Most people are not yet aware that autistic spectrum disorders (ASD) are treatable because mainstream medicine is so heavily influenced by the pharmaceutical industry. The medical industry has trained us to be skeptical of any research other than double-blind, placebo-controlled trials that have such a high cost that only the pharmaceutical industry can afford to conduct them. But there are several levels of evidence-based research that can lead to valid and effective treatments for medical conditions. Only a small segment of healthcare practitioners have been willing to do the needed clinical research to discover the underlying metabolic imbalances that cause ASD and other medical conditions, instead of applying the paradigm of strictly suppressing symptoms with drugs. These physicians and researchers practice under the paradigm of functional medicine, and the Defeat Autism Now! (DAN!) consortium of doctors are a subset of this group of physicians.

Functional Medicine
Functional medicine (FM) is a systems-based, science-driven approach to individualized medicine that focuses on uncovering the underlying causes of disease and dysfunction rather than on suppression of symptoms. It is evidence-based medicine that utilizes therapies from across the spectrum of medicine, not just mainstream western medicine. Its watchword is biochemical individuality. Though many chronic diseases and illnesses will have symptoms that are common in all affected patients with the same diagnosis, the individual’s genetic uniqueness must be considered. To fully identify the nature and complexity of imbalanced physiological processes underlying the individual’s condition, and since the condition will vary from person to person, the individual, not just the diagnosis, must be evaluated thoroughly. Functional medicine is patient-centered care and not disease-centered care. The Institute for Functional Medicine describes functional medicine as, “…dedicated to prevention, early assessment, and improved management of complex, chronic disease by intervening at multiple levels to correct core clinical imbalances and thereby restore each patient’s functionality and health to the greatest extent possible.” (Jones, et. al., 2010)

The authors of the Textbook for Functional Medicine summarize the difference between the current model of medicine and that of functional medicine: “The most important precept to remember about functional medicine is that restoring balance—in the patient’s environmental inputs and in the body’s fundamental physiological processes—can be both a precursor and a concomitant activity to evaluating and treating chronic illness, and to improving health. It involves much more than treating symptoms.” (Jones, et. al., 2010)

The functional medicine model outlines fundamental physiological processes that are investigated when fundamental clinical imbalances arise within those physiological processes. The fundamental physiological processes that ultimately determine health or disease include:

• Communication, both within and between cells
• Bioenergetics, or the transformation of food, air, and water into energy
• Replication, repair, and maintenance of structural integrity, from the
• cellular to the whole body level
• Elimination of waste
• Protection and defense
• Transport and circulation

The foundational principles of how the human organism functions—and how these physiological processes communicate and interact—are essential to the process of linking ideas about multifactorial causation with the perceptible effects we call disease or dysfunction.

The practice of functional medicine is characterized by an examination of the core clinical imbalances that arise within the previously-mentioned fundamental physiological processes, and underlie the expression of disease. These imbalances happen when environmental inputs are processed through a unique set of genetic predispositions, attitudes, and beliefs. The core clinical imbalances that arise from malfunctions within this complex system include:

• Hormonal and neurotransmitter imbalances
• Oxidation-reduction (redox) imbalances and mitochondropathy
• Detoxification and biotransformation imbalances
• Immune and inflammatory imbalances
• Digestive, absorptive, and microbiological imbalances
• Structural imbalances from cellular membrane function to the musculoskeletal system

Imbalances such as these are the precursors to the signs and symptoms by which we detect and diagnose organ system disease. These imbalances arise from dysfunction or defect within the fundamental physiological processes that cut across all organ systems and alert the healthcare provider to pay attention to the full expression of disease and dysfunction.

DAN! doctors are a subset of physicians that practice functional and integrative medicine. Functional medicine is the guiding paradigm that DAN! doctors employ in their clinical practice and research. For someone on the autism spectrum, it is best to see a DAN! doctor if seeking biomedical treatments, but should one not be readily available, a functional medicine physician can provide the same approach, albeit with less experience with ASD specifically.

DAN! doctors have developed a protocol of biomedical treatments for ASD patients that are evidence-based and broad in scope. These treatments include, but are not limited to, naturopathic therapies, ayurvedic medicine, nutraceuticals, supplements, genetic testing, pharmaceutical drugs, and homeopathic remedies. Mainstream medicine (mostly allopathic doctors) usually takes 10 to 15 years to incorporate new therapies such as these, despite having valid evidence available from the outset of the discovery.

