Biological Findings In Autism:
Developing A Medical Based Standard Of Care
"Despite the fact that the prevalence of autism spectrum disorder (ASD) continues to rise, no effective medical treatments have become standard of care. In this paper we review some of the pathophysiological abnormalities associated with ASD and their potential associated treatments. Overall, there is evidence for some children with ASD being affected by seizure and epilepsy, neurotransmitter dysfunction, sleep disorders, metabolic abnormalities, including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and gastrointestinal disorders."
Frye and Rossignol. Identifcation and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes.
Autism is primarily defined as a disorder affecting communication (verbal and non-verbal), socialization, and behavior with restricted and stereotyped interests. Individuals may fall on a "spectrum" of how they experience symptoms of autism ranging from severe and profound to mild.
The development of autism appears to be a complex interaction of multiple genetic and environmental factors. It may be that a paradigm shift from seeing autism simply as a heritable disorder caused primarily by genes, to one in which genetic susceptibility combined with environmental factors is more accurate.
Though there has been a tremendous amount of research published establishing multiple pathophysiological findings in persons with autism, many major medical institutions, organizations, and providers have yet to incorporate these into clinical practice.
In 2016, the Illinois General Assembly passed "The Autism and Co-Occurring Medical Conditions Awareness Act" in order to encourage greater awareness, education, and treatment for the various medical issues that occur more often in those with autism. As these findings are better understood, promising practices and novel treatments may be developed. Autism has proven to be very complex, and medical treatments should be based on the individual's unique clinical profile.
This website has been created in order to share a small sampling of significant research with the intended goal to increase recognition and treatment of the various co-occurring and underlying conditions that may occur more often in those also diagnosed with autism.
The provision of this information is not intended to replace regular medical care, nor should links to research be considered an endorsement. All patients should consult with their personal medical provider.
"Autism is clearly a multi-system disorder that impacts the brain, the immune system, the gastrointestinal tract, and other organ systems."
Consensus Paper: Pathological Role of the Cerebellum in Autism,S. Hossein Fatemi, et.al The Cerebellum September 2012, Volume 11, Issue 3, pp 777-807
"This thorough literature search provides an overview of relevant articles on medical comorbidity in ADHD and/or ASD, and shows that medical disorders in these children and adolescents appear to be widespread. Those who work with children with ASD and/or ADHD should be well aware of this and actively promote routine medical assessment."
Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review; Jet B. Muskens · Fleur P. Velders · Wouter G. Staal; Eur Child Adolesc Psychiatry DOI 10.1007/s00787-017-1020-0
“For patients with ASDs, a detailed history (including personal history of allergic disease, dietary history, and family history) and physical examination should be performed to accurately identify potential co-morbid allergic disease... The role of immune responses in the pathogenesis of gastrointestinal disorders with ASDs warrants additional investigation.”
Consensus Report on Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs, Buie, et.al.
"Autism has been modeled as a brain-based, strongly genetic disorder, but emerging findings and hypotheses support a broader model of the condition as genetically influenced and systemic. These include imaging, neuropathology and psychological evidence of pervasive (and not just specific) brain and phenotypic features; postnatal evolution and chronic persistence of brain, behavior, and tissue changes (e.g. inflammation) and physical illness symptomatology (e.g. gastrointestinal, immune, recurrent infection); overlap with other disorders; and reports of rate increases and improvement or recovery that support a role for modulation of the condition by environmental factors (e.g. exacerbation or triggering by toxins, infectious agents, or other stressors, or improvement by treatment)."
Martha R. Herbert, AUTISM: A BRAIN DISORDER, OR A DISORDER THAT AFFECTS THE BRAIN?; Clinical Neuropsychiatry (2005) P, 6, 354-379
CDC's National Center for Health Statistics 2014-2016 surveillance data of 3-17 year olds estimates 1 in 36 has autism, and every 1 in 28 boys has been diagnosed with ASD.
"The prevalence of ASD has increased significantly over the past three decades and now is estimated to affect 2% (1) or more (2) of children in the United States (US). Even more significant is the fact that ASD does not occur in isolation. Children with ASD require significant support from the educational, medical and social systems that results in a significant economic burden (3) which is estimated to cost the US approximately $268 billion in 2015 (4)."
Frye RE, Vassall S, Kaur G, Lewis C, Karim M, Rossignol D. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019;7(23):792. doi:10.21037/atm.2019.11.53
"Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes."
