The medical basis of autism spectrum disorder: Clues for treatment and improving the lives of the entire family

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Review Article
Volume 1(5): 116-119Pediatr Dimensions, 2016 doi: 10.15761/PD.1000127
Pediatric Dimensions
e medical basis of autism spectrum disorder: Clues for
treatment and improving the lives of the entire family
Richard E. Frye*
Arkansas Children’s Research Institute, Little Rock, AR, USA
Correspondence to: Dr. Richard E. Frye, Slot 512-41B, Room R4041, 13
Children’s Way, Little Rock, AR 72202, USA; Tel: 501-364-4662; Fax: 501-364-
1648; E-mail: REFrye@uams.edu
Received: August 03, 2016; Accepted: August 20, 2016; Published: August 25,
2016
e incidence of autism spectrum disorder (ASD) has risen at an
alarming rate over the last several decades, seeming to have stabilized
at a prevalence of almost 2% of children [1,2]. Although the reason
for the dramatic rise continues to be debated, [3] the fact remains
that a signicant number of children suer from ASD and that the
disability associated with ASD spills over onto the family [4]. Recently,
the combined medical, non-medical, and productivity costs has been
estimated to be around $268 billion annually, exceeding the costs of
stroke and hypertension [5].
Despite the fact that decade of research has investigated the basis
of ASD, the fact remains that the etiology of ASD remains poorly
understood [6]. We previously pointed out that genetic-based research
has long dominated the eld of ASD research and the number of papers
published on the genetics of ASD far outnumbers research papers on
other topics [6]. is has been driven in some part by the fact that ASD
appears to be highly heritable [7]. However, clinical genetic research
has not supported the notion of ASD being caused by Mendelian
inherited genetic defects. For example, the 2013 American College
of Medical Genetic guidelines estimate that known genetic defects
account for a little more than 30% of cases [8]. Most surprisingly
was a recent study that demonstrated a yield of a genetic diagnosis
for ASD of just 15.8% using both chromosomal microarray analysis
and whole-exome sequencing [9]. Perhaps more surprising is the fact
that a whole-genome sequencing study revealed that the majority of
siblings with ASD demonstrate dierent genetic mutations, thereby
suggesting that apparent familial forms of ASD are not driven by
simple Mendelian inherited mutations [10]. is is consistent with
studies that demonstrate a high rate of de novo mutations, which, for
the large part, are not absolutely deleterious by themselves, but involve
that mutations in genes connected through interactions of the proteins
they produce [11]. is raises the question as to whether genetic
mutations have arisen secondary to errors in deoxyribonucleic acid
(DNA) maintenance and/or the result of DNA damage due to exposure
to extrinsic and/or intrinsic stressors.
A relative large study of twins in California estimated that the
environment contributes a greater percent of the risk of developing
autistic disorder (58%) as compared to genetic factors (37%) [12].
A more recent study from Sweden that included twins, siblings and
cousins found a slightly higher genetic contribution (~50%) and
suggested that the etiology of ASD was most consistent with additive
genetic and non-shared environmental eects [7s]. ese studies
point to the fact that an important piece of the etiology of ASD, the
environment, must be included when considering the etiology of ASD.
Although environmental research focusing on ASD has been increasing
in recent years, [6] a recent review has pointed to the limitations in
previous studies and the need for further high-quality studies [13].
Most interestingly, the review pointed to the emerging evidence of the
potential interaction between genes associated with ASD and specic
environmental toxicants [13]. Of course one exciting consequence of
considering the environment in the etiology of ASD is the fact that
the environment is a potentially modiable risk factor that can be
manipulated to reduce the incidence of ASD.
Understanding the biological mechanisms of how the environment
may cause ASD is important. Several potential physiological mechanisms
could translate environmental exposure to adverse biological outcomes
including disruption in redox and mitochondrial metabolism as well
as dysregulation of the immune system.6 For examine glutathione, the
body’s major intrinsic antioxidant, has been shown to be abnormal in
cytosol and mitochondria from cell lines, [14-16] peripheral immune
cells, [17] blood [18] and brain tissue [19] derived from children with
ASD. Many toxicants biologically cause physiological damage through
oxidative stress and these abnormalities in redox metabolism can not
only cause damage to proteins, lipids and DNA, but can also cause
mitochondrial dysfunction and inammation [19,20] as well as result
in alterations in the transmethylation pathway and DNA methylation
[21]. As DNA methylation is essential for epigenetic control of genes,
this is a pathway which can silence the gene expression without causing
genetic mutations.
