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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

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

Athena Biomedical Institute
www.athenabiomedicalinstitute.org

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.
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: clsmith@bu.edu
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.

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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 nonassessed 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 be obtained from the diet or the billions of bacterial that
inhabit our bodies.
8. Folate, methionine, transulfuration and dopamine metabolic pathways are closely linked
to each other and to ASD in multiple ways.
8.1 These pathways are involved in DNA and RNA synthesis, epigenomic programming,
energy production, the cellular response to oxidative stress, and dopamine metabolism.
8.2 Multiple essential nutrients are required by these pathways.
8.3 Usually, most ROS are produced in the mitochondria during ATP (energy) production
8.31 Mitochondrial defects are found in a subset of ASD patients.
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8.32 ATP is required for all bodily responses, e.g. infection, inflammation, response to ROS etc.
8.4 Complex and system biology approaches are needed to understand the dynamics of
metabolic pathways in ASD.
9. Epigenomic regulation of development and function is disrupted in ASD.
9.1 Epigenomics represents the interaction between the genome and the environment.
9.2 The greatest amount of epigenomic programming occurs early in live.
9.3 Many and varied epigenomic changes are linked to ASD that include DNA methylation, histone
modification.
10. Treatment of medical and metabolic abnormalities will improve the quality of life and
behavior of patients.

About 20% of ASD patients, have "secondary autism", because a rare genetic
disorders with a single gene cause is present. Fragile X syndrome is the most common
genetic disorder linked to (1-2%) ASD patients, and is the most common cause of
hereditary mental retardation. Other single gene disorders linked to ADS are
developmental diseases that impact brain function and development.
The new ASD diagnostic criteria proposed in the Diagnostic and Statistical
Manual for Mental Illnesses (DSM-)-V, published by the American Psychiatric Association,
increases the number of disorders placed under the ASD umbrella without regard to
disease cause or treatment. For instance, Rett syndrome, a rare single gene disease linked
to a global deficite in epigenetic programming is now classified as part of the ASD
spectrum. Another group of genetic diseases linked to ASD involve “inborn-errors-of metabolism” (Karnebeek and Stockler, 2011). In some of these diseases, early dietary
interventions can prevent or reduce illness. An example of a severe brain disease
prevented by early detection and treatment is phenylketonuria. In the United States, all
newborns are tested for this disease because early and a simple dietary intervention
(elimination of phenylalanine) can prevents brain damage and disease.
Diagnosis of ASD based on behavioral abnormalities discourages genetic testing
for rare, treatable genetic diseases. Such a focus ignores research progress that defines
subsets of patients where prevention is possible, and adds un-necessary complexity to
basic and applied research and treatment.
Families segregating ASD with multiple family members affected by disease are
identified (Piven et al., 1997). In some families, ASD does not appear to be multigenerational. Instead, less severe behavior abnormalities are seen in earlier generations
reminiscent of "genetic anticipation". Genetic anticipation refers to diseases that become
more severe, or have an earlier age of onset in successive generations. Genetic
anticipation in ASD may not be surprising given the recent rapid increase in disease
occurrence.

a simple environmental factor. Nguyen et al. g. In the past. and elder fathers have an increased number of children with ASD (For review see Smith et al. time of life. more research funds are being spent on environmental factors linked to ASD. can affect outcome of an exposure.000 commercially important chemicals into the environment. Research on these chemicals is ongoing in a variety of arenas because of their potential to influence many biological and organ systems. This was unfortunate because of the widespread misunderstanding of heritability measurements especially in neurobehavioral disorders. Mutations that occur in egg and sperm will be passed to the next generation. 2012). Thus. 2003 and many more recent genetic studies) Mutations in sperm accumulate with paternal age. Today. ~80% of a disease phenotypic variability may be linked to both genetic and environmental factors. An ~80% heritability refers to the amount of disease phenotypic variation that is due to genetic variation and NOT the percent of disease due to genetic mutations. each patient has a unique set of mutations and each patient must be tested for a broad range of mutational liabilities. For example. some research funding agencies focused almost exclusively on genetic studies because ASD is said to have ~80% heritability. In addition. although the general perception remains that ASD is a genetic disease. and genetic anticipation. and diseases.. dose. For instance. Other complexities include exposure length. However. Elevated mutation rates are found in other neurobehavioral diseases (e. Environment Exposure History and Response Highly Variable: The industrial age included the introduction of more than 100. severity.A contributor to genetic anticipation in ASD can be the elevated rate of mutations found in patients. and the presence of confounding but un-assessed exposures and factors. heritability does NOT measure the affect of environment on disease variability. Further. the affect of multiple. several lines of evidence link ASD to increased mutation rate. One outcome of environmental research has been the reduction or elimination of some dangerous compounds from the environment. Importantly. Further. the myriad of symptoms. Similar results are found for other serious neuropsychiatric diseases like schizophrenia.. varied low dose exposures to different compounds may be important but is even more difficult to study. and can contribute to increasing disease liability. 7 . many environmental factors (discussed below) linked to ASD have the potential to increase mutation rates and affect genetic anticipation. the ability to define the effect of an environmental factor on humans remains difficult because of the great genetic variability and environmental-history differences between individuals. research has demonstrated that ambient temperature. 2010.

Genetic testing has identified deficits in these metabolic processes in some ASD patients. Sensitivity may be due to defects in xenobiotic metabolism responsible for detoxification of these compounds. heavy metal like mercury are linked to ASD. Similarly. The generally lack of interest in nutra-pharmaceuticals research in both the pharmaceutical industry and the medical community is not surprising. Other sensitivity is due to the production or removal of reactive oxygen species (ROS) and oxidative stress that is generated during the detoxification process. and interventions that improve these pathways are possible. the American Pediatric Association advocated for the inclusion of gastrointestinal disorder assessment and treatment in ASD (Buie et al. 2011). Gastrointestinal problems and malnutrition are often present in ASD patients. Many studies support the idea that a subset of individuals is sensitive to xenobiotics. in some cases. Holland et al. the Federal Vaccine Court ruled in 2010 that there was insufficient evidence to link vaccination to ASD. Pink disease occurs in a subset of individuals with elevated mercury levels.. the medical profession is not well versed in nutrition and many clinicians fail to appreciate or treat nutrients as pharmaceuticals. report good outcomes. Although.Although controversial. The picture became more complicated because trans-generation mercury exposure was linked to ASD (Shandley and Austin. Under-nutrition and malnutrition before two years of age will lead to behavioral abnormalities that resist nutritional interventions later in life (Galler et al. Nutrition and exercise is an under considered but un-refuted environmental factor important for good health. detection of faulty pathways. 1996). exercise is an under utilized but beneficial ASD treatment (Sowa and Meulenbroek. In 2011. medical insurance reimbursement for nutritional assessments and treatments are limited to those patients with classical and severe symptoms of malnutrition. 2012) as it is for many common illnesses. In this study. can lead to malabsorption and malnutrition.. xenobiotic. Gastrointestinal problems. Meanwhile. Recently. including infection and inflammation. Likewise. For instance. the use of dietary anti-oxidants can improve the response to oxidative stress and treatment regimes that remove detectable xenobiotics and reduced ASD symptoms have been reported. Although direct and indirect affects may be difficult to sort out in individual patients. parents of ASD patients continue to use nutritional interventions and. reported an increased incidence of ASD in vaccinated children. . Some theorized that mercury in vaccines was responsible for the increase in ASD. the controversy has not been put to rest. Nutritional interventions in ASD have not been evaluated yet in many conventional evidence based studies such as those used for pharmaceutical drug testing. grandchildren of pink disease (infantile acrodynia) patients had an astounding 1 in 22 probability of becoming ill with ASD. Generally.

2010. it is not clear that this testing will occur early enough to prevent disease occurrence or to reduce severity (see phenylketonuria above). Epigenetics programming is a fuzzy term that refers to gene-environment interactions. and developmental programs that enable a single inherited genome to code for multiple cell type such as neurons. Some affects may not be apparent until much later in life or even in another generation. and changes occur throughout life. medical and metabolic factors linked to ASD converge on the abnormalities in the Folate-Methionine-Transulfuration-Dopamine (FMTD) hub. Although a start. Nutritional. genetic. Epigenetics Programming and ASD: Genetic and environmental factors linked to ASD interfere with epigenomic programming directly and indirectly. dopamine metabolism. 9 . and epigenomic programming.2012). Smith and Huang. In brief. 2012). DNA and RNA synthesis.. epigenomic programming is dynamic. energy production. Interference in epigenomic programming in early in life has the greatest consequences because the largest number of cells and the earliest developmental programs are affected. 2008. Details are provided in Figure 1. Smith et al. the FMTD metabolic hub includes pathways involved in oxidative stress response. and the greatest sensitivity to factors that interfere with this process. However.. The brain has the greatest amount of epigenetic programming. environmental. The greatest amount of epigenomic programming occurs early in life. muscle and blood (for reviews see Abdolmaleky et al.

infection. Purines are required for DNA and RNA synthesis. and the amino acid cysteine (cys) from HCY. S-adenosyl methionine (SAM). Today a large research effort is focused on cataloguing the many epigenomic changes that occur in ASD. DNA. respectively. ATP and GTP. In the met cycle. Details of the FMTD hub are provided here.g. intracellular oxidative stress. The FMTD hub is sensitive to nutrition. a sulfur containing metabolite. dopamine). IMP is a precursor for the synthesis of all purine. proteins. The transulfuration pathway (green) synthesizes the major intracellular antioxidant. The folate cycle (blue) directly participates in the synthesis of dTMP from dUMP and IMP (red *).. inflammation. that is converted to methylated DRD4 (met-DRD4) by the additional of a methyl group from THF (purple). Here. and betaine/choline. Essential nutrients (dotted lines) that must be provided by the diet or from our microbiome are vitamins B9 (folate).Figure 1. the demethylated dopamine D4 receptor (HCY-DRD4). Direct links include epigenetic programming of genes involved in dopamine metabolism. epigenomic programming. and the energy currency of the cell. Some xenobiotic detoxification reactions utilize SAM. and dopamine metabolism are closely linked in the FMTD metabolic hub. The FMTD metabolic hub depicted in Figure 1 is the key global metabolic regulator of epigenetic programming. The enzyme MS has a second substrate. oxidative stress. Ultimately. Nutrition. is linked directly to the FMTD metabolic hub and ASD (for review Smith et al. DNA methylation is the best-studied epigenetic process. Met is obtained exogenously. In the FMTD hub. methyl transferases (MT) enzymes use SAM as a methyl group donor. The methylated DRD4 receptor (met-DRD4) covalently transfers the methyl group to lipopolysaccharides. dTMP is converted to dTTP and used for DNA synthesis. SAM is made from met and ATP. and B12. The folate-methionine-transulfuration-dopamine (FMTD) metabolic hub. the amino acid methionine (met). 2010. RNA. the discussion will focus on global epigenetic changes that are linked to ASD and likely contribute to the systemic and complex nature of disease. lipids and polysaccharides) and small molecules (e. g. is the major methyl donor required for epigenomic programming. Folate is converted to dihydrofolate (DHF). and toxic exposures. then tetrahydrofolate (THF) derivatives. In epigenetic programming. The major product of the met cycle (red) is S-adenosyl methionine (SAM). 2012). Methyl groups from SAM are donated to a wide variety of large (e. glutathione (GSH). changing cellular membrane characteristics. and methylation of the dopamine receptor D4 . DNA and RNA synthesis. the number of epigenetic changes will be at least an order of magnitude greater than the observed genomic changes linked to ASD. and generally DNA methylation of gene promoter regions is associated with a loss of expression. or betaine homocysteine methyl transferase (BHMT). a major process in the brain. Many epigenetic changes will affect the same pathways that have been identified in earlier genetic and environmental studies and are discussed above. Dopamine metabolism. degradation of dopamine by a methyl transferase (COMT). B6. and can regenerated from homocysteine (HCY) by the addition of a methyl groups from THF or betaine (obtained from choline in the diet) by the enzymes methionine synthetase (MS). Abnormalities in these processes are linked to ASD.

