Introduction

Autism Spectrum Disorder (ASD) is a developmental disorder that severely impacts the

nervous system. The word “autism” first arose in the early 1900’s referring to a range of

neuropsychological conditions, stemming from the Greek word “autos” meaning “self.”

Describing conditions in which an individual is removed from social interaction, hence, an

isolated self. Autism includes difficulty with communication and social interactions, and

repetitive behaviors and restricted interests. Prevalence of autism in U.S. children has increased

by 119.4 percent from 2000 (1 in 150) to 2010 (1 in 68). Autism is the fastest-growing

developmental disability. Autistic disorder is a biologically based neurodevelopmental disorder

with multiple causes including genetics, environmental factors, poor immune system and

abnormal brain growth and structural abnormalities. The purpose of this paper is to narrow down

and eliminate false theories and phenomena to come closer to a conclusion.

Diagnosis

More than 3.5 million Americans live with Autism Spectrum disorder. The DSM-V

(Diagnostic and Statistical Manual of Mental disorders) is the American Psychiatric

Association's classification and diagnostic tool used to classify autism. Impairments in social

interaction and communication, as well as restricted repetitive patterns of behavior are the three

areas of difficulties required for diagnosis. Social impairments include profound difficulty

relating to other people, lack of joint attention and impairment in theory of mind. Delays in

preverbal language development and unusual use of language such as pronoun reversals and

echolalia (a parrot-like repetition of words) are common communication impairments. Repetitive

behaviors and interests include obsessive insistence on maintenance of routines and self-

stimulatory behaviors, for example, rocking back and forth. ASD encompasses autistic disorder
(DSM 299.00), Asperger’s syndrome (DSM 299.80) and pervasive developmental disorder – not

otherwise specified (PDD-NOS) (DSM 299.80). ASD can be reliably diagnosed at 24 months but

the average age of diagnosis is five years. An onset prior to age 3 is required for diagnosis.

Genetic Influences

Genetic influences play a substantial role in the causes of autism. Studies show a 90%

heritability rate, clearly proving a pattern of autism or related disabilities in many families. The

broader autism phenotype, also known as Asperger syndrome, supports the theory of a genetic

basis because family members of those with Autism display higher rates of social and language

deficits. Concordance rates of monozygotic (70-90%) and dizygotic (30%) twin studies support

this theory. This study looked at the genetic heterogeneity between the triad of impairments that

define ASD. 3,400 8-year old twins from the Twins Early Development Study and their parents

completed the childhood Asperger Syndrome test. High heritability for extreme autistic-like

traits and autistic-like traits are measured on a continuum, with no significant shared

environmental influences. All three subscales showed high heritability but low covariation.

Distinct genetic influences were identified in the genetic modeling for all three components,

suggesting that the three impairments defining ASD is heterogeneous genetically (Ronald, et al.

2006). A different study looking at genetic causes of syndromic and non-syndromic autism

shows genotype-phenotype correlations between causal gene mutations or cytogenetic

abnormalities and behavioral or morphological phenotypes. Many children with ASD have some

degree of learning disability and genetic disorders associated with learning disability have also

been associated with ASDs. Some predict that alleles of 10 to 100 or more genes, each of small

effect, may underlie the autistic phenotype. Several loci have been identified, some or all of

which may contribute to the phenotype. Some of the autism loci were also common to learning
disability loci. However, not all children with predisposing genes develop autism, indicating that

the genetic alterations should be seen as a predisposing factor. Different genes have been

identified in a monogenetic heritable form of autism. Neuroligins interact with neurexins

expressed in presynaptic neurons. The NLGN3 and NLGN4 genes, located at human

chromosome loci, are mutated in 1/100 of individuals with ASD. The neurexin 1 gene (NRXNl),

encodes a neurexin 1 signal peptide variant. It is a neuronal cell-surface protein that is involved

in cell recognition and cell adhesion by forming intracellular junctions through binding to

neuroligins. Neurexin gene mutations have been identified in individuals with autism. Shank

proteins are involved in the assembly of specialized postsynaptic structures and are important

requirements for the development of language and social communication. Recent studies have

confirmed that SHANK3 mutations can cause ASD with phenotypes characterized mainly by

severe verbal and social deficits (Caglayan 2010). Autism tends to occur among individuals who

have certain genetic medical conditions, including fragile X syndrome, tuberous sclerosis,

congenital rubella syndrome and untreated phenylketonuria (PKU). A cluster of unstable genes

may interfere with brain development, resulting in autism.

Environmental influences

Emerging research points to the effects of the gestational and perinatal environment on

the developing neural and immune systems as they may be related to autism. Several studies

have implicated maternal immune dysregulation during pregnancy in association with ASD.

Theories of prenatal causes include premature birth, viral infection or exposure, or bleeding

during pregnancy. Prominent among them are reports of maternal antibodies that react against

fetal brain proteins (Van de Water 2013). Children today are surrounded by thousands of

synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in
laboratory models. Not surprisingly, fewer than 20% of high-volume chemicals have been tested

for neurodevelopmental toxicity. Indirect evidence for an environmental contribution to autism

comes from studies demonstrating developing brain sensitivity to external exposures such as

lead, ethyl alcohol and methyl mercury. The most powerful evidence comes from studies linking

autism to exposures in early pregnancy – thalidomide, misoprostol, and valproic acid; maternal

rubella infection; and the organophosphate insecticide, chlorpyrifos. The developing human

brain is understood to be susceptible to injury caused by toxic chemicals in the environment,

with greater vulnerability during embryonic and fetal life. The growing list of chemicals

implicated in the causation of neurodevelopmental disabilities include Lead, Methylmercury,

Polychlorinated biphenyl, Arsenic, Manganese, Organophosphate insecticides, DDT, and Ethyl

alcohol. Children today are at risk of exposure with these human developmental neurotoxins

common in hazardous waste sites, and commonly detected in air, food and drinking water.