While DAN! doctors have been implementing functional medicine principles into clinical practice for over three decades, Jeffrey Bland, PhD was responsible for initiating the development of the fully elaborated academic model of functional medicine that currently exists. This model will eventually serve to incorporate these new principles of medicine into the academic institutions that will train future medical practitioners. However, the work of both the DAN! doctors and Dr. Bland are a result of several pioneering researchers since the early 1900s, as well as more recent genomic researchers. They pioneered the concept that many agents modify gene expression and provided the breakthrough science that demonstrates that significant influences in this process include the environmental inputs of diet, nutrients, exercise, stress/trauma, air, water, xenobiotics, microorganisms, radiation, and lifestyle.

Definition of Autism Spectrum Disorders
Autistic spectrum disorders include the classic type I autism, which is considered an inborn error of metabolism that is present at birth, and regressive type II autism which is an acquired metabolic imbalance that results from environmental insults combined with a genetic predisposition. Like classic autism, regressive autism has always been present to some degree, but has become more prevalent because of the increased number and severity of acquired stressors in the environment, and better recognition and diagnosis. The regressive autism spectrum includes Asperger syndrome, autism type II, and pervasive developmental disorder (PDD). Attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) are considered milder forms of ASD. ASD is defined as a multifactorial medical disorder in which various biochemical imbalances create autistic symptoms.

The many factors that contribute to the condition of autism have not yet been fully identified but researchers have been able to identify several so far and do know that they result from a combination of environmental insults and a genetic predisposition. It is theorized that there are many “autisms” due to the various combinations of metabolic imbalances that differ from one autistic person to another. Despite the variation, there are a few characteristics that are common to all ASD sufferers in varying degrees. All people on the spectrum struggle with a “theory of mind” deficit, meaning that the person cannot understand the emotional and psychological mindset of others. With both Type I and Type II autism, there is an obvious absence of theory of mind ability and reciprocal social interaction. Other characteristics of ASD include impairment in verbal and non-verbal communication skills, restricted and repetitive interests and behaviors, and abnormal responses to sensory stimuli. Asperger syndrome (AS) differs from the more debilitating type II autism by its relative preservation of linguistic and cognitive development. Although not required for diagnosis, physical clumsiness and atypical use of language are frequently reported in AS patients as well.

Background
Since the 1970s, the incidence of type I versus type II autism per live births has dramatically increased. In the 1970s, the incidence of autism was about 3 to 5 children per 10,000 births. Of these autistic children, over two-thirds had classic Type I autism, while less than a third had the regressive (acquired) Type II autism. But by 1997, regressive autism had become over 80% of the total, up from less than 33% in the 1970s. In March, 2012, the Center for Disease Control and Prevention (CDC) estimated the autism rate to be 1 out of 88 eight-year-old children (1 out of 54 boys and 1 out of 252 girls). The current CDC data shows an increase of 78% in autism rates from 2002 to 2008 (CDC, 2012). This can be attributed to both better detection and diagnosis, along with the increased number and severity of environmental insults present today.

In the field of genomics it is known that genetics do not cause epidemics; rather epidemics are characteristic of environmental inputs that cause an illness. However, people with ASD have a genetic predisposition that makes them more vulnerable than others to the increased environmental insults of today. Regressive (acquired) autism is suspected of being triggered by toxic or infectious agents piled on top of metabolic processes that are not functioning optimally but could cope without such stressors. This is the ASD population that benefits the most from biomedical interventions discovered by DAN! doctors. The Defeat Autism Now! (DAN!) project, created by the Autism Research Institute, developed an approach to autism treatment called the “DAN! protocol” based on the biomedical theory of autism. DAN! doctors focus mainly on regressive autism and not classic autism.

The genetic mutations that cause classic autism are usually large-scale, single-gene mutations in which the genetic damage permanently affects structure or function from birth in a significant manner. Regressive autism is believed to have both minor polymorphisms and inducible genes as contributing factors. Inducible genes are influenced by the environment. Nutrients, toxins and xenobiotics that we expose ourselves to through diet, air, chemicals, water, etc. can induce genetic markers to turn on and off. The ASD child can also have polymorphisms that make him or her much more sensitive to environmental triggers. This is known as the field of epigenetics; the study of how environmental factors affect gene expression without altering the actual DNA sequence, and how these changes can be inherited through generations. For this reason, nutrition and everything ingested are often the most important factors to address with ASD patients. Food and other substances are, literally, information for the inducible genes, and can activate or deactivate genetic markers that regulate metabolic function.

