Mitochondrial Disorders & Autism - AND - Autism and Seizures: A Brief Overview by Richard E. Frye, MD, PhD & Jon Poling, MD, PhD

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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.
Each cEll has approximatEly 100 mitochondria mitochondria arE thE EnErgy producing factoriEs of thE cEll
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.
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
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.
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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 nonenergy 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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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 | THE AUTISM FILE 95
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
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
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? 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 in children with autism and associated 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
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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
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
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.
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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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,
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. | THE AUTISM FILE 97

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