. Most ROS within a cell are produced as a side product of energy production (ATP) in the mitochondria. abnormal microbiomes are detected in ASD (e. Villafuerte. is the primary intracellular antioxidant.. 2005. These exposures affect the FMTD hub because glutathione (GSH). 2012) Exogenous sources for essential nutrients include the diet and the microbiome. Although. difficile infections (Stollman and Surawicz.. 2005).(DRD4 receptor). 2012. Parracho et al. g. During evolution. are linked to changes in the microbiome (e. 2012. 2012).. ASD and schizophrenia (Smith et al. The FMTD hub is connected to the greatest number of intracellular reactions because two metabolites. Recently. amino acids. g. Methyl transferase (MT) enzymes that use SAM or folate as a methyl donor occur in all these reactions. and other neuropsychiatric patients (Severance et al. and sensitivity to unfamiliar conditions. Parracho et al. ATP and SAM. The microbiome refers to the billions of microorganism that share our bodies. and indirectly because the biological response to these events includes an increase in DNA and RNA synthesis. the extensive metabolic wiring optimized the FMTD and imparted unique characteristics: robustness to familiar conditions. infection by the pathogenic microorganism Clostridium difficile. this is a new area of research. The industrial age introduced new types and higher levels of xenobiotics. like xenobiotic metabolism and an oxidative stress response. Fecal transplants in ASD have yet to 11 . Xenobiotic exposures will increase the level of reactive oxygen species (ROS) and oxidative stress. for instance. Infection and inflammation will increase the level of intracellular ROS and oxidative stress directly. 2012). are the most used cofactors in the cell. Treatments with antibiotics to fight infection can change the microbiome detrimentally. and bind sulfur containing endogenous anti-oxidants. a sulfur-containing metabolite product of the FMTD hub. including ASD. will increase the level of ROS in the cells. Nutritional deficiencies including both folate and betaine/choline are linked to behavioral and brain abnormalities.. Blusztajn and Mellott. B vitamins. Gought et al. 2012. Severe gastrointestinal disorders in both adults and children. 2010. Some xenobiotics that affect the FMTD hub were not encountered previously during evolution. fecal transplants were used to successfully treat adult patients with C.. Increases in processes that require ATP.g. 2011). 2011) Multiple essential nutrients (e. and energy production.. and betaine/choline) required within the FMTD hub must be acquired exogenously. Deficits in mitochondrial function are detected in a subset of ASD patients (Anitha et al. Benache et a. Heavy metal exposures increase the level of reactive oxygen species (ROS).

. 2011). Folate and methionine supplementation alter psychotic symptoms (up and down. HCY and other metabolites are done on blood. Gene expression. and newly identified important metabolites. respectively) in adult schizophrenia patients. Hence. Some clinical tests. are used routinely to monitor health overall. 2009). the contribution of diet and the microbiome to human nutrition (or other internal processes) is largely unknown. In contrast to other diseases. including the measurement of single metabolites. Epigenomic changes and treatments based on this knowledge are revolutionizing the treatment of cancer. Research argues for monitoring ASD patient health using both old (e. especially blood displasias. Abnormal homocysteine (HCY) levels in blood are detected in many ASD patients. As a consequence of this observation. and more recent work has detected the DNA footprint of solid tumor cancer cells in blood. already. HCY is a key FMTD metabolite with changes found many common diseases (e. cancer. Changes in blood are monitored for many diseases. normalization of HCY levels through simple (single) nutritional interventions has not been accompanied by a reduction in disease symptoms. valporate treatment of pregnant rodents is used to create rodent model of ASD (Bambini-Junior et al. the affected tumor tissue is available for analysis. metabolic monitoring of ASD patients will need to be done with blood. neuropsychiatric. some pharmaceuticals useful in treated schizophrenia affect the FMTD hub directly.g. HCY levels are no longer monitored clinically. SNP testing and DNA sequencing which provide direct information about genetic make-up is now in the clinical arena.. Clinical tests of blood for folate. Global monitoring approaches used in systems biology can help understanding disease in individual ASD patients. and are likely to be able to treat less severe microbiome imbalances.. or another readily available tissue. and are linked already to ASD. in cancer. Whether changes are a direct or indirect consequence of disease.be done. and can serve as a sentinel of mental health. The affect of nutritional intervention in neurobehavioral disease is not clear. Valporate affects the production of SAM and epigenetic programming. and cardiovascular). Further. An example is the increased incidence of ASD like symptoms in children from mothers treated with valporate (to control seizures) during pregnancy (Bromely et a. In most cases. At this time. while others are only used when warranted by presenting symptoms. blood has. a stateof-the art research method. HCY). although dietary deficiencies alone are known to cause disease. g. monitors cell function and has been useful for diagnosing and treating cancer patients. As brain tissue is not readily available.

Research progress has increased our understanding of what processes are abnormal for these diseases. However. diet and exercise influence the health of all individuals. malnutrition. Research increasingly and repeatedly links environmental factors to many common disorders. the medical profession is recognizing that the standard-of-care for ASD should include detection and treatment of non-behavioral abnormalities. inflammation. Schizophrenia. The U. the funds spent on research do not reflect the relative cost of these diseases. ASD or schizophrenia can reduce disease. and research results. and in some cases mainstream medicine. have yet to be translated to the clinic. infections. The translation of recent research observations to the clinic. National Institute of Health is moving towards a paradigm of prevention rather than treatment of disease. Appropriate diet and exercise will improve health for all individuals. An estimated 20% of schizophrenia and ASD patients have underlying but undetected medical disorders. ASD clinics that try to treat medical and metabolic aspects of disease fall outside current insurance reimbursement schemes. for the most part. toxic exposures. 13 . ASD is an illness that costs the government about $60 billion per year in the US and is likely to increase.The new paradigm: ASD is a group of complex medical and metabolic diseases with behavioral abnormalities. It is a disgrace that patients are not tested and treated for underlying medical and metabolic problems. Today. Increasingly. a similar common neurobehavioral disorder costs about $160 billion per year. S. a ~40% decrease in breast cancer can be realized through diet and exercise. whether for breast cancer. Genetic make-up. severe and lifelong. Both ASD and schizophrenia are common. and reduce disease. For instance. ASD patients have multiple and varying medical and metabolic problems that need to be detected and treated.

Molecular autism 3:12. Parracho HM. Lewis JD. Central nervous system agents in medicinal chemistry 12:82-94. Shafa R. Rodrigues L. Childress D and Arndt S (1997) Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Nguyen GH. Alaedini A. Anitha A. Suzuki K. Schultz M. Dickerson FB and Yolken RH (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia. The American journal of psychiatry 154:185-190. Matsumoto K. Yang S. Pace Environmental Law Review 28:480-466. Smith CL. Gibson GR and McCartney AL (2005) Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Vaughan C. Thanseem I. Moreira JC. Li E and McGovern MM (2012) A microbial association with autism. Thiagalingam S and Smith CL (2008) Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics. Tsujii M. Glatt SJ and Tsuang MT (2004) Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation. Pharmacogenomics 9:1809-1823. Iwata Y. Brain research 1408:8-16. in Physiology and Pathophysiology pp 196-212. Conte L. Schizophrenia research 138:48-53. Stallings CR. Miyachi T. Keith L. Origoni AE.References: Abdolmaleky HM. Leweke FM. Buie TR. Halling M. Bingham MO. Jacobi D. Tolstoi LG. Bouchard J. Neuropsychiatric genetics 127B:51-59. American journal of medical genetics Part B. Toyota T. Severance EG. Abdolmaleky HM. Tsuchiya KJ. Nakamura K. Shaikh H and Manges AR (2011) Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Iwayama Y. Bambini-Junior V. Palmer P. Levy J. Galler JR. Fuchs III GJ. Faraone SV. B. Matsuzaki H. Holland M. Piven J. Ichikawa H. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 53:994-1002. Decker Inc. Behr GA. Herrera VL and Smith CL (2003) DNA stability and schizophrenia in twins. Sugiyama T. Baldwin C. Shumsky JR and Morgane PJ (1996) Malnutrition and brain development. Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 120B:1-10. Boselli MG. Yamada S. Shandley K and Austin DW (2011) Ancestry of pink disease (infantile acrodynia) identified as a . Yoshikawa T and Mori N (2012) Brain region-specific altered expression and association of mitochondria-related genes in autism. Riesgo R and Gottfried C (2011) Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Kooros K. Nguyen NC. Krakow R and Colin L (2011) Unanswered questions from the vaccine injury compensation program: A review of the compensated cases of vaccine-induced brain injury. Weshil BK and Winter H (2010) Recommendation for evaluation and treatment of common gastrointestinal problems in children with ASDs. Stone W. Zhou JR. Blusztajn JK and Mellott TJ (2012) Choline nutrition programs brain development via DNA and histone methylation. Gough E. C. Benach JL. mBio 3. Journal of medical microbiology 54:987-991. American journal of medical genetics Part B. Pediatrics 125: 219-S29. Furuta GT. Khushalani S. Gressitt KL. Yamada K.

Journal of toxicology and environmental health Part A 74:1185-1194. Smith CL. Smith C and Huang K (2012) Epigenomics of neurobehavioral diseases. Stollman N and Surawicz C (2012) Fecal transplant for Clostridium difficile. Sowa ME and Meulenbroek R (2012) Effect of physical exercise on Autism Spectrum Disorder: A meta-analysis. Amsterdam. in Epigenetics of Human Disease (Tollesfsbol T ed) pp 127-152. fragile sites. The Netherlands. van Karnebeek CD and Stockler S (2012) Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Molecular genetics and metabolism 105:368-381. Current genomics 11:447-469. Acta psychiatrica Scandinavica 123:95 15 . Bolton A and Nguyen G (2010) Genomic and epigenomic instability. schizophrenia and autism. Villafuerte S (2011)Suggestive evidence on the genetic link between mitochondria dysfunction and autism. author reply 825-826. Research in Autism 6:46-57. Archives of internal medicine 172:825.risk factor for autism spectrum disorders. Elsevier.

phenomenon observed in some genetic diseases where severity increases.demethylated DRD4 receptor MET-DRD4 .inosine monophosphate.folate-methionine-transulfuration-dopamine Folate .molecules that protect cells from chemical damage caused by free radicals ASD .refers to an imbalance in the level of reactive oxygen specie (ROS)s and the biological detoxification pathways ROS .measurement of mRNA or protein levels Genetic anticipation .methyl transferase enzyme Oxidative stress . Glossary of Scientific Terms and Acronyms Anti-oxidant .methionine. a sulfur containing amino acid DSM .deoxythymidine triphosphate.inborn error of metabolism disease Pink disease .Diagnostic and Statistical Manuel for Mental Diseases published by the American Psychiatric Association DHF .a small neutral metabolite that donates methyl groups to HCY BHMT . and/or age of onset decreases in successive generations. and processes that allow a single genome to develop into multiple cell types Fragile X disease .methionine synthase enzyme MT .deoxythymidine mononucleoside.vitamin B9 Gene expression .a large number of single gene diseases linked to metabolism Met .glutathione.most common cause of hereditary mental retardation Federal Vaccination Court .neurotransmitter DRD4 .single gene disorder with a mutation in MeCP (methylated cytosine binding protein) gene . Federal Claims Court that administers a no-fault system for litigations involving vaccine injury FMTD metabolic hub .autism spectrum disorder Betaine .reactive oxygen species Phenylalanine . GSH . a precursor for dTMP synthesis Epigenetics . a precursor to the synthesis of all purines Inborn-errors-of-metabolism .a fuzzy scientific term that involves gene-environment interactions.amino acid Phenylketonuria .Appendix 1.dihydrofolate Dopamine .betaine homocysteine methyl transferase enzyme CH3-lipopolysaccharide .dopamine receptor D4 dTMP .methylated lipopolysaccharide found in the cell membrane Cys .a disease found in a subset of individuals with elevated levels of mercury characterized by pink hands or feet Rett Syndrome .cysteine. S. a precursor in dTTP synthesis dTTP . a precursor used in DNA synthesis dUMP .homocysteine HCY-DRD4 . a tripeptide composed of glycine-cysteine-glutamine with a gamma peptide bond between the gamma carboxyl group of glutamine and the amino group of cysteine HCY .deoxyuridine monophosphate.refers to the Office of Special Masters of the U.methylated DRD4 receptor IMP . a sulfur containing amino acids MS .

the major methyl donor in the cell THF .tetrahydrofolate Transulfuration pathway .small molecular weight molecule not ordinarily present in a biological system Xenobiotic metabolism .metabolic pathway that converts homocysteine (HCY) to glutathione (GSH) and cysteine an amino acid Vitamin .SAM .small molecular compound essential to cells that must be obtained exogenously Xenobiotic .pathway that detoxifies a xenobiotic 17 .S-adenosyl methionine.

