BIOMEDICAL
Richard E. Frye, MD, PhD
Dr. Richard E. Frye received his
MD and a PhD in physiology and
biophysics from Georgetown
University. He is board certified
in pediatrics and in neurology
with special competency in child
neurology. Dr. Frye is an assistant
professor of pediatrics and neurology
at the University of Texas Health
Science Center and is the medical
director of the medically-based
autism clinic in the Division of Child
and Adolescent Neurology in the
Department of Pediatrics.
Jon S. Poling, MD, PhD
Jon Poling, MD, PhD is the Medical
Director of the Athens Regional Medical
Center Apheresis Unit, Clinical Assistant
Professor Medical College of Georgia,
and a partner at Athens Neurological
Associates. He is board certified by
the American Board of Psychiatry and
Neurology. Dr. Poling’s education and
training includes residency at the Johns
Hopkins University Department of
Neurology/Neurosurgery and completion
of study for both his MD and PhD at the
Georgetown University School of Medicine.
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Understanding the Biological
Basis of Autism
Autism is diagnosed based on observing
a triad of abnormal behaviors—
impaired social interaction, impaired
communication, and a restricted pattern
of stereotyped behavior. Several
abnormalities in brain development have
been identified in autism. These brain
abnormalities include the connections
between nerve cells, the modifications
of connections called synaptic plasticity,
and the organization of nerve cell
networks. Over the past decade, we have
come to understand that the biological
underpinnings of autism are not limited
to the brain and involve several organ
systems. Indeed, it is increasingly
recognized that children with autism
have many medical problems arising
from several separate body systems,
including the gastrointestinal, central
nervous, immune, and detoxification
systems. Identifying a common link to
tie the abnormalities in these systems
together would substantially advance
Each cell has
approximately 100
mitochondria
mitochondria are
the energy producing
factories of the cell
our understanding of what causes
autism and why. Furthermore, research
into the biological basis of autism has
unlimited potential to develop treatments
and strategies for prevention by early
identification of those at highest risk.
Although identification of such a link
has eluded us in the past, recent studies
have suggested that autism might be
linked to dysfunction of the mitochondria;
a mitochondrion is a subcellular structure
that is the powerhouse of every cell in
our body. We know that mitochondrial
disorders can cause medical problems
in many body systems, just like those
discovered in autism. This exciting new
evidence has raised the possibility that
dysfunction of the mitochondria may
be one of the keys that link the many
diverse symptoms seen in autism. In
this brief article, we outline some of the
evidence linking autism and mitochondrial
disorders. Although preliminary, this
evidence provides hope that we may have
a clearer understanding of at least one
piece of the puzzle in the near future.
ISSUE 31 2009

Recent studies have suggested that autism might
be linked to dysfunction of the mitochondria; a
mitochondrion is a subcellular structure that is the
powerhouse of every cell in our body.
The Mitochondria:
Why Are They Important?
Each cell has approximately 100
mitochondria. Mitochondria are the
energy producing factories of the cell.
These subcellular organelles process
nutritional fuels, both carbohydrates
and fats, to make a common energy
commodity, called adenosine triphosphate
(ATP). Cellular structures, systems, and
enzymes derive the energy they need
by breaking down ATP to adenosine
diphosphate (ADP). ADP is then recycled
by the mitochondria to make ATP, and the
cycle continues.
Since most of the cell’s systems can
only use energy in the form of ATP, the
mitochondria are essential for the cell to
function. The process of transforming
nutritional fuel into ATP from ADP is a
complex process that requires processing
the body’s fuels through several
mitochondrial enzyme cascades. Two of
these enzyme cascades, the tricyclic acid
cycle and the electron transport chain, are
the final common pathways for producing
energy. Several other key metabolic steps
occur in the mitochondria, including the
beta-oxidation cycle that breaks down fats
into smaller units that can be processed
through the tricyclic acid cycle, the urea
cycle that processes nitrogenous wastes,
and the porphyrin cascade that processes
heme, an important factor for the
transportation of oxygen in the red blood
cells and for detoxification enzymes.
Dysfunctional mitochondria can have
widespread effects on the cell. Aside
from a deficit in cellular energy, many
other metabolic pathways can become
deranged since both energy and non-
energy producing metabolic systems
feed their final biochemical products
into mitochondrial pathways. Thus, if the
mitochondria become non-functional,
final end products from several metabolic
systems may build up, resulting in the
metabolic systems themselves shutting
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down. Buildup of metabolic products can
also be toxic to the cell. The mitochondria
are essential for signaling when it is time
for the cell to die through the complex
process of programmed cell death called
apoptosis. Signaling apoptosis prematurely
can have profound effects on the cell,
tissue, and organism that it supports.