Frye RE. A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder. J Pers Med. 2022;12(3):464. Published 2022 Mar 14. doi:10.3390/jpm12030464
"Studies have shown that children with ASD show changes in their levels of immune response molecules. Our previous studies have shown that ASD is more common in children with folate receptor autoantibodies. We also found that children with ASD have abnormal gut immune function, which was characterized by a significant increase in the content of immunoglobulin A and an increase in gut-microbiota-associated epitope diversity. These studies suggest that the immune mechanism plays an important role in the occurrence of ASD."
Cai C, Yin Z, Liu A, et al. Identifying Rare Genetic Variants of Immune Mediators as Risk Factors for Autism Spectrum Disorder. Genes (Basel). 2022;13(6):1098. Published 2022 Jun 20. doi:10.3390/genes13061098
"Autism spectrum disorder (ASD) is acknowledged as a highly heterogeneous, behaviorally defined neurodevelopmental disorder with multiple etiologies. In addition to its high heritability, we have come to recognize a role for maternal immune system dysregulation as a prominent risk factor for the development of ASD in the child. Examples of these risk factors include altered cytokine/chemokine activity and the presence of autoantibodies in mothers that are reactive to proteins in the developing brain."
McLellan J, Kim DHJ, Bruce M, Ramirez-Celis A, Van de Water J. Maternal Immune Dysregulation and Autism-Understanding the Role of Cytokines, Chemokines and Autoantibodies. Front Psychiatry. 2022;13:834910. Published 2022 Jun 2. doi:10.3389/fpsyt.2022.834910
"A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system."
Eve M, Gandawijaya J, Yang L, Oguro-Ando A. Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder. Front Psychiatry. 2022;13:842755. Published 2022 Apr 15. doi:10.3389/fpsyt.2022.842755
"Many studies have reported abnormal gut microbiota in individuals with Autism Spectrum Disorders (ASD), suggesting a link between gut microbiome and autism-like behaviors. Modifying the gut microbiome is a potential route to improve gastrointestinal (GI) and behavioral symptoms in children with ASD, and fecal microbiota transplant could transform the dysbiotic gut microbiome toward a healthy one by delivering a large number of commensal microbes from a healthy donor."
Kang DW, Adams JB, Coleman DM, et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci Rep. 2019;9(1):5821. Published 2019 Apr 9. doi:10.1038/s41598-019-42183-0
"A diagnosis of ASD continues to be behaviorally defined. However, the body of research and accumulating evidence with respect to immune system perturbations in ASD suggest that a broader approach should be taken in order to understand biological systems as they pertain to ASD and associated behaviors."
Masi A, Glozier N, Dale R, Guastella AJ. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci Bull. 2017;33(2):194-204. doi:10.1007/s12264-017-0103-8
"Overall, we found there is evidence that ASD is associated with seizure and epilepsy, neurotransmitter disorders, sleep abnormalities, metabolic imbalances including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and GI disorders... Until further information is available on many of these treatments, it is reasonable to empirically treat children with ASD who are identified with specifically pathophysiological abnormalities if careful follow-up is maintained, and the medical professional is knowledgable regarding the treatment, particularly for treatments that have highly favorable adverse effect profiles and for patients that are unresponsive to standard behavioral therapy. As more information becomes available, treatment guidelines can be developed. Overall, the development of treatments that target specific pathophysiological disorders has the potential to provide significant improvement in the lives of children with ASD and their families."
Frye and Rossignol. Identifcation and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes. Clinical Medicine Insights: Pediatrics 2016:10 43–56 doi: 10.4137/CMPed.s38337.
"Autism is among the most complex diseases that I have ever encountered, in the scope of its physical effects on the human body... 'Autism' is merely one symptom of an underlying disease process that effects the immunological system, the gastrointestinal system, and the toxicological system, as well as the neurological system."
Bryan Jepson, M.D., Changing the Course of Autism; A Scientific Approach for Parents and Physicians
"Familial autoimmunity is a common risk factor, and maternal autoantibodies and inflammation during gestation significantly increase the risk of having a child with ASD. Furthermore, individuals with ASD have significant immune dysfunction and inflammation. They also suffer from immune-mediated co- morbidities much more often than the typically developing population, including GI dysfunction and dysbiosis. The presence of autoantibodies in individuals with ASD is increased, and evidence of neuroinflammation has been substantiated both in vivo and in post-mortem brain tissue."