2012 Last updated: January 31.Addendum I Suggested Medical and Metabolic Assessments Useful for ASD A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a Treatable Medical and Metabolic Disease with Behavioral Components Addendum I Suggested Medical and Metabolic Assessments Useful for ASD Prepared Statement: Congressional Autism Hearing Original: November 29. Athena Biomedical Institute Kazuko Grace Athena Biomedical Institute www. Smith Professor. Boston University Director of Research.org . Cassandra L. Biology and Experimental Therapeutics and Pharmacology.athenabiomedicalinstitute. 2013 Dr. Biomedical Engineer.

Athena Biomedical Institute and Kazuko Grace. Consumer Advocate Athena Biomedical Institute Contact Information: Email: clsmith@bu. Smith Professor. Addendum I Suggested Medical and Metabolic Assessments Useful for ASD . Biomedical Engineer.edu Tel: 617 571 3068 A Paradigm Shift in Diagnosing and Treating ASD patients: Autism is a treatable medical and metabolic disease with behavioral components.Prepared Statement of Dr. Biology and Experimental Therapeutics and Pharmacology. Boston University Director of Research. Cassandra L.

However. However. metabolic. Smith. and Kazuko Grace Boston University and Athena Biomedical Institute _____________________________ Introduction: Most governmental funds are directed towards studies on the causes of ASD while translation of research results to patients is minimal. patients likely to benefit the most from the new finding and technologies are those with neurobehavioral illnesses like ASD.4 In most cases. and needs direct input from researchers to insure maximal benefit to the patient. Today’s clinician is not well versed in all aspects of disease and research outcomes. Each patient must be viewed from a holistic rather than the traditional reductionist perspective.2 Hence.5 . epigenomic and behavioral symptoms. and untreatable illness. the answer is not simple. Systems biology is a field of biology that focuses on understanding the many varied complex interactions that occur in the body.1 Each patient is unique and can have a unique variety of medical. lifelong. testing alone is prohibitively expensive. insurance does not cover diagnostic procedures and treatments for the medical.3 There is a revolution in research on disease prompted by the human genome project. Patients who can self-fund benefit from the accumulated knowledge of research. metabolic and epigenomic abnormalities linked to ASD. Arguably.Addendum I . It is especially egregious not to identify patients with inborn-errors-of-metabolism in time for treatment interventions that may prevent a severe. complex diagnosis and treatment regimes need to be applied to patient care. requiring input from multidisciplinary fields characteristics of “systems biology”. Research has revealed some important ways to improve patient treatment today.Suggested Medical and Metabolic Assessments Useful for ASD Suggested Medical and Metabolic Assessments Useful for ASD Cassandra L.

early diagnosis and treatment can limit. comprehensive. bladder. Most physicians do not know that up to 20% of ASD patients have underlying undiagnosed and untreated medical illness. However. family-centered. compassionate. autism behavioral analysis includes hearing. reduce the estimated ~60 billion dollar per year expense for ASD. 14 21 . ear. Other testing that may uncover underlying medical or metabolic abnormalities that affect behavioral is not done. these problems may be expressed as behavioral issues such as aggressiveness. this will be expensive. Putting aside the general issue that children have difficulty describing symptoms. and culturally effective. infections etc. We present this list as a starting point for discussion to develop an optimized testing hierarchy and treatment regime that must include patient and advocate participation. 9 10 11 12 This Addendum includes testing for a plethora of abnormalities found in ASD patients with variable presentations. Behavior is influenced by medical and metabolic abnormalities: Today. ASD imposes an additional handicap. coordinated.13 A symptom of ASD is communication deficits.8 Admittedly. and some patients are nonverbal. we recognize the financial burden imposed by all this testing. continuous. screaming etc. prevent disease. speech and language. Because each patient is unique.6 7 Comprehensive health care insurance coverage of ASD will reduce the financial burdens on families with ill children. Many parents experience emergency room trip for their children with ASD but disturbing behavioral problems may prevent medical personnel from searching for and treating medical issues that can disrupt behavior. Instead. a wide range of testing is necessary to optimized individual treatments. however.The American Academy of Pediatrics believes that children's medical care should be accessible. and some cases. motor social skills. Children with ASD may not reveal health problems ranging from pain from the stomach.

but others metabolite abnormalities linked to ASD need to be added to the testing repertoire. Pharmaceutical companies have moved away from developing new drugs for neurobehavioral diseases because of unusually high expense. Unfortunately. including inborn errors of metabolism that in some cases are treatable. and not in line with the estimated ~160 million dollars per expense of schizophrenia. and testing is easy and relatively inexpensive. Schizophrenia. Research funds spent by the US government are minimal. Medical abnormalities in ASD should be assessed by conventional testing. . immune and inflammatory responses can be monitored with well-established laboratory tests. Comprehensive medical testing of schizophrenia patients are predicted to reveal underlying disease in 20% of patients. comprehensive medical testing is not done on schizophrenia patients. Concentrating research funds in the hands of a few investigators prevents innovation. Today. The historic low funding rates for research and treatment of neurobehavioral disease limits innovation and improvements in clinical treatments. the question is what should the standard of care be for ASD? Certainly. Some metabolite levels are measured clinically already. the situation continues to evolve towards the same unsatisfying and frustrated outcome seen in schizophrenia where patients are abandoned and viewed generally as being hopelessly ill. but who controlled the direction of research and treatment.Suggested Medical and Metabolic Assessments Useful for ASD Research Funds: ASD is at epidemic proportions. and by targeted analysis of metabolites linked to diseases. an orphan neurobehavioral disease similar to ASD also occurs in epidemic proportions. the underlying genetic liabilities associated with disease need to be determined. For instance.Addendum I . If comprehensive testing is not done on ASD. Further.15 A new standard of care for ASD: Today. the scarce research resources tend to be concentrated in specific centers. the field of mental health has been rift with soothsayers that are subsequently proven wrong.

Gene expression and epigenomic testing is well established and quite helpful in distinguishing between different types of cancer. This list is long and comprehensive. readily available tissue like blood. Individuals with sensitivities can be identified and monitored. epigenetic and environmental factors. In ASD gene expression testing might be done using a sentinel. or saliva. Comprehensive diagnostic testing using the new genomic approaches can reveal a wide range of metabolic conditions that warrant treatment.Gene expression. Some toxic chemical can be detected directly and removed. Recent findings show that solid tumors leave detectable DNA residues in the blood. epigenomic and metabolomics testing is important because these measurements represent functional test that reflect the combined affects of genetic. The molecular functional studies can reveal past and present toxic exposures. Prospective: Below we provide a suggested list of assessment that should be considered in the treatment of ASD patients. and is meant to serve as a starting point of discussion for a new treatment paradigm.16 23 .

......................................................................................................................................................................................................... Hormone Metabolism ............................................................................... 34 x.... 40 i.......................................... 27 iii................................................................... EVALUATION PROCESS ................ Hyperhomocysteinemia ....... IEM (Inborn Errors of Metabolism) ... c...........Addendum I .................................................................. Neurotransmission ...................................................... 36 xii.... 26 a................................... Urea cycle .......................... Risperidone............... 31 vii............................................ When full metabolic evaluation should be performed .................................................. b......................... 32 ix................................................................................................................................................................... 30 iii............................. 25 a......................... Metabolic Evaluation ........ Genetic Disease Testing (secondary autism) ................ Glucose transport & regulation ................................................................................................. Cholesterol & bile acids . 27 ii.............................................................. 37 xiv............. Organic acids ...................... 28 Metabolic Biomedical Phenotype Testing ............ 25 2.................................................................... 31 v.... 38 xvi... 40 ................................................................................... Genetic Genotype/Phenotype Testing .......................................... Vitamins/co-factors .................................................................................... 19 1............................................................................................................................... Physical Exam and History .................................. Mitochondrial Dysfunction ........................ 31 vi.................................................................................................................................................................................................................................. Creatine ........................ Amino Acids .......... DIAGNOSTIC TESTING ..................................................... 32 viii............................... 38 Drug Metabolism .. Lysosomes ........Suggested Medical and Metabolic Assessments Useful for ASD Addendum I Suggested Medical and Metabolic Assessments Useful for ASD Table of Contents Introduction ................... Metals ................................ 37 xiii..................................................................................................................................................................................................................................................................................................................................... 29 i............................................................................................... 26 i............. Epsilon-trimethyllysine hydroxylase deficiency ............................................................................................... 35 xi................................................................................................................................................................. Pyrimidines........................................................ 29 ii................................. Fatty Acid Metabolism Disorders ....................................... 25 i................................................................. 32 iv......... 37 xv.......................................................................................................

....................................... Xenobiotics (man-made environmental toxins) and Food Preservatives ......................................... 47 vii................................... Metabolic and Essential Fatty Acids ................................................................................................................................. 40 ii............................................. LIST OF ABBREVIATIONS ................................................................................. 48 ix.............................................. 41 iii............................. Biotoxins ........................... 40 i.......................................................................................................................... Ibuprofen ......................................... FAMILY TESTING.............................. 58 b............................................... 40 Functional Testing ................................................................................. 58 a........................................................... 63 25 ................ Acetaminophen .......................................................................... 57 i......................................... 57 ii........... 50 xi.................................................................................................................................................................................................... 47 vi.............................................. Neurotoxins ..................................................................................................... Aspirin................ Mast Cell......................................... 40 iv............... 56 g........................................................................... Detoxification Function ...................................................................................................................... 51 xii............................................................. 44 v.............................................................................................................. 58 4............................... 56 f....................... Organic Acids ..................................... REFERENCES .......................... 51 e.................................................................................................. 57 3......... Elemental Analysis ...... Father ..................................................................................................................................................... Chemistries .......................................................... Siblings ......................................................................................... 60 5................................................................................................................. ii......................................................................................................................................................................... 58 c........................ Immune function ...................................... 40 v.......................................................................................... Mother ......................................................................................................................................................................................... Risperdal ..................................................................................................................... 57 iii........................................................... Vitamins and Metabolic Function .............................. Heavy Metals ......... 48 viii.................................... Amino Acids .................................................. Mitochondrial Function ........... 40 iii.......................................... 41 iv.. Gastrointestinal Function ............................. Hormone Metabolism ........................... Peptides............................................................................................... 50 x...............d.............. Lipid Metabolism..............................................................................................................................................

physical and motor problems 29 30 15. narrow food preferences. pauses in breathing or instances of abnormally low breathing 17 18 19 2. bumps. When full metabolic evaluation should be performed: 1. sound sensitivity 12. Physical Exam and History i. color 33 19. Neonatal jaundice 34 20. abnormal snoring. Head Circumference: too large or too small 35 21. Eyes: Light sensitivity. abnormal odor of stool 28 11. MIA (maternal immune activation) risk factor to ASD like behavior 23 7. tempters. Hand and feet: cold hand and feet. Seizures 31 32 18. Hearing: Healing loss. pain 14. poor eye-hand coordination. Gastrointestinal: Diarrhea and/or constipation. Evaluation Process a. weight and head circumference 20 4. appetite loss 21 5. Abnormal body Sensitivities: Pain. Autonomic disturbances: excessive sweating. chewing/swallowing problems. soft and/or waved nail .Suggested Medical and Metabolic Assessments Useful for ASD Suggested Medical and Metabolic Assessments Useful for ASD 1. Joint and Muscle: poor muscle tone. abdominal discomfort. Repetitive infections 22 6. Height.Addendum I . Body weights: obesity (overweight) or underweight 3. vomiting. itches. poor appetite. "Allergic-like" symptoms 27 10. Repetitive asthma event 24 8. Blurred vision. Skin: rashes. Eating/Feeding disorders: food aversion. Sleep: sleep disturbance. poor circulation 17. Repetitive behaviors 25 26 9. yellowing of the eyes 13. touch 16.