Furthermore, dysfunctional mitochondria
can create reactive oxygen species that
can be damaging to neighboring healthy
tissues as well as to individual cell
function.
Mitochondrial Disease:
A Relatively New Medical Disease
The discovery that dysfunctional
mitochondria can result in a medical
disease was only realized within the
last thirty years. Since that time, over
thirty genetically-based mitochondrial
disorders have been described—all of
them rare. However, it has recently
been discovered that mitochondrial
dysfunction is involved in a diverse group
of medical diseases from Parkinson’s
disease to diabetes mellitus. Mitochondrial
dysfunction, as opposed to mitochondrial
disease, probably does not cause disease
directly; rather, dysfunction of this
important subcellular structure most
likely contributes to the development and
progression of these common diseases,
making some people more vulnerable and
allowing the disease to progress faster
in others. This issue presents a difficult
chicken-or-egg question that begs for
further intense scientific study. Studies
have recently estimated that the carrier
rate of pathogenic mutations in the
mitochondrial DNA is a staggering 1 in 50
persons, suggesting that approximately 1
in 4,000 people probably manifests some
form of mitochondrial dysfunction. This
suggests that mitochondrial dysfunction
may be relatively common, but since
obvious mitochondrial disorders are
still rare, this suggests that we are only
beginning to learn the significance of
mitochondrial disorders.
Mitochondrial Dysfunction:
Can It Explain Multiple Medical
Problems in Autism?
Those affected by mitochondrial disorders
may present with several non-specific
symptoms, including developmental
delay, loss of developmental milestones
(i.e., regression), seizures, muscle
weakness, gastrointestinal abnormalities,
and immune dysfunction. In general,
mitochondrial disorders affect the body
systems that have high energy demands.
Some of the same body systems that are
dysfunctional in mitochondrial disorders
are also the systems that are dysfunctional
in autism. In fact, the clinical criterion for
determining if a mitochondrial disorder
is present in a child depends upon the
presence of many of the same symptoms
that are common in children with autism.
This indicates that at least a subset of
children with autism reach criteria for
a “probable” mitochondrial disorder
by established criteria even before any
invasive tests are performed. By this line
of reasoning, the multisystem dysfunction
commonly seen in autism could be
explained by an underlying mitochondria
disorder. Consideration of this idea should
be tempered with the fact that some
high-energy organs commonly affected in
individuals with mitochondrial disorders,
such as the heart and the kidney, are not
commonly found to be dysfunctional in
autism.
Mitochondrial Dysfunction: Possibly
One of the Most Common Underlying
Medical Disorders in Autism
The issue of mitochondrial dysfunction
in autism is not a new finding but rather
a recent rediscovery of work performed
over twenty years ago. Dr. Mary Coleman
from Georgetown University described
a conspicuous increase in lactic acid
in the blood of a subset of children
diagnosed with autism. Elevated lactic
acid is now understood to be a marker
for mitochondrial disorders; however,
at that time, Dr. Coleman suggested
that this elevation in lactic acid was
representative of a more general disorder
of carbohydrate metabolism. Over the
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 BIOMEDICAL
past five years, others have confirmed
elevations in lactic acid as well as
abnormalities in other metabolic markers
of mitochondrial disorders in children with
autism. More importantly, definite cases
of mitochondrial dysfunction have been
documented in autism as well as in rare
cases linked to genetic mitochondrial DNA
disease. Studies that have documented
the precise mitochondrial disorder have
implicated dysfunction of the electron
transport chain - the final pathway for
energy production - in children with
autism.
One study from Portugal used
traditional markers to screen children
evaluated in their autism clinic for
mitochondrial disorders. Children with
abnormal markers underwent muscle
biopsies to confirm a mitochondrial
disorder. This population-based study
estimated that between 4% and 7%
of children with autism probably had
mitochondrial disease in their population.
However, other studies have suggested
that non-traditional serum markers,
rather than traditional markers, may be
elevated in children with autism. Thus,
it is possible that studies that do not
screen patients with these non-traditional
markers, such as the Portugal study, could
be missing the diagnosis of mitochondrial
disorders in some children. This raises the
possibility that the estimated prevalence
of mitochondrial disorders in children with
autism has been underestimated.
Mitochondrial Dysfunction in Autism:
Inherited or Acquired?
The more common genetic mutations
that can cause mitochondrial disorders
can be identified with simple blood tests.
