1. A REPORT ON
IDENTIFYING THE LINK BETWEEN THE ORIGIN OF
AUTISM AND SCHIZOPHRENIA
BY
HASITA KRISHNA V 2008A5PS631H
Under the Guidance of
Dr. VIDYA RAJESH
April, 2012
2. INDEX
Abstract
Method of Study
Autism and Autism Spectrum Disorders
Schizophrenia
Gestational Diabetes and its Implications
The Hypothesis
Summary of Findings
Scope for Further Study
3. Abstract
This paper aims to elaborate upon the possible link between autism and
schizophrenia. About 30% of all pregnant women in the world suffer from
gestational diabetes. The implications of gestational diabetes are far reaching
on the developing fetus, posing as a risk factor for the development of autism
and schizophrenia in these children. This paper hypothesizes that such a risk
is in fact very real. Further, we present our findings supporting this theory.
Both autism and schizophrenia are neurodevelopmental disorders resulting
from a multitude of possible factors. One of these risk factors is gestational
diabetes in the mother. Several changes occur in the mother due to GD, one of
which is that the maternal body uses lipids as a source of energy and directs
amino acids and ketones to the fetus. Fetal brain cells, rapidly dividing as they
are, begin to use all possible sources of energy including ketone bodies.
Ketone body oxidation causes damage to the developing neurons. When
mirror neurons are damaged in this process, the fetus is exposed to a higher
risk of developing autism or schizophrenia, or in rare cases both. As a result,
one can conclude that gestational diabetes is indeed a risk factor for autism
and must be treated with timely care.
Keywords: Autism, Schizophrenia, Gestational Diabetes, Ketone Bodies,
Mirror Neuron Systems.
4. Method of Study
The study started with an understanding of the basic pathology of autism and
schizophrenia. We outlined all the keywords one associates with autism and
schizophrenia. Of special focus was the fact that both disorders are
neurodevelopmental in nature.
The next step was to identify all possible factors that are, and several others
that may be, risk factors for one or both disorders. We zeroed in on
gestational diabetes, reasons for which we shall explain later. Further, we
understood gestational diabetes in detail and listed all the outcomes of GD in
the mother.
The next step was to identify which of these outcomes would have an impact
on the fetus, and what impact they could potentially cause. Once ketone
bodies were identified as the main culprit, we proceeded to sketch how they
may be causing said damage.
The final piece was to link this understanding with autism and schizophrenia.
We elaborate upon this aspect later in the report.
Throughout the course of the project, extensive literature survey proved as a
valuable resource, both to identify threads we could follow and to pursue
them. We have cited all the articles reviewed at the end of this report.
5. Autism and Autism Spectrum Disorders
Autism is a disorder of neural development characterized by impaired social
interaction, communication, and by restricted and repetitive behavior. These
signs all begin before a child is three years old. [1]
Autism, Asperger Syndrome, Childhood disintegrative disorder, Rett
syndrome; these disorders are marked by communication difficulties, social
deficits, repetitive behaviors and interests. Also, cognitive delays may be
observed. Although these diagnoses share some common features, individuals
with these disorders are thought to be "on the spectrum" because of
differences in severity across these domains. [2]
Schizophrenia
Schizophrenia is a mental disorder characterized by a breakdown of thought
processes and poor emotional responsiveness.[1] It most commonly manifests
itself as auditory hallucinations, paranoid or bizarre delusions,
or disorganized speech and thinking, and it is accompanied by significant
social or occupational dysfunction, usually observed later in life. [3] [4]
There is stark contrast between the manifestation of autism and that of
schizophrenia. Autism is observed exclusive in children and many of these
symptomsdisappear asthe individualgrows. Schizophreniaon the other hand
is mostly observed in later stages of life. The similarity, however, lies in the
fact that both are neurodevelopmental disorders. [5] [6]It can thus be
believed that one or more common causative factors can potentially trigger
one or both these disorders.
Causative factors were shortlisted on a broad spectrum and grouped together
into the following factors: [7]
Mechanical trauma, resulting in head injuries to the fetus or newborn.
Emotional distance, due to social conditions of the child.