Regressive autism is an example of what is believed to be a combination of polymorphisms and inducible genes causing metabolic dysfunction combined with increased environmental insults. But even those with classic autism may benefit from biomedical interventions. Even though one may have genetic mutations at birth, it is possible to intervene and improve the quality of life. One example of an inborn error of metabolism (but not necessarily specific to classic autism) is phenylketonuria (PKU). This genetic flaw causes the amino acid phenylalanine to be synthesized improperly such that there is a continually high level that is dangerous to the brain. Phenylalanine is an essential amino acid that is present in many proteins at a level of about four percent. If an infant continues to ingest phenylalanine at normal levels from birth through childhood, the child will become mentally retarded after a period of time, but if that child restricts phenylalanine from the diet to the low levels indicated, she will develop normally and be self-sufficient. If an inborn error of metabolism that is permanent in nature can be influenced by diet, imagine the potential to influence genes that are inducible as in ASD.

Genetic polymorphisms associated with ASD cause dysfunction in many systems of the body: the immune system, the gastrointestinal system, the detoxification system, and the brain and nervous system. These polymorphisms cause disruptions of critical metabolic processes like methylation, transsulfuration, acetylation, phosphorylation, and sulfation. The process of methylation is already known to be affected by environmental and dietary influences, and the methylation of genes controls gene expression that limit or alter protein formation. Ensuring that an ASD patient is methylating properly can have a significant effect on proper expression of genes across the genome.

Though regressive autism is not a purely genetic disease, researchers have discovered several genetic polymorphisms, called single nucleotide polymorphisms (SNPs or “snips”), that have a direct impact on metabolic function in ASD patients. When the resulting nutritional deficiencies or excesses caused by these SNPs are corrected, there is a corresponding improvement in symptoms. These SNPs are some of the “factors” that make up the multifactorial nature of ASD. From individual to individual, the combination of genetic SNPs and environmental sensitivities will vary. However, despite a variation of SNPs, the three defining characteristics of autism, namely 1) limitations in social interaction; 2) language delays and oddities; and 3) repetitive and stereotypical behaviors, remain constant.

Cindy Schneider, MD emphasizes the importance of the methylation pathways as a focus for SNP candidate genes: “Rather than thinking in terms of an autism gene, we would be wise to think in terms of autism pathways. Methylation pathways are the best candidates, as permutations in these reactions could lead to any of the deficits and symptoms described in autism, and the biomedical treatments that have met with success are ultimately impacting these pathways.” (McCandless, 2009)

The SNPs identified to date that are associated with ASD are:

1. C4B: complement component 4B (Chido blood group)—controls function and regulation of the immune system and is involved in eliminating pathogens such as viruses and bacteria from the body.
2. MTHFR: methylene tetrahydrofolate reductase—an enzyme important for a chemical reaction in the body involving forms of the vitamin called folate. The MTHFR enzyme transforms folate into new forms that can be used by the body for making proteins and other important compounds.
3. COMT: catecholamine O-methyltransferase—methylates and inactivates dopamine in the brain. One of several enzymes that degrade catecholamine neurotransmitters such as dopamine, epinephrine, and norepinephrine.
4. GST: glutathione S-transferase—conjugates (joins or binds) toxins to reduced glutathione molecules, so the toxins can be excreted from the body.
5. MTRR: methionine synthase reductase—this enzyme maintains adequate levels of methyl B-12, the activated form of vitamin B-12.
6. DHPR: dihydropteridine reductase—this enzyme (also known as a cofactor) is responsible for one step in the chemical pathway that recycles a molecule called tetrahydrobiopterin (BH4). Tetrahydrobiopterin plays a critical role in processing several protein building blocks (amino acids) in the body, and is also involved in reactions that produce neurotransmitters in the brain.
7. CBS: cystathionine-β-synthase—an enzyme that catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine.
8. SAHH: S-adenosylhomocysteine hydrolase—this enzyme catalyzes the hydrolysis (the decomposition of a chemical compound by reaction with water) of S-adenosylhomocysteine, causing it to be transformed to adenosine and homocysteine.
9. ADA: adenosine deaminase—this enzyme eliminates a molecule called deoxyadenosine, which is generated when DNA is broken down. ADA converts deoxyadenosine (which is toxic to lymphocytes) to another molecule called deoxynosine, which is not harmful.
10. PON1: Paroxonase—a high-density lipoprotein (HDL)-associated enzyme that prevents oxidative modification (oxidative stress) of low-density lipoprotein (LDL).
11. RFC: reduced folate carrier—controls the delivery of folate to the cells.
12. TCN2: transcobalamin 2—the major transport carrier required for B12 uptake into the cells.
13. RELN: reelin—a large glycoprotein that helps regulate processes of the developing brain by controlling cell to cell interactions. Besides this important role in early brain development, reelin continues to work in the adult brain by controlling synaptic plasticity.
14. BHMT: betaine-homocysteine methyltransferase—an enzyme that contributes to the regulation of homocysteine and methionine levels. Increases in homocysteine levels are considered a risk factor for cardiovascular diseases, among other issues.

