR, Bhanot A, McDougle CJ, Hooker JM. A systematic review of molecular imaging (PET and SPECT) in autism spectrum disorder: current state and future research opportunities. NeurosciBiobehav Rev. 2015 May;52:56-73.
6. Wang C, Geng H, Liu W, Zhang G. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine (Baltimore). 2017 May;96(18):e6696
7. Modabbernia A, Velthorst E, Reichenberg A. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol Autism. 2017 Mar 17;8:13
8. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A. RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.
9. Plotkin S, Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clinical Infectious Diseases. 2009 Feb 15;48(4):456-61.