6. Metabolic disorders in the mother during pregnancy.
Mechanical trauma is a broad topic to broach and may result not only in
autism or schizophrenia, but also in generic mental retardation. Emotional
abandonment cannot be quantitatively studied. Its statistical nature is beyond
the scope and timeline of this project. Metabolic disorders in the mother are
quite common. Accordingto the American Pregnancy Association, about 5% of
all pregnant mothers suffer from gestational diabetes. This percentage would
be higher in third world countries. Considering the world’s population and
world natality rate, [8] [9] about 70lakh children are exposed to the
consequences of gestational diabetes every year. Given these factors, we
zeroed in on studying the impact of metabolic disorders in the mother-more
specifically gestational diabetes.
Gestational Diabetes and its Implications
Gestational Diabetes Mellitus is a condition in which women who have
previously never been diagnosed with diabetes show high blood
glucose levels during pregnancy. [10]
Mothers who develop gestational diabetes use lipids as substrate for
oxidation, and redirect amino acids to the fetus. These amino acids are further
catabolized to ketone bodies in the fetus. (Ketosis occurs). Ketone bodies are
used as a substrate for cerebral oxidation. The products of oxidation (acetone
being the primary compound) are known to cause [11]
Detrimental effects on the individual’s IQ, and [12]
Significant mental retardation.
During our study, we also discovered that gestational diabetes is a
manageable condition. With the right diet and education on the topic, it is
possible to keep the disorder in check.
The genetic links establishing the pathway from ketosis to mental retardation
and/or psychoses were found at Harvard Autworks. The tree diagram is
presented here.
7.
8. Source: autworks.harvard.hms.edu
The path from gestational diabetes to mental retardation needs to be
elaborated upon. Gestational diabetes causes several changes to take place in
the mother’s body, which have consequences on the developing fetus. Some of
these consequences include [11]
Fetal macrosomia as a result of hyperglycemia.
Fetal hypertrophic myocardiopathy.
Hypocalcemia in the infant.
Ketosis in the fetus.
Of these factors, macrosomiaand ketosis have been studied in cases of autism,
the rest of the factors seem unrelated. Fetal macrosomia does not express a
9. cause and effect relationship with autism and thus was ruled out. Focus was
primarily shifted to ketosis.
Due to the mother’s body perceiving glucose to be ‘absent’ in blood, it begins
to use lipids as a source of energy. In lipid metabolism, each fat molecule
(triacylglycerol) is madeup of three free fatty acid moleculesand one glycerol.
Source: www.openlearn.open.ac.uk
Metabolism is by the Tricarboxylic Acid (TCA) cycle. Each triacylglycerol
molecule breaks down successively into diacylglycerol, monoacylglycerol and
finally the free fatty acids and glycerol. The fatty acid metabolism is the key
here. Fatty acids pass into the Krebs cycle at the cellular level and are oxidized
to provide energy. Ketone bodies-acetone, β-hydroxybutyrate and
10. acetoacetate-are generated as metabolic byproducts and released into the
system. [13] [14]
In adults, ketones are excretory products. They are expelled through sweat,
urine and expiration. In fetuses, a different scenario persists. Ketone bodies
are small, unbound molecules which are nonpolar in nature. Being small and
unbound, they pass the placenta by passive transport. Once across, the blood
brain barrier of the fetus has the potential to stop them. This does not happen
due to the fact that they are very small, nonpolar molecules. They are easily
carried into the developing brain. It is a known fact that rapidly dividing cells
depend on glycolysis for energy generation even in the presence of oxygen, a
phenomenon termed as the Warburg Effect. Inducing a ketogenic
environment to the cells drastically reduces the rate of growth. [15] This
technique is indeed being studied in cancer research. Extending the same
analogy to our model, the presence of ketone bodies interferes with the rapid
division of nerve cells in the fetus. This also serves to explain why adult nerve
cells are not affected by ketone bodies-they do not divide.
The exact damage caused by ketone bodies under these circumstances
remains unknown. But there is reason to believe that the damage caused is
irreparable and has far reaching consequences, such as mental retardation.
A question thus arises. How can wedetect the presenceand quantity of ketone
bodies in the fetus? How do we establish the threshold of ketone bodies that
cause mental retardation and other detrimental effects? Studies have
established the threshold level of ketone bodies in blood to be 0.3mg/dL. Any
amount over and above this threshold is medically identified as ketosis.