Studies finding direct evidence with specific environmental exposure include prenatal exposure

to Thalidomide. 100 Swedish thalidomide embryopathy cases had at least four that met

diagnostic criteria for autism. Misoprostol and Valproic acid were found to be relevant when

exposed during the first trimester of pregnancy. In utero exposure of rates to valproic acid has

been shown to produce behavioral abnormalities analogous to autism. Epidemiological and

clinical studies have linked maternal rubella infection in early pregnancy with autism. Risk for

autism appeared when infection occurred in the first 8 weeks post conception. Chlorpyrifos is an

organophosphate insecticide used extensively in agriculture and was previously used in school

buildings. Perinatal exposure of newborn rodents to low doses was shown to cause reduced

number of neurons that decreases the intelligence and persistent alterations of behavior. Each of

these findings show environmental exposure that appeared to have occurred prenatally, in the
first trimester. These findings have substantial implications for understanding the environmental

contribution to the causation of autism.

Structural Abnormalities

An abnormally large head circumference is characterized by 20% of those diagnosed.

Structural abnormalities include a smaller cerebellum and functional and structural abnormalities

in the limbic system: the amygdala and the hippocampus. The cerebellum receives information

from the sensory systems, the spinal cord, and other parts of the brain and then regulates motor

movements. The cerebellum coordinates voluntary movements such as posture, balance,

coordination, and speech, resulting in smooth and balanced muscular activity. It is also important

for learning motor behaviors. The Amygdala is the integrative center for emotions, emotional

behavior, and motivation. The hippocampus is thought to be the center of emotion, memory, and

the autonomic nervous system. These structural abnormalities explain some of the deficits that

are associated with ASD.

Vaccines?

Vaccinations have been a proclaimed theory of possible causes contributing to autism.

The MMR vaccine protects against three dangerous infectious diseases; measles, mumps and

rubella, which can cause severe morbidity, disability and even death. Multiple studies involving

14,700,000 children under the age of 15 has shown that the MMR vaccine is effective in

preventing measles and mumps in a majority of cases but no studies were done to assess the

vaccine against clinical or laboratory confirmed rubella. No specific association between the

MMR immunization and autism were found. Asthma, leukemia, Crohn’s disease, type 1

diabetes, and bacterial or viral infections were also found to have no association. SafeMinds, an

anti-vaccination group, provided $250,000 to scientists at the University of Texas Southwestern

school of medicine, the University of Washington, the Johnson Center for Child health and

development and other research institutions. Between 2003 and 2013 they conducted a long-term

investigation evaluating behavioral and brain changes of baby rhesus macaques that were

administered a standard course of childhood vaccines. 79 infant monkeys were subjected to six

different vaccination schedules. Neurodevelopmental outcomes and social behavior were then

assessed. “We examined behavior, and neuropathology in three brain regions found to exhibit

neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the

cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008

vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no

significant differences in negative behaviors between animals in the control and experimental

groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus

macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those

observed in ASD”(Bharathi, et al. 2015).

Current Research

Zebra fish (Danio rerio) are able to provide insight into mechanisms controlling

embryogenesis, organogenesis, physiology and behavior. Using zebra fish as a model has

benefits in developmental neuroscience, used to understand mechanisms of underlying brain

disorders that lead to functional and behavior deficits such as autism. They are used to study

embryological decisions including lineage (what the cells will become), timing of commitment

(when cells decide to assume a certain fate) and mechanisms by which cell fate is acquired.

Studies of abnormal neuroanatomy reveal consistent findings relating to the structure and

circuitry of the cerebellum, hence the reason for using a model with a similar brain structure and

all of the classical sense modalities. Three main avenues may effectively model abnormalities
including a candidate gene approach, designing a focused genetic screen for mutations that affect

brain structure and genetic screens designed to detect behavioral deficits in larve or adults that

may model the deficits that define autism. Initiating mating behavior is an example relating to

social behavior in humans. The zebra fish is a powerful analytic tool for investigating the

genetic, cellular, morphological and biochemical underpinnings of brain development and

function. Establishing innovative zebra fish models will be useful for analyses of brain

development and function in future research (Tropepe, et al. 2003).

Conclusion

The major problem in developing a unifying theory of autism is the large number of

variations of the disorder. Autism is a biologically based disorder of brain development. Genetic

factors including mutations, deletions, and copy number variants are clearly implicated in the

causation of autism. Environmental factors, including exposure to external toxins and viral

infections during pregnancy has proven to be relating factors. Structural abnormalities in the

brain such as a smaller cerebellum and functional abnormalities in the limbic system play a

contributing role. Vaccinations have been ruled out as a cause of autism due to no convincing

evidence relating the two, although SafeMinds is not satisfied with the results. Studies suggest

that environmental factors, genetic predisposition, poor immune system performance and

abnormal brain growth and structures may lead to causes of autism. The large increase in

diagnosis is partly due to greater awareness and the spectrum approach. A stable conclusion has

yet to be found but researches and scientists are continuing to research effective models, such as

the zebra fish for analyses of brain development and function with direct relevance to human

autistic etiology.