These known disease-causing genetic
mutations have only rarely been reported
in children with autism and mitochondrial
disorders. This raises the possibility that
many of these mitochondrial disorders
found in children with autism could be
acquired. Indeed, we know that certain
environmental toxins including heavy
metals, like lead and mercury, can poison
mitochondrial function. Additionally,
short-chain fatty acids, such as propionic
acid, that can be produced by gut bacteria
have been very recently shown to inhibit
mitochondrial function. Further research
96 THE AUTISM FILE | www.autismfile.com REPRINTED WITH PERMISSION © THE AUTISM FILE
This exciting new evidence has raised the possibility that
dysfunction of the mitochondria may be one of the keys
that link the many diverse symptoms seen in autism.
will be needed to understand why
mitochondria are dysfunctional in
autism, but evidence is growing for
acquired, rather than a genetically
inherited, cause for mitochondrial
dysfunction in children with autism.
If such evidence is substantiated, this
would mean that dysfunction of the
mitochondria is only one part of the
complex cascade that results in autism,
and that mitochondrial dysfunction might
be treated by removing substances that
cause their dysfunction.
Mitochondrial Dysfunction:
How Can It Be Diagnosed? in children with autism and associated
Methods for diagnosing mitochondrial
disorders are still in the development
phase. Currently, diagnosis of a
mitochondrial disorder involves a
series of blood and urine tests to look
for specific markers for mitochondrial
dysfunction. It is difficult to diagnose
mitochondrial disorders with one abnormal
marker, and a pattern of abnormalities is
usually considered when reviewing the
results of blood tests. This is akin to a
biochemical “fingerprint.” These markers
are not always abnormal, and they may
intermittently fluctuate, sometimes
resulting in false negative results. On
the other hand, it is not uncommon for
these biological markers to be falsely
elevated due to a difficult blood draw
or the tourniquet being on too long.
Thus, many times these blood tests
need to be repeated or drawn serially
relative to timing of a meal. In fact, some
mitochondrial specialists recommend
documenting abnormal biochemical
markers three times before accepting the
biochemical markers as truly abnormal.
Once a mitochondrial disorder is
suspected, the exact type needs to be
determined. In order to diagnose the
correct type of mitochondrial disorder,
many children undergo a procedure called
a muscle biopsy. In this procedure, the
surgeon removes a very small piece of
muscle through a small incision, usually on
the thigh, under general anesthesia. Once
the muscle is obtained, it can be examined
under the microscope for signs of a
mitochondrial disorder. Most importantly,
several of the important enzymes in the
critical energy producing enzyme cascades
can be tested to determine their ability to
function.
Mitochondrial Dysfunction:
How Can It Be Treated?
There have been few randomized clinical
trials for children with mitochondrial
disorders, but none have been conducted
metabolic disorders. One compound that
has been studied in Friedreich’s ataxia, a
disease with mitochondrial dysfunction
at its core, is the coenzyme Q10 analog,
idebenone. This compound has been
shown to prevent cardiomyopathy. This
compound has not been widely studied in
mitochondrial disorders or autism.
The precise diagnosis of the type
of mitochondrial disorder may lead to
vitamin supplement therapies or diets
based upon rational biochemistry and
knowledge of what vitamins/cofactors
may supplement the defective enzyme
machinery or which diet may provide
the best fuels for the specific disorder.
Interestingly, these supplements and diets
are many of the same treatments that
have been recommended by the autism
ISSUE 31 2009
biomedical community for years. This
clearly represents an intersection between
mainstream and alternative medicine
practices.
Treatment also consists of specific
precautions to avoid prolonged fasting,
dietary recommendations, anesthesia
precautions for surgery, and the avoidance
of infections, if possible. Specific
recommendations are also available
Autism and Seizures: A Brief Overview by Richard E. Frye, MD, PhD
Autism is associated with a high
prevalence of both clinical and
subclinical seizures and epilepsy. It is
important to understand the distinction
between clinical seizures, subclinical
seizures, and epilepsy.
A clinical seizure occurs when abnormal
rhythmic electrical discharges in the
brain result in abrupt characteristic motor
behavior usually associated with loss
of consciousness. Most people think of
generalized tonic-clonic seizures when
they think of a seizure occurring. During
a generalized seizure, a person loses
consciousness and both arms and legs
move synchronously either in a repetitive
jerking fashion or become stiff. Most
generalized seizures only last a few minutes
and will not result in long-term damage,
but seizures that go on for ten minutes or
more can be dangerous to a person and
require intervention. Most parents who have
children with epilepsy have a medication
such as Diastat that can be used to stop the
seizure if it continues on for a prolonged
period of time. Some people have partial
seizures. These types of seizures are limited
to abnormal rhythmic movements on one
side or one portion of the body, for example
the arm or the face. When these types of
seizures are associated with a change in
consciousness, they are known as partial
complex seizures. Still another type of
seizure is a myoclonic seizure which can be
localized or generalized. Many other types
of seizures exist, and many other abnormal
movements such as tics and movement
disorders can be mistaken for seizures, so
it is important for a medical professional
to evaluate anyone suspected of having
seizures.