An Example of Epigenetics and Inducible Genes within ASD
Jon Pangborn, PhD outlines a good example of inducible genes with ASD in his book Autism: Effective Biomedical Treatments:

“Many autistics have oxidant stress due to metabolic limitations with glutathione synthesis and metabolism, persistent infection (such as measles) and intestinal inflammation, often with intestinal dysbiosis. Excessive oxidized glutathione and cytokine levels are present, and this condition perpetuates deficient methylation of homocysteine by the enzyme methionine synthase. To make matters worse, in homocysteine methylation capability, the methionine synthase (MS) enzyme can also become deficient by contamination with toxins like ethyl mercury, thimerisol, and possibly antimony, something very common in ASD patients. If there is a problem in homocysteine synthesis because of the MS enzyme, this further diminishes glutathione synthesis and increases oxidant stress.”

Unfortunately, in regressive autism, the biochemistry that should relieve the oxidant stress is dysfunctional, and this causes the oxidant stress and decreased methylation to continue, unresolved. In this situation, the patient would be given a ubiquitin ligase enzyme supplement to break the cycle of decreased methylation and oxidant stress. “This is an example of an acquired condition (oxidant stress) upregulating the activity,” through gene expression, “of an enzyme-degrading protein (ubiquitin) that is also abnormal in a purely genetic disease (Angelman syndrome) that features autism.” (Pangborn, 2007)

Why Autism affects Males more than Females
The role of genetics cannot be overlooked when ASD impact males significantly more than females. The ratio of males to females with ASD is about four to one. In his book Autism: Effective Biomedical Treatments, Jon Pangborn lists five plausible theories for this difference:

1. Girls get two X chromosomes, boys get one X and one Y. Many autistic traits have X-linked faults and girls have two chances to get it right, boys have only one chance.
2. Testosterone amplifies the neurotoxicity of mercury, aluminum and probably other toxins (all of which ASD individuals can have trouble detoxifying from the body), while estrogen has protective effects.
3. Males require more methylation, more homocysteine recycled to methionine, and more creatine than females because of specific muscle mass and other physiologic requirements. A defect in methylation capacity affects males more than females.
4. Relevant to the oxidant-stress condition of autism, differences in innate immunity between human males and females may make males more prone to inflammation and TNFα (tumor necrosis factor alpha) elevation than females.
5. Males use their brains differently than females for cognitive activities. Males use gray matter for intensive focus on single events and tasks, and that is the majority of their thinking capacity. Females use white matter for integrative comprehension of multiple events, and that is a majority of their thinking capacity. If neuronal networks lose synchronization, males suffer most with integrative tasks because they are more limited in this ability to begin with. However, this may leave the male and a few females with networks that provide savant or highly-specialized skills in mathematics, puzzle-solving, art, music, memory, etc.