DSCR1. ACTA. GABRB3. chemical. CTA1. Urine: Abnormal odors. GABRG. CYP1A1*2A. COL1A1. APO E4. CYBB. CPT2. CYP2C9*2. C4B 39. CNTNAP2. CNTFR. C2Oortf7. G6PDH. CYBA*8. CHD7. CACNA1D. BCKDK. CYP1A2. CDC42BPB. CYP3A4*3. AHCY. CUL3. Metabolic Evaluation i. Genetic Genotype/Phenotype Testing 36 37: AANAT. BRWD1. Hair: Steely. CYP3A4. CYP2C19*3. GABRA6. ATD.GABRG2. AGTR1. FOXP1. DRD342 43. CYP3A4*17. CACNA1E. ACSL4. ACP*1A. CDH5. CYP2D6*3. GABRG1. DNMT3B. CHD8. CTH. CYP2D6 41 . GABRA6. BRSK2. COMT 40. GABRA1 45. CDH10. GABRD. Dyrk1a. inhalant. GABRA5. dark color 25. Vitals: elevated heart rate. CD36. Factor V. Others as pediatricians feel necessary With any developmental delay is occurring. AGTR2. G6PD. FTSJ1. GABRD. ABCD1. ACE. FOXP2. ADA. CETP. paternal. CYP2C9*3. ALA. CDKL5. BHMT. DISC1. CYBA. APO E3. ASMT. CYP3A4*1B. Factor I. FBXO10. low or high oxygen level 23. 2. APO E2. CYP1B1. CYP2C19*2. CYP2C19. CUL5DAT1. CHDH. DLX2. ACAT1. ANoA. AGT. DYRK1A. FOXL2. DRD2. ACP1. ALT. APOC3. DR13. ASMTL. eNOS. CCP1. Factor II. CD19. GABRA4. continuous low-grade fever. CYP 1B1. Rapid breathing or shortness of breath 27. ADCY5. EAAT3. EHD2. CNOT4. Family History: Metabolic Disease in maternal. CYP2E1*5A. GABAᴀ 44. BHMT2. GABRB1. CHD3. CADPS2. CTNNB1. ATXN1. BCOR. Diagnostic Testing a. Increase incidence of allergies: Foods. ASMT1. AGT1. GABRG1. low/high blood presser. GABRA2. BMPR2. CYP27B1. mold 24. DLX1. CNTNAP1. CYP2A6. spots of gray hair 26. CYP21A2. GABRG. CBS. ADRB2. DVR. ARID1B. BDNF 38. CYP1A1.22. CYP1A1*2C. CD44. and siblings 28. CD8. DHPR. AP3B2. GABRB3. ADNP. CALCR. GABRB1 46. 27 . CTT1.

LPL. MT-ND1. MARK1. HCE2 (CES2). MTR. TGFBR1. NLGN1. HLA-DQ8. IL-10. MTND2. TIMM8A. PTS. MS-MTRR. TCOF1. VDR. TNF – alpha. RPS6KA3. MnSOD. TMEM1. PON1. SELS (SEPS1). VCX3A. HDLBP. STK39. MT. IL-8. UPP1. MTRR. NOS. NDUFS6. NDUFAF2. SAHH (AHCY). IL-23. MT-T52. NDUFA11. PCV2b. GDI1. TM4SF2 (TSPAN7). GSTM149. NDUFA1. PTPRK PAI-1. NTRK2. OPRL1. HYR1. SETBP1.56 PCBD1. SNRPN. SESN2. PPAR-g2. GP3a. NRCAM. UMPS. HLA-A2. MS(MTR). SOD3. PITX1. SCN1B. others. MBD5. IL-12. NTNG1. IL-4. MIF. MAT. SVF1. NTNG1. TMLHE. MET 53. NDUFS4. PON2. PTEN. MECP2. Pink Disease 63 e. PSEN1. SHMT1. GSS. GCPII. RUVBL1. TH-1. Celiac Disease 62 b. α7nAChR 61. MERRF. GRM5 48. TPH1. GP3APL(A). IL-5. TGFBR2. SCN1A. GSTO1. HCCS. MTF1. Rett syndrome 64 f. IFN-γ/α/β. SELE.Suggested Medical and Metabolic Assessments Useful for ASD GABRP. NAT 2. PCDHB4. GNB3. OTC. MT1 (L/E). NAPQI. HOXA1. GNMT. PDCD1. SAM. SUOX. NR4A2. TPH2 59 60. GABRR1. TGF-β 58. NAT 1. GRINL1A. NADH2. NPY5. ii. SLC6A4. MT-2. TGF-β1. HMX1. MLL3. SOD2. IFN-γ. IL-2. Genetic Disease Testing (secondary autism): 1. TCN2. IL-1 β 51. ZnT1. KATNAL2. MT-ND5. MTHFR 54 55. NNMT. IL-13. GSTP1. Sickle Cell Anemia .Addendum I . MAOA. GCLM. NDUFS1. PCV2a. G6PD (Glucose-6-Phosphate Dehydrogenase) Deficiencies c. GAD 1. MT-ND6. HADH2. IL-12p70. MT-ND3. MT-ND4. MT3. HTR1D. GCLC. Mitochondria Disease d. HLA 50. MDM2. mMT-I. SLC40A1. IL-6 52. Genetic Disease with ASD like features including: a. IL-12p40. RELN. GATA3. GPX2. RGMA. GRIP2. HDGFRP2. MTHFS. GCH1. QDPR. OXTR. GAD. GAD 2. TH-2. IL-13. GABRR2. MSR(MS_MTRR). GRIP1 47. PEMT. NPY1. RORA 57. TDF. NDUFS2. SLC19A3. ITGB3. Mic B. RFC1. SOD2. NOTCH3. SLC25A12. GPS1. TH. MDMA. PTEN. HLA-DR4. ITGA4. MCP-1. IL-17. GPX1. TGIF.

Down’s Syndrome b. Glucose transport & regulation (GLUT1) deficiency syndrome 12. Genetic Disease with secondly ASD a. Hyperinsulinism hyperammonemia syndrome 14. others 2. Neurotransmitters DHPR (Dihydropteridine reductase) deficiency 29 . Wilson’s Disease i. Fatty aldehydes Sjögren–Larsson syndrome 11. Congenital intrinsic factor deficiency 9. Cerebral folate receptor deficiency 7. BH4 deficiency 68 3. Menkes disease-occipital horn syndrome 19. Imerslund Gräsbeck syndrome 16. Lysosomal Gaucher disease 18. Fragile X Syndrome c. Co enzyme Q10 deficiency 8. Abnormal intestinal permeability 67 2. Dysfunction of mitochondrial β-oxidation 70 10. IEM (Inborn Errors of Metabolism): 66 1. Immune / Autoimmune Dysfunction 72 73 74 17. Hyperphenylalaninemia 71 15.g. others iii. Carnitine palmitoyltransferase II deficiency (CPT-II) 6. Mitochondria dysfunction 75 76 77 20. Tourette syndrome 65 h. C4B deficiency 69 5. Biotin responsive basal ganglia disease 4. Glucose-6-Phosphate Dehydrogenase deficiency 13. Mitochondrial Oxidative Phosphorylation (OXPHOS) Dysfunction 21.

Phenylketonuria 79 24. l. BCKDK (16p11. PHGDH deficiency: D-3-phosphoglycerate dehydrogenase (serine deficiency) 25. Ornithine translocase c. 614901 b. HHH syndrome (hyperornithinemia. Metabolic Biomedical Phenotype Testing: 80 (a) OMIM#81. hyperammonemia. Mt: mitochondrial i. (c) Gene(s). 238970 b.Suggested Medical and Metabolic Assessments Useful for ASD 22. SLC25A15 (AR) 3.2) 2. PTPS (6 Pyruvoyl Tetrahydropterin Synthase) deficiency (biopterin deficiency) 28. Tyrosine hydroxylase deficiency 33. Vitamins/co-factors Biotinidase deficiency b.o.: late-onset form.o. Branched-chain ketoacid dehydrogenase kinase deficiency 82 c. peripheral blood (PB) monocytes and specific polysaccharide antibody deficiency (SPAD) 78 23. Non-ketotic hyperglycinemia . AD: autosomal dominant. Branched-chain ketoacid dehydrogenase kinase deficiency a. Smith–Lemli–Opitz Syndrome 30. Pyridoxine dependent epilepsy 29. PSAT deficiency: phosphoserine aminotransferase deficiency (serine deficiency) 26. SPR (Sepiapterin Reductase) deficiency 31. Remark: l. (b) Biochemical deficiency. homocitrullinemia) a. Thiamine-responsive encephalopathy 32. PSPH (phosphoserine phosphatase) deficiency (serine deficiency) 27.Addendum I . AR: autosomal recessive. Amino Acids: 1.

Aminomethyltransferase/glycine decarboxylase/glycine cleavage system H protein c. Phenylketonuria a. DHCR7 (AR) 31 . PSPH deficiency (Serine deficiency) a. PAH (AR) 5. PHGDH deficiency (Serine deficiency) a. Phosphoserine phosphatase c. Smith–Lemli–Opitz Syndrome a. Tyrosinemia type II a. Cholesterol & bile acids 1. PHGDH (AR) 6. 605899 b. 270400 b. 614023 b. 276600 b. 7-Dehydroxycholesterol reductase c. PSAT1 (AR) 7. Cerebrotendinous xanthomatosis a. CYP27A1 (AR) 2.a. Phosphoglycerate dehydrogenase c. Phosphoserine aminotransferase c. Sterol-27-hydroxylase c. PSAT deficiency (Serine deficiency) a. Phenylalanine hydroxylase c. 601815 b. AMT/GLDC/GCSH (AR) 4. 610992 b. PSPH (AR) 8. 261600 b. TAT (AR) ii. 213700 b. Cytosolic tyrosine aminotransferase c.

612736 b. 270200 b. 277400 b.Suggested Medical and Metabolic Assessments Useful for ASD iii. GLUD1 (AR) vi. Hyperinsulinism hyperammonemia syndrome a. GLUT1 deficiency syndrome a. Sjögren–Larsson syndrome a. Guanidino-acetate-N-methyltransferase c. Hyperhomocysteinemia 1.Addendum I . ALDH3A2 (AR) v. Fatty Acid Metabolism Disorders 1. Cobalamin C deficiency a. GAMT deficiency a. Creatine 1. Methylmalonyl-CoA mutase and homocysteine :methyltetrahydrofolate methyltransferase . Creatine transporter Defect a. Arginine: glycine amidinotransferase c. Fatty aldehyde dehydrogenase c. Glucose transporter blood–brain barrier c. Creatine transporter c. 606762 b. AGAT deficiency a. SLC6A8 (X-linked) 3. SLC2A1 (AR) 2. 606777 b. GATM (AR) 2. Glutamate dehydrogenase superactivity c. 300352 b. Glucose transport & regulation 1. 612718 b. GAMT (AR) iv.

LMBRD1 (AR) 5. α-Mannosidosis a. Cystathatione β-synthase c. 250940 b. 208400 33 . 277380 b. 248500 b. Methylenetetrahydrofolate reductase deficiency c. Lysosomal cobalamin exporter c. l. Cobalamin F deficiency a. Lysosomes 1. Aspartylglucosaminuria a. 277410 b. 236270 b. Cobalamin D deficiency a. Cobalamin E deficiency a. MTHFR deficiency a. Methionine synthase reductase c. 236200 b. C2ORF25 protein c. Smethyltransferase c. MAN2B1 (AR) 2. Cobalamin G deficiency a.o. MTRR (AR) 4.c. MTR (AR) 6. CBS (AR) 7. 236250 b. MMADHC (AR) 3. α-Mannosidase c. 5-Methyltetrahydrofolate-homocysteine. Homocystinuria a. MMACHC (AR) 2. MTHFR (AR) vii.