Epilepsy is defined by more than one
unprovoked seizure. Many children will have
febrile seizures. Since the fever provoked
the seizure, by definition, children with
febrile seizures do not have epilepsy. Many
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regarding anti-pyretic (fever) therapy,
intravenous hydration, and nutritional
supplements during acute illnesses.
Mitochondrial Dysfunction and
Autism: Implications for the Future
In summary, there is much still to
be learned regarding the biology of
autism spectrum disorders and that of
mitochondrial disease. Both older and
typically developing children also will have
more than one unprovoked seizure and be
diagnosed with epilepsy. The epilepsy will
resolve in most of these children in one or
two years.
Autism is associated with an increased
risk of epilepsy and almost every type of
seizure has been described in autism. There
appears to be two age peaks when epilepsy
presents itself in autism: before five years
of age and in adolescence. The risk of
epilepsy in autism increases with severe
mental retardation and/or cerebral palsy.
Several genetic syndromes associated with
autism, such as Rett’s, fragile X, Angelman
syndrome, and tuberous sclerosis, are
associated with a particularly high rate of
epilepsy. Thus, the underlying etiology, if
known, can be very helpful for predicting
whether an individual with autism will
develop epilepsy.
Children with autism have a high
prevalence of subclinical epileptiform
discharges. These rhythmic electrical
disturbances in the brain do not manifest
themselves as a typical clinical seizure (as
described above), but may disrupt cognitive
development. Some individuals may have
subtle signs of subclinical seizures such as
periodic episodes of unresponsiveness in
which they stare into space, but others will
not have any other symptoms aside from
atypical cognitive development. When these
subclinical discharges affect development,
the seizure syndrome can be called an
epileptic encephalopathy. Two of the best
studied epileptic encephalopathy syndromes
are Landau-Kleffner syndrome and
continuous spike waves during slow-wave
sleep (CSWS). Both of these syndromes
are characterized by continuous rhythmic
discharges occurring during sleep. Children
with these syndromes undergo sudden or
gradual regression in language usually after
three years of age and manifest behavioral
symptoms that include hyperactivity,
very recent evidence clearly supports
parallels between these two seemingly
different disorders. It is probable that at
least a subpopulation of autistic children
have mitochondrial disease as the core
biological lesion triggering the cascade
of complex medical and neuropsychiatric
issues. The field of mitochondrial
medicine holds much promise to unlock
the mystery of autism.
aggressiveness, and depression. However,
we are starting to recognize that other
non-classic epileptic encephalopathies also
exist. Recently, we have reviewed a series
of children with subclinical epileptiform
discharges and atypical developmental who
were treated at our facility. We found that
over half of these children presented with
a language disorder, attention problems,
and mild autism symptomatology, and most
children did not have any overt signs of
seizures or a history of language regression.
Importantly, the majority of these children
improved with antiepileptic treatment.
Most of the time, epilepsy is a
treatable disorder. The mainstay for
treatment is antiepileptic medication;
however, sometimes epilepsy does not
respond to antiepileptic medication.
Sometimes epilepsy appears to respond
to immunomodulatory therapies such as
steroids and intravenous immunoglobulin
(IVIG). Other treatments, such as the
ketogenic diet, can also be used to treat
epilepsy. Surgery is sometimes considered
for epilepsy that does not respond to other
therapies. A small part of the brain can be
removed if the epilepsy arises from a small
silent part of the brain. Other procedures,
such as multiple subpial transection (MST),
can be used if the seizures arise from an
eloquent part of the brain that is involved
in language processing or another critical
cognitive operation.
Children with autism are at increased
risk of being diagnosed with epilepsy, but
epilepsy is usually a treatable condition.
As long as seizures are controlled,
epilepsy should not have a major adverse
impact upon a child’s life. Some children
with autism could have an epileptiform
encephalopathy that may respond to
standard treatment for epilepsy, particularly
if their symptoms of autism are mild.
Interestingly, many of the treatments for
epilepsy overlap treatments used for autism.
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