Best known for their essential role in the production of adenosine
triphosphate (ATP) through oxidative phosphorylation, the
mitochondria are also intimately involved in other essential cellular
functions such as calcium buering, redox regulation, apoptosis
and inammation. ATP produced by the mitochondria is essential
for a large number of cellular systems. In general, mitochondria sit
at the convergence of many of the cell’s metabolic pathways where
they are thought of as central to the majority of cellular metabolic
functions. us, abnormal mitochondrial function can aect a
large number of cellular systems. Abnormalities in mitochondrial
function is being recognized as one of the most prevalent metabolic
disorders aecting ASD [22] and many children with ASD manifest
symptoms, [23] biomarkers, [22] neuroimaging ndings [22] and
electron transport chain defects [25] consistent with mitochondrial
disease. Interestingly, only about 25% of those children with ASD and
mitochondrial disease have identied genetic abnormalities to account
for their mitochondrial disease, [22] suggesting that mitochondrial

Frye RE (2016) e medical basis of autism spectrum disorder: Clues for treatment and improving the lives of the entire family
Volume 1(5): 116-119Pediatr Dimensions, 2016 doi: 10.15761/PD.1000127
dysfunction could be secondary to other unknown cellular metabolic
defects or due to damage from environmental agents. Indeed many of
the same environmental agents that have been linked to autism, such
as heavy metal, [13] pesticides [22] and iatrogenic medications such
as acetaminophen, [26-29] have also been linked to mitochondrial
dysfunction.
Still, we can think of environmental inuences in a boarder sense.
One of the most inuential environments a child experiences is the
intrauterine environment during gestation. More and more evidence
is accumulating that the maternal environment is important in the
development of childhood diseases, particularly ASD. One of the most
compelling ndings is maternal antibodies to fetal brain proteins.
Mothers with particular combinations of these antibodies have
ospring with ASD that may have a severe phenotype [30] and more
extreme brain enlargement [30] as compared to others with ASD. Still
others have provided data that points to the critical role of folate during
gestation and around the time of conception in protecting from the
development of ASD [32-34] and a recent rodent study suggests that
folate receptor alpha autoantibodies, autoantibodies that have been
found in both children with ASD and their parents, [35] may have a role
disrupting folate metabolism during pregnancy [36]. Other research has
pointed to the fact that a genetic polymorphism in the reduced folate
carrier in mothers increases the risk of ASD in the ospring [37]. Any
disruption in folate metabolism can alter methylation at a critical time
during the pre-implantation stages of embryo development, resulting
in devastating change to the embryo [38]. ese provide examples of
the importance of the maternal environment in the development of
ASD and provide other examples of pathways toward interventions
that may prevent the development of ASD.
Another important environmental factor is the microbiome,
the trillions of microorganisms that live on our bodies. ese
microorganisms can have inuence our immune system and inuence
metabolism. ere is growing evidence that children with ASD
have imbalances in the enteric microbiome [39]. e microbiome is
being increasing recognized as involved in the development of many
childhood diseases including ASD, allergic disease and obesity [40].
Interestingly, once thought as sterile, it is being revealed that the
prenatal environment has its own microbiome [41,42] suggesting
that the maternal microbiome during pregnancy can aect childhood
health [42]. e microbiome is established within the rst two years of
life [43] and preliminary data suggests that probiotics are most useful
in preventing childhood disease when given during gestation or early
in life [44]. As there is some evidence that microbiome disturbances
could be linked to metabolic abnormalities associated with ASD,
[45,46] manipulation of the microbiome could be an promising focus
of ASD treatment [39].
A better understanding of the etiology of ASD can lead to the
developed of treatments that target underlying pathophysiology
associated with ASD as well as core and associated ASD symptoms. We
recently reviewed some of the evidence for pathophysiology associated
with ASD and the evidence for potential treatments [47]. It is important
to recognize that considering the underlying pathophysiology of ASD
is critical to developing better treatments. Failure to appreciate this
fact had led to the misdirection in drug development. For example,
Selective Serotonin Reuptake Inhibitors showed promising results
on adults with ASD in initial studies but they could not be shown to
have ecacy in the target childhood ASD population [48] his reects
dierences in the pathophysiological processes believed to underlying
well studied psychiatric diseases and the unique nature of ASD.
