A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a treatable medical and metabolic disease with behavioral components Prepared Statement: Congressional Autism Hearing Original: November 29, 2012, Last Updated: Jan 31, 2013 Cassandra L. Smith, PhD¹ ² Professor, Biomedical Engineer, Biology and Experimental Therapeutics and Pharmacology, Boston University¹ Director of Research, Athena Biomedical Institute² Kazuko Grace² Consumer Advocate, Athena Biomedical Institute² 1 A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a Treatable Medical and Metabolic Disease with Behavioral Components A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a Treatable Medical and Metabolic Disease with Behavioral Components Prepared Statement: Congressional Autism Hearing November 29, 2012 Last updated in January 31, 2013 Dr. Cassandra L. Smith Professor, Biomedical Engineer, Biology and Experimental Therapeutics and Pharmacology, Boston University Director of Research, Athena Biomedical Institute Kazuko Grace Abstract: Research on autism and autism spectrum disorders Athena Biomedical Institute (hereafter referred to as ASD), and other serious neurobehavioral www.athenabiomedicalinstitute.org disorders, has minimally influenced patient outcome or disease prevention. Although research links many genetic and environmental factors to these diseases, no single or small number of factors is responsible for disease in the majority of patients. An increasing number of seemingly disparate factors (genetic, environmental, and epigenetic) linked to ASD are converging on specific medical anomalies. Additionally, research tells us that each patient is unique. The medical abnormalities found in ASD are serious and debilitating and, in some cases, have been known for a long time. However, diagnosis and treatment of ASD remains focused on behavioral abnormalities. The translation of research to the clinic means that a new diagnostic and treatment paradigm must be developed that acknowledges the unique spectrum of medical and behavioral symptoms present in each patient. Diagnosis and treatment of medical abnormalities will improve patient quality of life and behavior. Today, this new paradigm is only benefiting a small number of individuals that can either personally pay for treatment, or are patients in free non-insurance reimbursed clinics. ABI©2012, 2013 Prepared Statement of Dr. Cassandra L. Smith Professor, Biomedical Engineer, Biology and Experimental Therapeutics and Pharmacology, Boston University Director of Research, Athena Biomedical Institute and Kazuko Grace, Consumer Advocate Athena Biomedical Institute Contact Information: Email: [email protected] Tel: 617 571 3068 A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a treatable medical and metabolic disease with behavioral components. Abstract: Research on autism and autism spectrum disorders (hereafter referred to as ASD), and other serious neurobehavioral disorders, has minimally influenced patient outcome or disease prevention. Although research links many genetic and environmental factors to these diseases, no single or small number of factors is responsible for disease in the majority of patients. An increasing number of seemingly disparate factors (genetic, environmental, and epigenetic) linked to ASD are converging on specific medical anomalies. Additionally, research tells us that each patient is unique. The medical abnormalities found in ASD are serious and debilitating and, in some cases, have been known for a long time. However, diagnosis and treatment of ASD remains focused on behavioral abnormalities. The translation of research to the clinic means that a new diagnostic and treatment paradigm must be developed that acknowledges the unique spectrum of medical and behavioral symptoms present in each patient. Diagnosis and treatment of medical abnormalities will improve patient quality of life and behavior. Today, this new paradigm is only benefiting a small number of individuals that can either personally pay for treatment, or are patients in free non-insurance reimbursed clinics. 