Further, since ketone bodies are oxidized in fetal brains along with, and not
exclusive of, glucose, there is no practical need to understand how much of it
can cause damage. Ketosis as a condition alone is enough to trigger the
oxidation process. How much is a question that experiments will have to
answer. Further, testing for ketone bodies in fetus can be directly achieved by
testing for the amount of acetone in maternal urine. [16]
11. The next step was to identify potential links between autism and
schizophrenia. Arrays of factors, ranging from genetic to geographical, were
found to link both these disorders. But none of these factors linked back to
ketosis. A lot of time was thus invested in ruling out all those factors that did
not directly link back to neuronal damage as a result of external causes. [17]
Breakthrough was achieved when we chanced upon the idea of mirror
neurons and pursued this thread. [18] [19] During recent times, the mirror
neuron system has gained interest as a research area. Mirror neurons are
identified as specialized neurons in the supra temporal sulcus and prefrontal
cortex and have been conclusively discovered in primates. These neurons, as a
system, help in reciprocation, responsiveness and the ability to learn. In other
words, they help an individual to ‘mirror’ the activities of others and form the
ground for social cognition. A damaged mirror neuron system can be
implicated as one manifestation in both the disorders.
How do we as humans know the agency of actions? In particular, how does
one discriminate one’s actions from that of another person? If I am a normal
adult, when I move my hand, I know I moved it and also know that someone
else did not move it. The same goes for speech and thought. Yet
schizophrenics may commit actions such as verbal utterances and hand
movements that they erroneously attribute to other agents, and they may
erroneously attribute the actions of others to themselves. The symptoms of
schizophrenia include delusions, hallucinations, disorganized speech,
disorganized or catatonic behavior. Hallucinations can take on the form of a
constant verbal running commentary or even include two or more voices
conversing with each other. In addition to having an understanding of what
one is doing, it is also important to know what other people are doing. For
this, we need a notion of action, what is being done, and agency, who is doing
it. Indeed, humans and many other animals have a way of placing themselves
in the actions of others. [20] In case of autism, the notion of action itself seems
to disappear. The patient remains unresponsive irrespective of the nature of
auditory stimuli provided.
Both these anomalies pointto a disruption in the mirror neuron system. While
it appears to be hyperactive in one case, it is subnormal in the other.
12. The Hypothesis
Mirror neurons, among other nerve cells, are affected by the fetal brain’s
usage of ketone bodies as a substrate for oxidation, making gestational
diabetes a potential risk factor for both autism and schizophrenia.
Summary of Findings
Although found to occur at different stages of life and showing dissimilar
outward manifestations, autism and schizophrenia are bound by the fact that
they are neurodevelopmental in nature. Several factors have the potential to
cause neuronal damage, and the mother’s health during term plays a very
important role in determining the child’s health. One such influential factor is
gestational diabetes. Among other changes, the maternal system begins to use
lipids as a source of energy, generating ketone bodies in the process. Ketone
bodies are small, unbound, nonpolar molecules that can cross the placenta
and subsequently the fetal blood brain barrier. Once in the cerebral tissues,
they are used up by the rapidly dividing nerve cells as a source of energy.
Owing to their inhibitory effect on cell division, ketone bodies cause neuronal
damage. Among the affected neurons are the mirror neurons. These neurons
have the special purpose of helping the individual respond and reciprocate,
thus aiding in social cognition. As a result of the damage inflicted on them by
the ketone bodies, the developing infant has a higher risk of developing
autism or schizophrenia antepartum. Thus, gestational diabetes can be
identified as a potential risk factor for autism and schizophrenia. Pregnant
mothers must be educated on this issue [21] and steps must be taken to keep
ketosis under check in mothers diagnosed with gestational diabetes. [22] [23]
14. Scope for Further Study
There is immense scope to pursue the following ideas:
Experiments can be designed to identify damage to neurons due to
ketone body oxidation. This would add perspective to our findings.
Mirror neuron system can be studied in greater detail. The relationship
between autism, schizophrenia and mirror neurons can be conclusively
established.
Studies can identify potential targets (as pregnant mothers with
gestational diabetes), control ketosis in them and track the mental
health of the child over a period of time. This is a time consuming study
and requires a huge sample population.
15. Bibliography
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Help Group.