Pangborn states that “None of these theories are wrong; they are just different points of view from different frames of reference. But the last theory is the most comprehensive explanation that also agrees with the scientific findings arrived at by researchers thus far.” (Pangborn, 2007)

In her 2003 DAN! conference presentation, Jill James, PhD explains in more detail the theories listed in numbers 2 and 3 above. She states: “It is well-established that females have lower homocysteine levels than males. After menopause, however, the difference in homocysteine levels between sexes narrows, suggesting that estrogen regulates the rate and activity of methionine turnover (to homocysteine) and transsulfuration (from homocysteine to cysteine to glutathione). Evidence suggests that both cellular methylation capacity and antioxidant activity are higher in females than males. The increased rate of methionine transsulfuration, methylation, and glutathione antioxidant activity in females may have a protective effect against the development of autism.” (James, 2003)

Causes of Autism
The causes of ASD can be broadly thought of as being those of immunological, detoxification, neurological, and gastrointestinal issues combined with a genetic predisposition. However, there are several models of causation that researchers have posited that narrow in on contributing factors. Among the current causes believed to contribute to regressive autism are: the genetic model; the autoimmunity/allergy model; the detoxification model, including toxic chemical and heavy metal contamination models; the vaccination model; the viral model; the gluten/casein, enzyme deficiency and yeast overgrowth model; and the metallothionein model.

The genetic model posits that there can be genetic vulnerabilities that make an ASD individual more sensitive to environmental toxins and nutritional deficiencies. It is not positing that regressive autism is purely genetic, since there have been epidemic increases in the rates of regressive autism over the past three decades. In this model, researchers and clinicians are working to identify several SNPs that are common to ASD patients. Over a dozen SNPs have been identified so far.

The autoimmunity/allergy model posits that many ASD children appear to have immune dysregulation that is either overactive or suboptimal. If the child’s immune system suffers an environmental insult, such as exposure to mercury in dental amalgams or to a weakened virus in a vaccine, the child’s immune system responds by attacking not only the actual antigens but also look-alike antigens that are actually necessary molecular structures in the child’s brain. There is evidence of many ASD children having familial autoimmune and allergy histories.

The detoxification model posits that ASD children are especially sensitive to insults from chemicals and heavy metals, and these triggers disrupt various biochemical pathways common to ASD. Polychlorinated biphenyls (PCBs) and organophosphate pesticides are an important class of toxic chemicals that can cause brain damage and are suspected of affecting ASD children. Lead contamination from old paint and mercury contamination from vaccines and dental amalgams are also believed to trigger ASD because these children have a dysfunctional detoxification system that would normally clear the toxins and heavy metals from the body.

The vaccination model states that vaccinations with live viruses have contributed to childhood autistic regression, and that mercury poisoning from ethylmercury, in the form of thimerisol (a preservative), has produced a correspondence in autistic traits that is highly significant and includes varying degrees of autoimmunity. Additionally, since 1991, children receive more total vaccinations (22 before the age two), and have them closer together and earlier in life than ever before in history.

The viral model states that some ASD children suffer from viral infections that interfere with critical metabolic processes. Treatment can involve antiviral medications, but usually addresses the patient’s diet, nutrients, intestinal permeability, and removal of heavy metals first to enable the child’s own immunosuppression abilities to be restored.

The gluten/casein, enzyme deficiency and yeast overgrowth model states that there is a high incidence of intolerance to the dietary proteins of gluten (found in wheat, rye, and barley) and casein (found in animal milk), due to a deficiency of the dietary enzymes needed to breakdown these proteins. If the child is suffering from intestinal permeability, these proteins can cross the lumen of the intestine and enter the bloodstream in an undigested form that can create many problems, like an autoimmune response to this foreign molecule. Similarly, candida albicans yeast overgrowth is associated with the gut dysfunction common to ASD children. Yeast overgrowth has been found to cause poor concentration, hyperactivity, short attention span, irritability, and aggression. Eliminating yeast overgrowth can improve a range of symptoms from hyperactivity and repetitive behaviors to poor eye contact, poor concentration, and speech anomalies.

The metallothionein model is the work of William Walsh, PhD of the Pfeiffer Treatment Center in Naperville, Illinois. Dr. Walsh theorizes that a small peptide is the “missing link” in ASD. Metallothionein is a protein that is involved in many processes in the body. These processes include 1) regulation of zinc and copper levels in the blood (many ASD children have zinc/copper imbalances); 2) detoxification of mercury and other heavy metals; 3) development and functioning of the immune system and brain neurons; 4) production of enzymes that breakdown casein and gluten; and 5) response to intestinal inflammation. He stated at the October 2001 DAN! conference in San Diego that environmental insults during gestation, infancy or early childhood may disable the metallothionein protein system, resulting in halted neuronal development and provoking the onset of autism.