Niemann–Pick disease type C a. 257220 b. 309900 b. Sly syndrome (MPS VII) a. Sanfilippo syndrome D (MPS IIId) a. Acetyl-CoA glucosamine-N-acetyl transferase c. ß-Glucosidase c.Suggested Medical and Metabolic Assessments Useful for ASD b. Sanfilippo syndrome B (MPS IIIb) a. β-glucuronidase c. Aspartylglucosaminidase c. Iduronate-2-sulfatase c. 231000 b. AGA (AR) 3. GBA (AR) 5. 252920 b. NAGLU (AR) 7. Aspartylglucosaminidase c. N-acetyl-glucosaminidase c. GUSB (AR) 10. IDS (X-linked) 6. HGSNAT (AR) 8. Intracellular transport cholesterol & sphingosines . N-acetyl-glucosamine-6-Sulfatase c. 252930 b. 252940 b. AGA (AR) 4. 253220 b.Addendum I . GNS (AR) 9. Aspartylglucosaminuria a. Sanfilippo syndrome C (MPS IIIc) a. Hunter syndrome (MPS II) a. Gaucher disease type III a. 208400 b.

prenyl diphosphate synthase subunit 2. PDH complex deficiency a. Co enzyme Q10 deficiency a. E3) c. coenzyme Q8. Ceruloplasmin (iron homeostasis) c. 540000 b. MTTK.MTND6. MTTS2 (Mt) 3. MTND1. APTX. MTND5. PDHA1 (X-linked). NPC1 NPC2 (AR) viii. Wilson disease a. Aceruloplasminemia a. 245349 b. Menkes disease/Occipital horn syndrome a. COQ2. ATP7B (AR) ix. prenyl diphosphate. MTTS1. Mitochondrial Dysfunction 83 1. Mitochondrial energy deficiency c. Metals 1.c. CP (AR) 2. MTTL1. COQ9 (most AR) 2.PDSS2. synthase subunit 1. coenzyme Q9 c. MTTH. Pyruvate dehydrogenase complex (E1α. 277900 b. aprataxin. CABC1.DLAT (AR). MTTQ. MTTC. PDHX (AR) 35 . 245348. OMIM# according to each enzyme subunit deficiency:312170. ATP7A (AR) 3. Coenzyme Q2 or mitochondrial parahydroxybenzoatepolyprenyltransferase. E2. 604290 b. PDSS1. Copper transport protein (liver to bile) c. MELAS a. 607426 b. 304150 b. Copper transport protein (efflux from cell) c.

PTS (AR) 5.3) x. PCD deficiency (biopterin deficiency) a. SSADH deficiency a.32) 5. Mitochondrial Elongation Factor G1 a. palmitoyltransferase II Dificiency Infantile c. SPR deficiency (biopterin deficiency) a. 261640 b. GTP cyclohydrolase c.Suggested Medical and Metabolic Assessments Useful for ASD 4. PCBD1 (AR) 4. DHPR deficiency (biopterin deficiency) a. ALDH5A1 (AR) . 6-Pyruvoyltetrahydropterin synthase c. GFM1 (3q25. CPT2 (1p32. SPR (AR) 6. Carnitine palmitoyltransferase II a. 264070 b.Addendum I . 261630 b. QDPR (AR) 2. Combined oxidative phosphorylation deficiency 1 c. 609060 b. GCH1 (AR) 3. Sepiapterin reductase c. 233910 b. Succinic semialdehyde dehydrogenase c. 600649 b. PTPS deficiency (biopterin deficiency) a. Neurotransmission 1. 612716 b. 271980 b. Pterin-4α-carbinolamine dehydratase c. GTPCH1 deficiency (biopterin deficiency) a. Dihydropteridine reductase c.

210210 b. Glutaric acidemia I a. 250950 b. Tyrosine Hydroxylase c. Organic acids: 1. 3-Methylglutaconic aciduria type I a. Mitochondrial acetoacetyl-CoA thiolase c. l. MMAB (AR) 6. AUH (AR) 3. Cob(I)alamin adenosyltransferase c. 251110 b. β-Ketothiolase deficiency a. GCDH (AR) 37 . 251100 b. Mitochondrial sulfur dioxygenase c. Ethylmalonic encephalopathy a. 203750 b. 3-Methylglutaconyl-CoA hydratase c. Tyrosine Hydroxylase Deficiency a. Glutaryl-CoA dehydrogenase c. MCC1/MCC2 (AR) 2. 3-Methylcrotonyl CoA carboxylase (3-MCC) c. ACAT1 (AR) 4. Cobalamin A deficiency a. 602473 b. 605407 b. TH (AR) xi.7. ETHE1 (AR) 7. MMAA (AR) 5. GENE OMIM # 210200. 3-Methylcrotonyl glycinuria a. 231670 b.o. Cobalamin B deficiency a. MMAA protein c.

mHMG-CoA synthase deficiency a. Smith-Lemli-Opitz syndrome (SLOS) 84 a. 245050 b. Multiple acyl-CoA dehydrogenase c. 300872. ETFA. Propionyl-CoA carboxylase c. NT5C3 (AR) xiii. Mitochondrial 3-hydroxy-3-Methylglutaryl-CoA synthase c.Addendum I . Hormone Metabolism 1. 606224 b. HMG-CoA lyase deficiency a. 231680 b. 605911 b. ETFDH (AR) 9. Smith-Lemli-Opitz syndrome c. HMGCL (AR) 10. 246450 b. OXCT1 (AR) xii. Pyrimidines 1.o. Pyrimidine-5-nucleotidase Superactivity c. Epsilon-trimethyllysine hydroxylase deficiency 85 a. 270400 b. 606054 b. Succinyl-CoA 3-oxoacid CoA transferase c. Glutaric acidemia II a. HMGCS2 (AR) 11.Suggested Medical and Metabolic Assessments Useful for ASD 8. 209850 (Autism susceptibility 1) . Propionic acidemia a. PCCA/PCCB (AR) 12. ETFB. l. 3-Hydroxy-3-methylglutaryl-CoA lyase c. Pyrimidine 5-nucleotidase superactivity a. SCOT deficiency a. DHCR7 xiv.

o. Argininosuccinate Synthetase c.o. 605814 b. Epsilon-trimethyllysine hydroxylase deficiency c. Argininosuccinate lyase c. 215700 b. OTC (X-linked) 7. l. Citrin (aspartate–glutamate carrier) c. CPS1 (AR) 4. Arginase 87 c. CPS deficiency a.o. OTC Deficiency a. NAGS deficiency a. Argininosuccinic aciduria a. Urea cycle 86 1. Citrullinemia a. 237310 b. 311250 b. NAGS (AR) 6. Vitamins/co-factors 1. SLC25A13 5. l. L. 237300 b. ASL (AR) 3. TMLHE (Xq28) xv.o.b. N-acetylglutamate synthetase c. 207800 b. l. 207900 b. Carbamoyl phosphate synthetase c.o. ARG1 (AR) 2.o. ASS1 (AR) xvi. Argininemia a. l. l. Citrullinemia type II a. Biotin responsive basal ganglia disease 39 . Ornithine transcarbamoylase c.

261100 b. ALDH7A1 (AR) 8. 613068 b. MOCS1. SLC19A3(AR) 2. Cerebral folate receptor-α deficiency a. Pyridoxine dependent epilepsy a. 261000 b. 607483 b. GIF (AR) 4. MOCS2. 252150 b. Intrinsic factor deficiency c. IF-Cbl receptor defects (cubulin/amnionless) c. Biotin transport c. a. Sulfite oxidase & xanthine dehydrogenase & aldehyde oxidase c. Cerebral folate transporter c. Biotinidase deficiency . Holocarboxylase synthetase c. (AR) 7. HLCS (AR) 5. Congenital intrinsic factor deficiency a. Holocarboxylase synthetase deficiency a. 253270 b. Molybdenum co-factor deficiency type A a. Thiamine responsive encephalopathy a. Thiamine transport c. 266100 b. CUBN & AMN (AR) 6. 606152 b.Suggested Medical and Metabolic Assessments Useful for ASD a. SLC19A3 (AR) 9. Imerslund Gräsbeck syndrome a.o.Addendum I . Pyridoxine phosphate oxidase c. FOLR1 (AR) 3.

14396A>G.a. MCH. abnormal clotting. and Basophils). Eosinophils. Hemoglobin. CYP2C9*1. blood proteins. MCHC. rs3798220 d. Risperidone 1. rs8179183 is a SNP in the leptin receptor LEPR gene. BTD (AR) c. Hematocrit. Ibuprofen 1. Risperdal 1. and infection. 253260 b. Monocytes. RDW. CBC is performed on the blood: WBC. Platelet Count. also known as g. MPV and Differential (Absolute and Percent Neutrophils.G) v. Lymphocytes. MCV. located in the cytochrome p450 CYP2C9. iii. Biotinidase c. rs1057910(C). rs1467558(A. Drug Metabolism:88 i. and electrolyte and acid/base balance. CYP2C9*3. Ile359Leu or A1075C. Chemistries: 1. Functional Testing: 89 90 i. Acetaminophen 1. Complete Blood Count (CBC) is a standard. CMP is performed on 41 . Basic Comprehensive Metabolic Panel (CMP) is a standard panel of tests that provides important information about the current status of the kidneys. blood sugar. in the 5hydroxytryptamine (serotonin) receptor 3A HTR3A gene ii. rs1176713 is a SNP. Aspirin 1. SNP rs1057910(A). RBC. rs5918(C). liver. Ferritin 2. broad screening test used to check for disorders such as anemia. iv.

Dicarboxylic acid iii. OAT. ALT. AST. 3-Oxoglutaric Acid d.5-dicarboxylic Acid e. Potassium. Creatinine with GFR Estimated. Total Protein. plasma a. Alkaline Phosphatase. Sorcosine 3. urine a. Mitochondrial Function 1. Acylcarnitines. Citramalic Acid b. Proline e.dimethyl glutaconate d. 5-Hydroxy-methyl-furoic Acid c. Amino Acids. Glycine d. Alanine b. Carnetine b. BUN/Creatinine Ratio (calculated). TCA intermediates b. blood plasma and whole blood 91 a. Chloride. Sodium. Arabinose . Tartaric Acid g. Alanine/Lysine ratio c. Acryl free carnitine ratio 2. Furan-2. Albumin/Globulin Ratio (calculated). Tyrosine f. Urea Nitrogen ii. Basic Metabolic Panel: Albumin. Glucose.Suggested Medical and Metabolic Assessments Useful for ASD the blood.Addendum I . Total Bilirubin. Ethylmalonate c. Calcium. Globulin (calculated). Carbon Dioxide. Furancarbonylglycine f. Organic Acids: 92 93 1. 3. General Indicators of Gastrointestinal Dysbiosis: a.

Glycolytic Cycle Metabolites: a. Malic Acid d.h. Tricarballylic Acid j. Glyceric Acid b. Succinic Acid b. 4-Hydroxybenzoic Acid m. HVA and VMA 43 . Krebs Cycle Metabolites: a. 3-Indoleacetic Acid p. 4-Hydroxyphenylacetic Acid l. Pyruvic Acid c. 2-Hydroxybutyric Acid 4. Citric Acid 5. Neurotransmitter Metabolism: a. Fumaric Acid c. DHPPA(dihydroxyphenylpropionic acid) 2. 2-Hydroxyphenylacetic Acid k. Oxalic Acid 3. 2-Oxoglutaric Acid e. 4-Cresol r. Carboxycitric Acid i. Glycolic Acid c. Hippuric Acid n. HPHPA 94 (3-(3-hydroxyphenyl)-3-hydroxypropionic acid) q. Aconitic Acid f. 4-Hydroxyhippuric Acid o. Oxalate Metabolism: a. Lactic Acid b.

Pyridoxic Acid l. Quinolinic Acid / Kynurenic Acid Ratio f. N-Acetylcysteine Acid r. Pantothenic Acid m. Kynurenic Acid (KYNA) e. 5-Hydroxyindoleacetic Acid c. Uracil b. or celiac disease o. Quinolinic Acid d. Nutritional Markers: j. Acetoacetic Acid c. Methylcitric Acid 8. Glutaric Acid n. Thymine 7. 3-Hydroxybutyric Acid b. valproic acid (Depakene). Ketone and Fatty Acid Oxidation: a. Pyrimidine Metabolism: a. 4-Hydroxybutyric Acid d. 3-Hydroxy-3-methylglutaric Acid q. Ethylmalonic Acid h. Ascorbic Acid p. Orotic Acid . Adipic Acid e. Suberic Acid f. Sebacic Acid g. Indicators of Detoxification: a. Methylsuccinic Acid i. Pyroglutamic Acid b. Methylmalonic Acid k.Addendum I .Suggested Medical and Metabolic Assessments Useful for ASD b. Quinolinic acid / 5-HIAA Ratio 6.