Developing treatments that target underlying pathophysiology
can also steer research to developing disease modifying treatments
rather than symptomatic treatments. For example, the only Food
and Drug Administration (FDA) approved treatments for ASD are
atypical antipsychotic medications which are indicated associated, not
core, ASD symptoms. ese medications do not appear to be disease
modifying but rather are associated with adverse cardiometabolic eect
within a short time period (i.e., < 3 months) [49] and increase the risk
for developing Type II Diabetes in children [50]. Subjecting children to
the development of such adverse health risk factors can certain result in
complicated medical management as they grow older into adulthood.
us, there is an urgent need for drug development for children with
ASD, as there currently are no FDA approved medical treatments for
ASD that targets the core symptoms of ASD or corrects underlying
physiological abnormalities.
Treatments that target underlying pathophysiological processes
might not only alleviate ASD symptoms but may improve the lives of
individuals with ASD by improving or preventing the development
of comorbid disease. An interesting recent study from Sweden
demonstrated substantially higher mortality rates (2.6 times higher)
in individuals with ASD as compared to matched controls with lower
functioning individuals with ASD having higher mortality rates than
higher functioning individuals with ASD [51]. Although this was
recently veried in a Danish study, [52] the Danish study primarily
found evidence for neurologic and psychiatric comorbidities as a cause
for higher mortality. As others have pointed out, there is a high rate of
mortality associated with epilepsy in ASD, [53] providing an example of
how comorbid conditions substantially impact the lives of individuals
with ASD. Although the study from Sweden did indeed conrm
previous studies demonstrating the substantial higher mortality
rate from neurologic and psychiatric disease in ASD, especially in
lower functioning individuals, it did demonstrate higher mortality
rates due to other diseases including neoplasm, endocrine disease,
cardiovascular, respiratory, digestive and genitourinary systems and
congenital malformations [51]. Most importantly the recent study
from Sweden showed the excess mortality due to suicide in higher
functioning individuals with ASD, thereby highlighting potentially
poorly controlled or undertreated or poorly recognized psychiatric
problems in these individuals.
us, ASD is a complicated disorder with morbidity that spreads
beyond the core behavioral symptoms which dene it. Examining ASD
from a biological perspective may give us insights into the treatments
and prevention strategies. It is most important to consider that
individuals with ASD have complicated biology that can manifest in
many disease processes beyond neurologic and psychiatric disease that
can cause distress and reduce quality of life and increase morbidity.
Gastrointestinal [54,55] and sleep [4] disorders are two for the most
obvious but other disorders such as immune, atopic and nutritional
disorders can also substantially eect children with ASD [47]. is
strongly argues for a multispecialty approach to evaluate and treat
children with ASD in order to improve quality of life and decrease
morbidity and mortality.
It is also important to appreciate that ASD is not a disease that is
isolated to an individuals. Children with ASD need substantial support
from their family as well as the educational and medical system. e
fact that full-time behavioral therapy is recommended as the standard
of care for children with ASD, demonstrates the load on the education
and health systems. However, we must factor in the fact that many
times at least one parent in consumed with coordinating, advocating

Frye RE (2016) e medical basis of autism spectrum disorder: Clues for treatment and improving the lives of the entire family
Volume 1(5): 116-119Pediatr Dimensions, 2016 doi: 10.15761/PD.1000127
and caring for a child with ASD. In this sense ASD no longer aects
1 in 68 children, but 3 or more times that many individuals. We
recently demonstrated the spillover eect in terms of comorbidities
in sleep disturbances [4]. Improving sleep onset with melatonin [56]
and behavioral modication can improve the quality of life of both
the parent and the child. So, even simply interventions can have a
substantial impact of the whole family.
us, it is time to take a more integrated approach to managing
complex childhood diseases like ASD. Innovation is needed to integrate
care for complex children and their families. Understanding the
pathophysiology of ASD will lead to the development of more eective
treatments and potentially even prevention strategies. Complete care to
treat and prevent ASD will require the cooperation and coordination
of multiple pediatric specialties as well as obstetricians and internal
medicine specialists, potentially rivalling the current model of medical
care.
Conict of interest
e author has no conicts of interests to declare.
Acknowledgements
is work was supported in part by the Arkansas Biosciences
Institute.
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