3 Introduction: Research has linked many genetic, epigenetic and environmental factors to ASD and other serious neurobehavioral diseases like schizophrenia. Many factors should be linked to these diseases because the brain is the most complex and evolved organ, and will be sensitive to the greatest number of factors. Although research findings do not provide the simple sought after answer, useful new information on how to diagnose and treat serious symptoms in ASD should not be ignored. Increasingly, seemingly disparate genetic, environmental, epigenetic and medical factors linked to ASD are converging on deficits in specific metabolic processes. The medical and metabolic abnormalities of ASD patients need to be diagnosed because available treatments can improve the quality of life and behavior of these patients, and in some cases prevent disease. Diagnostic regimes must be broad because research tells us that each patient is unique. "Biomedical" diagnosis and treatment is increasingly, albeit slowly, becoming recognized as important to these patients. Here, we will provide an overview of genetic, environmental and epigenetic factors linked to the medical and metabolic abnormalities present in ASD patients. A synopsis of the content of this paper is presented in Table 1. The issues raised are important discussion points for not only ASD but also other serious neurobehavioral disorders like schizophrenia. Clearly, these suggestions entail a major change in the manner in which neurobehavioral diseases are viewed within the medical field, and by the public. Appendix 1 has a glossary of scientific terms, abbreviations, and acronyms used in this document. The Addendum has a list of suggested testing for comprehensive assessment of each ASD patient. The Addendum is meant as a starting point for discussion. Diagnosis and treatment is based on behavioral criteria: ASD is diagnosed by the presence of behavioral abnormalities that include impaired verbal and nonverbal communication and social interactions, and stereotypic behavior and interest. In most cases testing for genetic (e.g. genotyping, gene expression and epigenetic assessment) or medical (e. g. metabolite, screening for toxic chemical, infections, inflammation, digestions issues, and nutritional status) problems is not done, although these issues commonly occur in ASD. Likewise, treatment regimes focus on insurance covered behavioral interventions. Genetic Liability Highly Variable: There are over 100 genetic loci linked to ASD. These genes code for proteins involved in a variety of processes including: brain development and function; metabolic pathways important in DNA and RNA replication; energy production; cellular responses to inflammation and infection, xenobiotic exposures, oxidative stress; and epigenomic programming. Table 1. Synopsis: ASD is a group of complex medical and metabolic diseases with behavioral abnormalities. 1. Diagnosis and treatment of ASD patients are focused on behavioral abnormalities and not the cause of disease, or presenting medical and metabolic problems. 2. Many varied (genes, environmental, medical and metabolic) factors are linked to ASD. 2.1 The brain is the most highly evolved organ should have the greatest number of factors linked to its development and function. 2.2 Early life is uniquely and especially sensitive to disruption. 2.3 Heritability measurements in ASD are mis-interpreted as saying disease is mainly due to genetic causes. 3. Over 100 genes are linked to AS 3.1 Genes linked to ASD are involved in neurodevelopment and brain function, metabolic pathways, and known medical conditions. 3.2 Some genes linked to ASD are also linked to rare genetic diseases caused by known single gene mutations. 3.21 Some rare genetic diseases are preventable through early diagnosis and intervention. 3.3 ASD displays genetic anticipation with successive generations have more severe and early onsets of disease. 4. ASD is linked to elevated rates of mutation making each patient unique. 4.1 Genetic and environmental factors linked to ASD can increase mutation rates and contribute to genetic anticipation and the spectrum of symptoms. 5. Xenobiotic exposures that increase the presence of reactive oxygen species (ROS) are linked to ASD but are difficult to assess. 5.1 Both major and minor xenobiotic exposures can be important. 5.2 A subset of individuals may be sensitive to xenobiotics like the heavy metals mercury. 5.3 Sensitivity to exposure can have a genetic origin, or be confounded by other, even non- assessed environmental factors. 5.4 Sensitivity can be due to deficits in the detoxification process, or the production and cellular response to the accompanying oxidative stress. 6. Infection and inflammation, commonly seen in ASD, impede biological processes and hinder the bodies response to stress. 6.1 Infection and inflammation impede DNA and RNA synthesis. 6.2 Gastrointenstinal disorders can lead to malabsorption and malnutrition. 6.2 Malnutrition before 2 years of age leads to behavioral abnormalities that resists nutritional interventions. 7. Nutrition is under-appreciated in pharmaceutical industry and in medicine. 7.1 Typically, medical professionals are not well-versed in nutrition, and insurance does not pay for such consultations unless symptoms are overt and classical. 7.2 Early nutritional interventions can prevent some ASD. 7.3 Essential nutrients must