Alpha-amino-N-butyric acid e. Argininosuccinic acid 45 .c. Alanine d. 2-Hydroxyisovaleric Acid b. 3-Methylhistidine c. 2-Hydroxyhippuric Acid 9. Phenylpyruvic Acid i. Mandelic Acid g. Anserine (dipeptide) h. Phosphoric Acid iv. Phenyllactic Acid h. 1-Methylhistidine b. Homogentisic Acid j. 2-Hydroxyisocaproic Acid e. 3-Methyl-2-oxovaleric Acid d. Amino Acid Metabolites: a. 2-Oxoisocaproic Acid f. 4-Hydroxyphenyllactic Acid k. 2-Oxoisovaleric Acid c. Ammonia g. Plasma Amino Acids:95 a. Amino Acids: 1. 3-Hydroxyglutaric 10. Methylglutaric Acid n. Arginine i. 3-Methylglutaconic o. Malonic Acid m. N-Acetylaspartic Acid l. Bone Metabolism: a. Alpha-aminoadipic acid f.

Sarcosine jj. Glycine w. Asparagine k. Glutamic acid u. Cystathionine r. Urea pp. Gamma-aminobutyric acid t. Taurine ll. Beta-aminoisobutyric acid n. Valine . Carnosine (dipeptide) o. Threonine mm. Cyst(e)ine q. Ethanolamine s. Serine kk. Lysine cc. Aspartic acid l. Phosphoserine hh. Phenylalanine ff. Tryptophan nn.Suggested Medical and Metabolic Assessments Useful for ASD j. Phosphoethanolamine gg.Addendum I . Tyrosine oo. Leucine bb. Histidine x. Proline ii. Methionine dd. Citrulline p. Homocystine y. Isoleucine aa. Ornithine ee. Hydroxyproline z. Glutamine v. Beta-alanine m.

Isoleucine aa. Ornithine ee. Homocystine y. Alpha-aminoadipic acid f. Cyst(e)ine q. Leucine bb. 1-Methylhistidine b. Anserine (dipeptide) h. Glutamine v. Argininosuccinic acid j. Histidine x. 3-Methylhistidine c. Beta-alanine m. Glutamic acid u. Carnosine (dipeptide) o. Urine Amino Acids: a. Alanine d. Lysine cc. Phenylalanine 47 . Cystathionine r. Citrulline p. Beta-aminoisobutyric acid n. Arginine i. Ethanolamine s. Hydroxyproline z. Alpha-amino-N-butyric acid e. Asparagine k. Gamma-aminobutyric acid t. Methionine dd.2. Glycine w. Ammonia g. Aspartic acid l.

Threonine mm. Tryptophan nn. Copper. Manganese (Mn). Selenium (Se). Chromium.Addendum I . Zinc 2. Iron. Copper (Cu). Phosphoethanolamine gg. Homocysteine 6. Sodium. Manganese. Molybdenum. Total cholesterol: a. Tyrosine oo. Urine: Barium. Copper. Potassium. Vanadium. Serum Elements: Calcium. Phosphoserine hh. Calcium. Lithium. Molybdenum. HDL 2. Lithium (Li).Suggested Medical and Metabolic Assessments Useful for ASD ff. Boron. Phosphorus. Lipoprotein (a) (Lp (a)) 5. Chromium. Apolipoprotein A-I (Apo A-1) 3. Molybdenum (Mo) 3. Zinc (Zn). Selenium. Elemental Analysis: 97 1. Urea pp. Calcium. Serine kk. Cobalt. Magnesium (Mg). Magnesium. Taurine ll. WBC: Calcium (Ca). Sarcosine jj. Triglycerides vi. Magnesium. . Manganese. Magnesium. Valine v. Apolipoprotein B (Apo B) 4. Iron 4. Iron. LDL b. Phosphorus. Strontium (Sr). Proline ii. Potassium. RBC 98: Boron. Lipid Metabolism: 96 1.

Barium.Phosphorus. Copper. Magnesium. Hair 99: Calcium. Potassium. Molybdenum. Vitamins and Metabolic Function : 100 101 1. Vitamin B: a. Zirconia 5. Total Omega 3 5. Vanadium. Vitamin B3 (Niacin) c. Selenium. Sulfur. CoQ10 2. Strontium. Phosphorus. Vitamin B6 (Pyridoxine) d. Total Saturated 2. Total b. Vitamin A 4. Iodine. Sodium. 25-OH. Vitamin D. Cobalt. Zinc. Rubidium. Boron. Vitamin B1 (Thiamine) b. 25-OH. Vitamin H (Biotin) 9. Vitamin D: 103 a. Vanadium. Sulfur. Chromium. Selenium. Zinc/Cadmium. Vitamin D. Metabolic and Essential Fatty Acids: 104 105 1. Strontium. D3 c. Vitamin MeB12 (Methylcobalamin) 5. Total Monounsaturated 3. Folic Acids 102 3. Zirconium. Manganese. D2 7. Sodium/Potassium. Sodium. Calcium/Phosphorus vii. Vitamin K viii. Zinc. Iron. 25-OH. Lithium. Vitamin E 8. Potassium. Zinc/Copper. Vitamin D. Vitamin C 6. Total Polyunsaturated 4. Germanium. Total Omega 6 49 . Ratios: Calcium/Magnesium.

Omega 9 Series a. Gamma-Linolenic c. Docosapentaenoic d. Ratios: Triene-to-Tetraene 14. Saturated: Caprylic. Stearic. Docosatetraenoic 9. Omega 3 Series: a. Eicosatrienoic 10. Docosapentaenoic f.Suggested Medical and Metabolic Assessments Useful for ASD 6. Lauroleic b. Vaccenic f. Pentadecanoic . Total Fatty Acids 7. Alpha-Linolenic b. Eicosapentaenoic c. Linoleic b.Addendum I . Branched-chain: Pristanic. Palmitic. Elaidic 16. Oleic g. Monosaturated Series a. Docosanoic. Tetracosanoic. Docosahexaenoic 8. Arachidic. Nervonic 11. Dihomo-Gamma-Linolenic d. Hexacosanoic 12. Lauric. Hexadecenoic e. Phytanic 13. Myristic. Palmitoleic d. Myristoleic c. Margaric 17. Behenic 15. Omega 6 Series: a. Arachidonic e. Nervonic 18.

Free T4 c. Cryptosporidium EIA i. Intestinal Permeability 113 2. Thyroid 106 107 108 a. Melatonin (N-acetyl-5-methoxytryptamine) 110 4. aerobic b. Calprotectin h. Growth hormone binding protein (GHBP) e. dehydroepiandrosterone (DHEA) f. IGFBP-3 d. IGF-1 b. DHEA sulphate (DHEAS) x. Growth Hormone 111 a. Bile Acids g. Pancreatic Elastase 51 . anaerobic d. Free T3 b. Giardia lamblia EIA m. Deoxycholic Acid j. Hormone Metabolism: 1. TSH 2. LithoCholic Acid n. Plasma Leptin 109 3. Eosinophil Protein X (EPX) l.ix. aerobic x 3 c. Bacteriology Culture. Reverse T3 d. Bacteriology Culture. Gastrointestinal Function: 112 1. Bacteriology Culture. Entamoeba histolytica k. Comprehensive Digestive Stool Analysis: 114 a. Beta-Glucuronidase f. IGF-2 c. Beneficial SCFAs e.

coli xi. Concentrate Prep p. pylori Stool Antigen w. antibodies to metallothionein protein (anti-MT) xii. Parasite Identification. Peroxidase Glutathione (GPX) 4. IgE. Shiga Toxin E. Melatonin 8. n-Butyrate % t. Total Oxidant Level 2. Cysteine/Cystine Ratio 7. Uric Acid Urine b. Reduced Glutathione c. Glutathione 116 117 118: a. Uric Acid: a. antinuclear antibodies against nucleolar antigens (ANoA) b. Total Glutathione b. Trichrome Stain q. H. Immunoglobulins IgA.Addendum I . Metallothionein antibodies (anti-MT) a. IgG . Glucose-6-Phosphate Dehydrogenase (G6PD) 119 9.Suggested Medical and Metabolic Assessments Useful for ASD o. pH u. Putrefactive SCFAs r. Clostridium difficile Toxin A and B v. Immune Deficiencies: 121 a. Yeast Culture s. Superoxide Dismutase (SOD) 5. Parasite Identification. Uric Acid Blood 3. antilaminin antibodies (ALA) c. Detoxification Function: 115 1. IgM. Immune function 120 1. Cysteine/Sulfate Ratio 6.

Apricot. Garlic. AutoImmune 124 a. Mushroom. Food Allergies 128 i. Mango. Potato. Almond. Millet. Pineapple. Banana. Casein. Pumpkin. Pinto Bean. Apple. Spinach. Soybean. Walnut. Tuna. Salmon. Onion. Avocado. B Lymphocyte Antigen D8/17 123 2. Sunflower. Lentil. Apricot. Almond. Corn. Sweet Potato. Coffee. Orange. Kidney Bean. Sardine. Baker’s Yeast (Saccharomyces cerevisiae). Gluten. Egg Yolk. Sesame. Yeast (Brewers). Lemon. Serum Neurokinin A / Anti-ribosomal P protein antibodies 126 3. Monoclonal antibodies 122 d. Lobster. Asparagus. 53 . Pork. Shrimp. Crab. Turkey. Peanut. Cheese. Raisin. Grape. Oat. Bamboo Shoot. 2. Beef. Green Bean. Watermelon. Honey. Lamb. Wheat. Whey. Eggplant. Chicken. Garbanzo Bean. Blueberry. plasma progranulin 125 b. Beef. Lettuce. Radish. Rice. Egg White. Pecan. Plum. Cod Fish. Papaya. Apple. Lima Bean. Goat’s Milk Cheese. Rye. Strawberry. Carrot. Celery. Yeast (Bakers). Flax. Buckwheat. Pear. Black Pepper. Cranberry. Banana. Asparagus. Beet. 3 and 4 c. Green Pepper. Hazelnut. Cabbage.b. Zucchini ii. Pistachio. Halibut. Cane Sugar. Tomato. Cashews. Cocoa. Milk. Barley. Adzuki Bean. Bonito. Grapefruit. Peach. Barley. Avocado. Pea. Coconut. Yogurt. Broccoli. IgG Food Antibodies: Abalone. Allergies 127 a. IgE Antibodies: Almond. IgG Subclasses 1.

Cane Sugar. Tuna. Lobster. Cod fish. Hazelnut. Mushroom-Shiitake. Curry – IgG. Cloves – IgG. Cranberry. Broccoli. Fennel seed – IgG. Brewer’s Yeast (Saccharomyces cerevisiae). Black Pepper – IgG. Sardine. Egg Yolk. Halibut. Peanut. Eggplant. Basil – IgG. Miso. Cheese. Walnut. Pinto Bean. Kiwi. Casein. Oolong Tea. Cherry. Tomato. Horseradish – IgG. Blueberry. Spinach. MushroomEnoki. Crab. Cucumber. Rice. Duck. Cayenne Pepper – IgG. Olive. Sweet Potato. Cashews. Sesame. Turkey. Grape. Papaya. Vanilla Bean. Pumpkin. Mozzarella Cheese. Coconut. Milk. Lettuce. Chicken.Addendum I . Buckwheat. Jack Mackerel. Marjoram – . Chestnut. Pistachio. Bay leaf – IgG. Honey. Oat. Watermelon. Gliadin. Orange. Curry Powder. Pork. Laver (Nori). Sorghum. Clam. Radish-Daikon. Plum (Prune). Mackerel. Carrot. Kidney Bean. Lima bean. Goat’s Milk Cheese. Shrimp. Spices IgG: Allspice – IgG. Rye. Grapefruit. Strawberry. Cocoa.Suggested Medical and Metabolic Assessments Useful for ASD Buckwheat. Yogurt iii. Pecan. Lentil. Coffee. Kombu (Kelp). Celery. Millet. Cabbage. Green Tea. Salmon. Oyster. Mango. Soybean. Whey. Wheat. Green Pepper. Onion. Garbanzo Beans. Ginger. Seaweed (Wakame). Lemon. Cumin – IgG. Pineapple. Burdock (Gobo). Lotus Root. Pear. Wheat Gluten. Green Bean. Garlic. Mustard. Chicken. Melon. Pea. Egg White. Corn. Cinnamon – IgG. Flax. Ginger – IgG. Peach. Dill – IgG. Pacific Saury. Beet. Squid. Red Pepper. Candida albicans. Radish. Sunflower. Lamb. Mushroom. Potato.