Hughes HK, Mills Ko E, Rose D and Ashwood P (2018) Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Front. Cell. Neurosci. 12:405. doi: 10.3389/fncel.2018.00405
"Overall, when considering environmental exposures, it is important to take time to consider that the prevalence rates for ASD have increased dramatically over the last 10–20 years. These rates continue to increase year-on-year...To illustrate the connection between immunity, genes, the environment, and neurodevelopmental outcome, consider two scenarios: First, an individual may be genetically poised to mount an inappropriate immune response to an infectious or toxic exposure. This individual might respond either too robustly or too weakly to resolve the threat without collateral damage to the brain and other body systems (including the immune system). Second, an individual may lack appropriate genetic machinery to excrete toxins; leading to their accumulation in tissue. This could lead to an amplification of the toxin’s effects on a variety of body systems, including the brain and immune system. For each child, an environmental challenge during a critical window of development could have especially severe consequences, causing abnormal CNS function, altered immune phenotypes, and perhaps autism. These scenarios represent an emerging global view of autism that considers a broad contribution of several factors, including genes, the environment, and the immune system."
Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicology and teratology. 2013;36:67-81. doi:10.1016/j.ntt.2012.07.006.
"Autism involves the whole body. As a physician, I've seen so many autistic children with similar medical problems that I can't believe it's just a coincidence. And we know through thousands of scientific papers and an ocean of clinical experience that the health of the body can affect the function of the brain.
At this point, I think there is enough evidence to say that while autism certainly involves the brain, it is really a problem of the whole body, including the brain, from molecules to cells, from organs to metabolism, from immune to digestive systems. Even for those with autism who show no obvious medical problems, take a careful look for hidden issues."
Martha Herbert, M.D., Ph.D., The Autism Revolution: Whole Body Strategies for making life all it can be; Harvard Health Publications, 2012.
"Many individuals with ASDs have symptoms of associated medical conditions, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts...Although ASDs are behaviorally defined disorders, current thinking suggests multiple “autisms” with varying biological underpinnings."
Coury, D, et.al, Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda
Pediatrics Nov 2012, 130 (Supplement 2)
"This paper first reviews research which shows that autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Many of these disturbances have effects in most of the systems of the body. In particular, clinical evidence exists for increased oxidative stress, inflammation, and immune and mitochondrial dysfunction which can affect almost every cell in the body. Three promising research areas are discussed, hierarchical, subgroup analysis and modeling over time. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas. Autism poses a rich test bed for systems biology modeling techniques."
Randolph-Gips M, Srinivasan P. Modeling autism: a systems biology approach. Journal of Clinical Bioinformatics. 2012;2:17. doi:10.1186/2043-9113-2-17.
"Over the last decade, we have started to understand that some children with ASD suffer from undiagnosed co-morbid medical conditions such as abnormalities in the peripheral nervous, musculoskeletal, endocrine, gastrointestinal, immune, detoxification, redox regulation and energy generation systems (3). This has changed our view of ASD from a primary CNS disorder to a disorder that affects multiple physiological systems. This recognition has resulted in the evaluation of children with ASD by a wide variety of medical practitioners and leads to the justification for a wide variety of medical treatments for ASD."
Frye, Richard E., and Daniel A. Rossignol. “Mitochondrial Dysfunction Can Connect the Diverse Medical Symptoms Associated with Autism Spectrum Disorders.” Pediatric research 69.5 Pt 2 (2011): 41R–47R. PMC.
"While the cause of autism remains elusive, autism is considered a multifactorial disorder that is influenced by genetic, epigenetic, and environmental factors. Accumulating evidence from our studies and that of other groups suggests that oxidative stress may be a common feature in autism linking the mechanism through which the environmental factors exert their deleterious effects with the purported genetic alterations in autism. The oxidative stress and intracellular redox imbalance can be induced or triggered in autism by prenatal or postnatal exposure to certain environmental factors such as heavy metals, viruses, bacterial infections, air pollutants, toxins, valproic acid, thalidomide, terbutaline, retinoic acid, and ethanol. Genetic factors can also modulate the threshold for vulnerability to oxidative stress in autism. In addition to behavior impairments, some individuals with autism may have a higher prevalence of gastrointestinal (GI) disturbances. Several studies suggest that infammatory phenomena, immune dysregulation, and certain autoimmune risk factors may also contribute to the development and pathogenesis of autism."
Chauhan, et.al Autism: Oxidative Stress, Inflammation and Immune Abnormalities; 2010 by Taylor and Francis Group, LLC
Links to continuing medical education and additional resources
Autism Research Institute
Medical Academy of Pediatric Special Needs
CME and mentor program
The Foundation for Children with Neuroimmune Disorders
TACA: The Autism Community in Action
Selected studies related to biomedical findings and autism
Simons Foundation Autism Research Initiative
Focused on genetic research and autism
Health and Human Services
Interagency Autism Coordinating Committee
The Autism Healthcare Collaborative