IgE. Dandelion.IgE.IgE. June Grass (Kentucky Blue). Mesquite Tree.IgE. English PlantainIgE. Total IgG.IgE. Cultivated Oat Grass. Rough Pigweed.IgE.IgE. Maple TreeIgE. Olive Tree. Dog dander. Thyme – IgG. Oak Tree.IgE.IgE. Nettle. Oregano – IgG. Scale.IgE.IgE. Walnut Tree. Eucalyptus Tree.IgE. Rosemary – IgG. Mustard – IgG.IgE.IgE. Pecan Tree.IgE.IgE.IgE.IgE.IgE. Cocklebur. Cottonwood Tree. Common Ragweed. Parsley – IgG. Sweet Vernal Grass. Cockroach.IgE. Red Top. Rough Marsh Elder. Vanilla – IgG iv. Australian Pine Tree. Mite Generic. Timothy Grass. Bahia Grass. Mountain Cedar Tree.IgE.IgE. S100 protein 55 . Giant Ragweed. Johnson Grass.IgE. Acute-phase reaction (APR) markers i.IgE. Peppermint – IgG.IgE.IgE. Perennial Rye Grass.IgE. Paprika – IgG.IgE.IgE.IgE.IgE.IgE. Bermuda Grass.IgE.IgE.IgE. Russian Thistle. Cat dander.IgE. Sage – IgG. Western Ragweed. Canary Grass. Birch Tree. Total IgE. Inflammation a.IgE.IgE. IgE Inhalant Allergies: Alder Tree. Nutmeg – IgG. White Mulberry TreeIgE 4. Mold Generic. Brome Grass. Lamb's quarters. C-Reactive Protein (CRP) ii. Orchard Grass. Elm Tree.IgE.IgG.IgE.

Herpes simplex virus type 1 (HSV-1) 11.Addendum I . Rubeola/Measles Edmonston Strain Inactivated Cell Extract b. DNase antibodies in serum (ADB) 2. Herpes simplex virus type 2 (HSV-2) ii. Human Herpes Virus-7 (HHV-7) 6. Group A β-hemolytic Streptococci (GABHS) 135 1. Toxoplasma gondii iv. Infection (blood test): 130 a. BK virus (BKV) 132 2. Bacteria: i. Vector-Born:136 i. Opiate Receptors: Gluten / Casein Peptides 129 a. Antistreptolysin O titer (ASO) c. Casomorphin (peptide from dairy) 6. PCV2b 10. Epstein Barr virus (EBV) 4. Human Herpes Virus-6 (HHV-6) 5. Retroviruses iii. Lyme disease Western blot .Suggested Medical and Metabolic Assessments Useful for ASD 5. Borrelia burgdorferi c6 peptide antibodies by ELISA ii. Chlamydia pneumonia 134 iii. JC virus (JCV) 7. Simian virus 40 (SV40) 133 8. Gliadorphin (peptide from wheat) b. Mycoplasma pneumonia ii. Virus:131 i. Varicella-Zoster virus (ZVZ) 9. Cytomegalovirus (CMV) 3. Polyomaviruses 1.

Neurotensin (NT) 139 ii. Aspergillus fumigatus 7. Tau and Related proteins g. 2. Monoclonal Antibodies 1. Beta-amyloid peptide iii. Neurotoxins 143 57 . Beta-Amyloid Precursor Protein 140 1. IgE/anti-IgE iii. Tubulin 3. Tau. Plasma Chemokines 137 e. 24 hours to measure vascular endothelial growth factor (VEGF) release by ELISA or for 6 hours or quantitative PCR f. Mast Cell 138 i. Tubulin 3. Peptides i. Mycology: i. (sAPP-α ELISA)142 iv. AD/PD related Proteins 7. Beta Amyloid 2. mitochondrial DNA. Synuclein 4.d. Corticotropin-releasing hormone (CRH) ii. Neuropeptides / Brain Inflammation (13 amino acid neuropeptide) 1. Calmodulin 8. Apo E 6. Amyloid Precursor Protein (APP) 141 5.

mold.Suggested Medical and Metabolic Assessments Useful for ASD i. Silver (Ag). Heptacarboxy (7-CP) c. Cadmium. lyme disease 153. Tin. Biotoxins: Biotoxins are poisons that come from plants or animals. Beryllium. Mercury. Nickel (Ni). clamydia. Fecal: Antimony. Lead. Urine 151: Aluminum. Antimony. WBC: Arsenic (As). fungal toxins and toxins produced by viruses iii. Nickel. Xenobiotics (man-made environmental toxins) and Food Preservatives: 154 . Uroporphyrins (UP) 2. Arsenic. unspecified toxins from streptococci. Thallium. Copper. Tungsten. Nickel. Porphyrins: 147 a. botulinum toxin. Spot Urine: Urine protein to creatinine ratio (PrCP) 152 7. Beryllium. staphylococci. Mercury. Platinum. Tungsten. Thallium (Tl). Precoproporphyrin (PreCP) f. Bismuth. Bismuth. Thallium. Barium (Ba). Cobalt (Co).Addendum I . Lead. Tin. Mercury. Platinum. Lead. Nickel. ascaridin (from intestinal parasites). Hair 148 149: Aluminum 150. Titanium 3. Antimony. Uranium. Thallium. Coproporphyrin I and III (CP) b. Hexacarboxy (6-CP) d. Pentacarboxy (5-CP) e. Platinum (Pt). Thallium 4. Beryllium. Cadmium (Cd). Cadmium. Cadmium. Uranium 6. tuberculosis. black mold. Lead. Mercury. Thorium. Platinum. Lead (Pb). Cadmium. Bismuth. Mercury (Hg). Arsenic. Arsenic. Heavy Metals: 144 145 146 1. Silver. Thorium. Uranium (U) 5. RBC: Arsenic. Uranium ii. tetanus toxin.

CBS. 3. Family Testing a. fluoride. Decabromodiphenyl Ether (DECA). Mercury 166 2. Butylated Hydroxyanisole (BHA). Fluoride. Polychlorinated biphenyl (PCB)156. Butylated Hydroxyanisole (BHA). Asbestos. BHMT. Metabolism Genes: MTHFR. Asbestos. Comprehensive Metabolic Analysis 164 1. Genotype and Phenotype Genetic Tests: 161 iii. Organic Acids 165 vi. Polybrominated diphenyl ethers (PBDEs) 157. 160 ii. methyl-and propyl-paraben. Oxybenzone. aspartame. Pesticide 158. Decabromodiphenyl Ether (DECA). Phthalates. Bisphenol A (BPA). Essential Minerals 168 viii. Perfluorooctanoic Acid (PFOA). The Hazards Lurking at Home. dioxin. Neuroinflammation 162 iv. etc. Vitamin D 170 171 ix. Parabens. Oxybenzone. Phthalate. Drug Metabolism (Pregnancy) 163 v. Vitamins 1. Xenobiotics173 174 59 . COMT. formaldehyde.Thimerosal155. Perchlorate. Mother 159 i. Heavy Metals: 1. TCN2. phthalates. etc. MTRR. Folic Acids 169 2. Lead 167 vii. Parabens. wood preservatives. FOLR2. insecticides. The Hazards Lurking at Home. caramel colorings. Perfluorooctanoic Acid (PFOA). Perchlorate. Vitamins and Minerals (Prenatal Vitamins) 172 x.

Sibling(s) 181 i. Infection 175 176 xii. Infection 180 c.Addendum I . Genotype and Phenotype genetic testing 182 .Suggested Medical and Metabolic Assessments Useful for ASD xi. Genotype and Phenotype genetic testing 178 179 ii. Antioxidants 1. Father i. Glutathione 177 b.

4. Pentacarboxy 5-HT: serotonin 5'-IMP: 5'-inosine monophosphate 5'-NT: 5'-nucleotidase 6-CP: Hexacarboxy 7-CP: Heptacarboxy AD Alzheimer’s disease ADA: adenosine deaminase Ag: Silver APO A-1 Apolipoprotein A-I APO B Apolipoprotein B As: Arsenic ASD Autism spectrum disorders Ba: Barium BBB Blood brain barrier BHA: Butylated Hydroxyanisole Perfluorooctanoic Acid BKV: BK virus BPA: Thimerosal . List of abbreviations 4-AA: 4-aminoantipyrine 5-CP:. Bisphenol A Ca: Calcium Cd: Cadmium CMV: Cytomegalovirus CNS Central nervous system Co: Cobalt CP: Coproporphyrin CPS-1: carbamoyl phosphate synthetase-1 Cr: creatine CRP: C-reactive protein Cu: Copper DECA: Decabromodiphenyl Ether EBV: Epstein Barr virus EHSPT: N-ethyl N-(2-hydroxy-3-sulfopropyl)-3-methylaniline 61 .

and Evaluation GS: glutamate synthase GSH: Glutathione H2O2: hydrogen peroxide Hg: Mercury HHV-6: Human Herpes Virus-6 HHV-7: Human Herpes Virus-7 HPLC: high-performance liquid chromatography HSV-1: Herpes simplex virus type 1 HSV-2: Herpes simplex virus type 2 IBS irritable bowel syndrome IDO Indoleamine 2.Addendum I .3-dioxygenase Ig immunoglobulin IL Interleukin JCV: John Cunningham Virus Li: Lithium Lp (a) Lipoprotein (a) MeB12: Methylcobalamin Mg: Magnesium Mn: Manganese Mo: Molybdenum MPTP: mitochondrial permeability transition pore mtCK: mitochondrial creatine kinase Ni: Nickel NLH nodular lymphoid hyperplasia . casein-free Gln: glutamine Glu: glutamate GRADE Grading of Recommendations Assessment.Suggested Medical and Metabolic Assessments Useful for ASD FAP functional abdominal pain GABA: gamma-aminobutyric acid GDH: glutamate dehydrogenase GERD gastroesophageal reflux disease GFCF gluten-free. Development.

phosphorylcreatine PCV2a: Porcine circovirus genotype 2a PCV2b: Porcine circovirus genotype 2b PDD pervasive developmental disorder PFOA: Perfluorooctanoic Acid PLS LYME patients with prior treatment and persistent symptoms PNP: Purine Nucleoside Phosphorylase POD: peroxidase PreCP: Precoproporphyrin Pt: Platinum Redox Reduction-Oxidation Se: Selenium SIV: Simian Immunodeficiency Virus Sr: Strontium SV40: Simian Virus 40 Tl: Thallium TNF Tumor necrosis factor U: Uranium UP: Uroporphyrins XOD: xanthine oxidase Zn: Zinc ZVZ: Varicella-Zoster virus α-KG: α-ketoglutaric acid 63 .NMDA N-Methyl-D-aspartic acid NO: nitric oxide NOS not otherwise specified OTC: Ornithine Transcarbamylase PANDAS Pediatric autoimmune diseases associated with strep Pb: Lead PBDEs: Polybrominated Diphenyl Ethers PCB: Polychlorinated Biphenyl PCr.

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2 Irva Hertz-Picciotto. Rong Wang. Fallin MD. Huganir. Audrey E Mars. Richard L. Pletnikov M. Chitra Reddy. 2011 Mar 22. Niranjan T. Kaufmann W. 49 Steven Buyske. 108(12): 4920–4925 48 Mejias R. George H Lambert and William G Johnson (2006) Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism: BMC Genetics 2006. Huganir RL.6.108(12):4920-5. Daniele Fallin. Folsom TD. Gareth M. 51 Paul Ashwood. Tanishia A Williams. 2011 March 22.eM.4. Walter Kaufmann.1186/1471-2156-78 50 Torres AR.3. 7:8 doi:10. Edward S Stenroos. Reutiman TJ. Thuras PD: (2009) Expression of GABA(B) receptors is altered in brains of subjects with autism: 8(1):64-9 47 Rebeca Mejias. Thomas. Schwartz CE. Wang T. (2011) Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Victor Anggono. Stevenson RE. Skinner C. Anggono V. Charles E. Rosenspire AJ. Kamal Sharma. Stevenson. Adamczyk A. (2012) HLA Immune Function Genes in Autism: Autism Res Treat. Abby Adamczyk. Epub 2011 Mar 7. Cindy Skinner. Epub 2012 Feb 15.2012:959073. Madhura Sreenath. Tejasvi Niranjan.6 Isaac Pessah. Mikhail Pletnikov. Westover JB. Marivic F Factura. 2012. David Valle.46 Fatemi SH. Valle D.* Paula Krakowiak.: Proc Natl Acad Sci U S A. Sharma K.2. Schwartz.6 and Judy Van de Water5. Sue X Ming. and Tao Wanga: (2011) Gainof-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism: Proc Natl Acad Sci U S A.e Roger E. Thomas GM.6 Robin Hansen.6 (2010) 71 .1.

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org . Cassandra L. Athena Biomedical Institute clsmith@bu. Biology and Experimental Therapeutics and Pharmacology. Boston University Director of Research. Biomedical Engineer. 2013 Dr.edu Kazuko Grace Athena Biomedical Institute www.Addendum II Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients Research and Clinical Research Direction 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 January 31.athenabiomedicalinstitute. Smith Professor.

Clinical research is directed towards understanding cause and effect relationship and the established scientifically proven therapeutic treatments. treating and managing patients. educators and families seeking cause(s). (Addendum II) Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients Research and Clinical Research Direction . researchers. robust diagnostic criteria and most importantly effective treatments and preventive measures.Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients: Research and Clinical Research Direction Addendum II Cassandra L. The best effort must include input from a variety of individuals including patients and caregivers who are excluded generally from medical and scientific discussion to improve diagnosing.i Our goal is to develop state-of -the-art diagnostic assessment protocols and individualized treatment regimes for patients with autism and related disorders that are consistent with available but admittedly complex data. This aspect is especially problematic in neurobehavioral diseases. The expert group needs to include computer scientist and system biologists who are expert at handling and analyzing complex datasets. and Kazuko Grace Boston University and Athena Biomedical Institute Abstract: Autism remains a complex disorder that resists the best efforts of dedicated clinicians. Smith.

Autism is not a single disorder like Down's syndrome that is due to a single cause. The development of a publically available database with various research and clinical results from individual studies from anonymized patients. such as the Autism Diagnostic Observation Scales (ADOS). Instead. Current diagnostic strategies are observational in focus. and system biologist used to handling large datasets. staff. and where individuals wanting to analyze the samples agree to testing the entire reference set and to put results into the public domain. Diagnosis depends on the observational and clinical skills of the examiner. The results of each of groups should be made publically available. The formation of a group of working committees composed not only of researchers and clinicians but also parents. 1) What causes autism and the increase incidence of disease? Autism has many underlying etiologies difficulties. or out. autism is defined primarily by behaviors symptoms. and patients to tackle the demanding task of formulating new approaches (diagnosis.Introduction: This document is being provided as a starting point for discussion for how to improve the lives of autism patients and their families. We hope the discussion will include the collective experiences of clinicians. Towards this end. chromosome 21 trisomy. and genetic tests are done primarily to rule in. patients and families. Diagnosis is based on pooling all of the acquired information resulting in a diagnostic impression. EEG’s. non-specific evaluations such as intelligence. any contributing medical disorders. Today. The development of a reference set of anonymized patient samples that will be publically available. we encourage the Oversight Committee to support: 1. Autism Diagnostic Inventory (ADI) and others. Specific autism inventories and questionnaires that are age specific. but include: extensive medical history and physical exam. Similar diagnostic strategies are used for virtually all mental health and developmental disorders. This community effort requires the participation of computer scientists. 3. language and achievement testing. 2. treatment and management) to autism based on what might seem to be a bewildering array of research results. staff. blood and urine tests. Medical testing such as MRI or CT scans. autism is the pathological outcome of variety of assaults on the 96 .

However. Autism is linked to many genetic and environmental factors. as are other common diseases. and adverse environmental exposures are all areas that are being studied as well. The many and varied medical and metabolic aspects of disease need to be carefully and scientifically assessed for each patient and where necessary treated. Instead a robust diagnostic and predictive tool that combines testing of factors linked to autism needs to be established. Although research worldwide is identifying factors that contribute to autism.developing brain. rare genetic diseases. At present there is no useful set of markers to aid diagnosis. and is at best an inexact science. Likewise a better understanding and integration of factors linked to autism can reduce the increasing incidence of autism. Many of these issues overlap factors linked to other common diseases that do not appear to be increasing. Much progress has been made in understanding the genetic liabilities with over one hundred genes linked to autism. changes in diagnostic criteria proposed in DMS-V are putting rare genetic diseases with precise causes under the umbrella of autism subtracting rather than increasing our knowledge of disease. or screen families for risk factors for developing autism. Many different etiologies have been linked to an increase in autism including genetic predispositions. (Addendum II) Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients Research and Clinical Research Direction . we are left with a diagnosis based on behavior. 2) How to improve diagnosis of autism? Without knowing the causes. these findings have had little affect on patient treatment or outcome. Further. infectious diseases. we need better integration of results in order to improve understanding of disease presentation in individuals. nutrition and exposures to toxins. Research into toxicity mechanisms is ongoing although not to the same level of organization and intensity as genetics. dietary problems. infectious agents. Immune system abnormalities. 3) What treatments make a significant difference to autism patients? Our current treatment strategies are focused on behavioral outcomes. and this is fraught with inconsistencies.

An additional concern is the affect of xenobiotic metabolism on metabolic process indirectly through the production of oxidative stress. skin color.iii Pharmacogenomics: One form of personalized medicine involves pharmacogenomics. ii Ten million DNA differences between any two individual representing only 1% of the genome. families and patients. Just as genetic variation can determine hair color. However. The primary source for energy metabolism in the cell is the mitochondria. xenobiotic metabolism will produce oxidative stress indirectly because this process itself requires energy. Research is tell us that making inroads into autism and other serious neurobehavioral disorders will require theranostic approaches. and ethnic/racial characteristics and how we respond to medications and even foods. we advocating for what some have called a theranostic medicine approach. The treatment of patients is slowly changing. and may impair mitochondrial function. there are genetic variants that determine how an individual metabolizes specific medicines. Further. All treatments should be monitored scientifically whether nutritional or otherwise non-conventional so that the best information is available for what treatments are most effective for which subsets of patients. before diagnosis and even a single dose of medication. Theranostics approach to autism: Here. although clearly all patients will benefit from a change in attitude. we are all aware that there are significant differences in humans.Parents have instituted treatment regimes that are not scientific proven. a simple DNA test could reveal the medication 98 . but have been reported to improve the health and behavior of autism patients. This approach includes a portmanteau of diagnostic testing and the development of individualized treatment regimes. another mutation will make the same medication less potent in other individuals. Xenobiotic metabolism will produce reactive oxygen species and induce oxidative stress directly. mutations may cause certain drugs may stay in one person's body longer than usual lead to serious side effects. Energy production will increase the level of reactive oxygen species. Today. Two major areas of personalized medicine are pharmacogenomics and nutritional genomics. For example. This is a branch of pharmacology which deals with how inherited genetic variations influence the body’s response to medications by correlating single-nucleotide polymorphisms to a drug’s efficacy or toxicity. This type of understanding only comes about through cooperation between clinicians. Alternatively. Excess activity of an enzyme like a P450 enzyme located within the mitochondrial membrane will interfere with energy production. researchers. These genetic differences lead to variations in obvious phenotypes such as height. caregivers.

chronic fatigue. Most important. The basic premise of nutritional genomics is that dietary recommendations based on our understanding of nutrient-gene interactions will be important for the management of complex chronic diseases. alcoholism/substance abuse. In some cells. These pathways (Addendum II) Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients Research and Clinical Research Direction . cancer. and methylation of the dopamine receptor D4.S. National Institutes of Health (The Case for Personalized Medicine.10 Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme that directs folate (vitamin B12) obtained from food towards DNA and RNA synthesis. deafness. diabetes. 5. M. For example. glutathione. Personalized medicine will also help in adjusting pharmaceutical dose. Food and Drug Administration -Francis Collins. we expect to see more efficient clinical trials based on a more thorough understanding of the genetic basis of disease.D. Parkinson's. the synthesis of key metabolites: S-adenosyl methionine. We also anticipate that some previously failed medications will be recognized as safe and effective and will be approved for subgroups of patients with specific genetic markers. neurological disorders. and stroke. S-adenosyl methionine is the second most used metabolite in the cell after ATP the major energy transducer produced in the mitochondria. and increased resistance to drug treatment in a majority of patients. U.” -Margaret Hamburg. dietary choline can substitute for folate at least for the production of S-adenosyl methionine. multiple sclerosis. The outcome is eventual improvements in a minority. Ph.and dose to be used in a particular patient. behavioral disorders.D.D. homocysteine. “As the field advances.iv v This is especially important for patients with neurobehavioral disorders like schizophrenia that are subjected to one severe treatment regime after another. medicine will move into a new era where patients are no longer guinea pigs that are subjected to trial and error with toxic drugs. and glutathione. 3rd Edition 2011) Nutritional Genomics: Nutritional imbalances are observed in many disease including: aging.. Homocysteine is the major metabolite shared by these pathways. Glutathione is the major intracellular antioxidant and increasing evidence links oxidative stress to autism. macular degeneration. Director. Genetic testing can aid the design and application of better drugs in the pharmaceutical arena and decrease medical costs. M. osteoporosis. homocysteine. Commissioner. immune disorders. cysteine. cardiovascular diseases.

including autism. Further. physical/occupational therapy. we can make inroads into the development of best practices for the evaluation and treatment of individuals struggling with consequences of autism. Researchers have vast knowledge in basic and in some cases applied science but generally do not treat patients. There is no one individual who is or can be an in all these areas. education. caregivers. The treatment of neurobehavioral disorders is difficult and involves knowledge across many fields including psychology. Then. Genetic variations in the MTFHR (C677T and A677T) code for enzymes with lower levels of activity. and can make important observations from their own experiences that often provide direction for treatment and research strategies. and molecular tests should enable improvements in patient's health. cardiovascular disease. and medical. research. in some cases treatment of schizophrenia patients with folate improves psychotic symptoms.required other nutrients that must be obtained from the diet such as vitamin B6. 100 . and requires the input of system biology approaches to integrate large and complex data sets. neural tube defect. genetics. As important as these experts are. schizophrenia. medicine. patients and families have personal experiences with autism. nutrition. Lower activity of the MTHFR enzyme as well as low levels of vitamins B12 and B6 leads to increased levels homocysteine linked to many diseases. and cancer. Instead. Clinicians have many years of training and experience in medicine and sometimes research. The idea that nutrition is important in neurobehavioral diseases was advocated by 50 years ago by Linus Pauling the only individual to receive two undivided Nobel prizes. and computer science. Summary: Research examining a reference set of individuals with a large variety of biochemical. Folate deficiencies during pregnancy are linked to increased incidence of schizophrenia and autism in offspring. respective expertise must be shared in an environment that is conducive to trust and mutual respect. B9. This is a combination of research and clinical research approach. and methionine. behavior.

C. Editor (2012) Genomic Medicine — An Updated Primer: N Engl J Med 2010. Gregory Feero. Guttmacher. J.. M. M. Alan E. C. Ph. Marsit. F. Third Edition (2009) Personalized Medicine Coalition v (Addendum II) Epigenetics and Clinical Origen of Behaviors to Optimizing Health of ASD Patients Research and Clinical Research Direction . M.. Conradt. Editor. 362:2001-2011 iii President's Council of Advisors on Science and Technology (2008) Priorities for Personalized Medicine : PRESIDENT’S COUNCIL OF ADVISORS ON SCIENCE AND TECHNOLOGY iv The Care for Personalized Medicine. 12:47:13 ii W. Lester.D. E.D. Padbury (2012) Behavioral epigenetics and the developmental origins of child mental health disorders: Journal of Developmental Origins of Health and Disease (DOHaD) pp 1-14 i Davide Brambilla(2012) Polymeric nanoparticles as original theranostic approach for alzheimer‟s disease: Lundi 18 Juin 2012. Bromer and J.References: B.D..

Biomedical Engineer.athenabiomedicalinstitute. Biology and Experimental Therapeutics and Pharmacology. Athena Biomedical Institute Kazuko Grace Athena Biomedical Institute www. Boston University Director of Research.Developing a New Diagnostic and Treatment Paradigm for Autism Autism is a Treatable Medical and Metabolic Disease with Behavioral Components Prepared Statement of Dr. 2012. Cassandra L. Last updated January 31. Smith Professor.org Original: November 29th. 2013 Page 1 .