Laboratory Testing
The means by which doctors determine an individual’s biological imbalances involves conducting tests that target each body system affected (as in the above-mentioned causation models) based on a patient’s history. Some of these tests are traditional lab tests, but many are considered functional lab tests that are new to medicine. These tests are not yet used extensively in mainstream medicine because only a portion of the medical community is currently informed about them. These tests give doctors information about numerous metabolic functions. There are also a few genetic tests available to help guide physicians to areas of metabolic dysfunction. Though genetic testing can be helpful to the physician, treatment can usually be instituted without extensive and expensive genetic testing. There are several specialized laboratories that conduct functional and genetic lab tests throughout the U.S and are currently being used mostly by functional and integrative physicians.

The strategy of choosing biomedical options for an autistic patient involves judgments about previous intervention outcomes, symptom status of the patient, and what else could be tried. There is no single abnormal analyte (i.e. homocysteine levels, cholesterol levels) from a test that is common to autism in general, but lab tests show aspects of the physiology, biochemistry, and immunology that are disordered in a particular individual’s case. Lab results guide the physician to recommend treatments such as nutrition, supplements, ayurvedic herbs, homeopathic remedies, hyperbaric oxygen therapy, intravenous immunoglobulin therapy (IVIG), pharmaceutical drugs, or numerous other options.

There are several tests that cover various analytes common to ASD, as well as other items of interest to the physician. Tests include:

Blood chemistry and CBC analysis
Stool analysis
Intestinal permeability test
Serum ammonia (blood levels)
Food allergy tests
Urinary peptide measurements
Amino acid analysis
Organic acid analysis
Fatty acid analysis
Element (metals) analyses and metallothionein assessments
Immune testing
Genomic testing

Neurotransmitters, catecholamines, monoamine oxidase and other enzymes, T-lymphocytes, nutritional factors, and toxic burdens are examples of analytes checked in ASD patients. The analytes of most significance that should be checked in ASD include:

Blood plasma cysteine
Blood or cell GSH or GSH/GSSG ratio (reduced glutathione; ratio of reduced to oxidized glutathione)
Plasma methionine
Plasma SAMe and SAH (S-adenosylmethionine, S-adenosylhomocysteine)
Plasma adenosine
Serum creatine
TNFα (tumor necrosis factor alpha)
Urine taurine and beta-alanine
Erythrocyte DHA and other cell membrane fatty acids
Venous blood ammonia
Intestinal flora (stool analysis)
Specific Food IgE and IgG levels (or food elimination trials)
Pyruvate, lactate, and pyroglutamic acid (pyroglu, organic acids)
Urine toxic elements, especially mercury
Erythrocyte elements—essential and toxic, including magnesium

Treatments
Once the physician has the needed lab results, she can decide which treatments will be of most benefit. There are many more therapies available today to treat ASD. Some of these treatments are behavioral, sensory, language, technological (i.e. transcranial magnetic stimulation, neuro-feedback, or the use of an iPad for communication), physical, dance, animal-assisted intervention, and biomedical treatments. The DAN! protocol of biomedical treatments posits that the goal is to fix the underlying biochemistry so that the patient can have greater success with the other therapies.

Biomedical treatments generally can be thought of as three broad categories of 1) replacing what the patient is missing; 2) removing what is causing harm; and 3) breaking the inflammatory cycle. Almost all biomedical treatments for ASD fall into one of these categories. The order in which treatments are given can depend on the history of the patient but, addressing nutritional status through dietary changes is usually the first step. Some additional specific therapies are:

Correcting nutritional deficiencies

• Elimination diet to remove what is causing harm (category 2): e.g., gluten, casein, oxylate, sugar, preservatives, or other food intolerances.
• Nutritional supplements to support acquired or inherited deficiencies/excesses and replace what is missing (category 1): e.g., vitamins B1, B2, B3, B5, B6 & B12, magnesium, zinc, taurine, vitamins A & C, calcium, fatty acids, melatonin, probiotics, dimethylglycine (DMG) and trimethylglycine (TMG), creatine, amino acids, S-adenosyl-methionine (SAMe), methylfolate (5-MTHF), N-acetylcysteine (NAC), L-glutamine, carnosine, alpha lipoic acid, vitamin E, selenium, inositol, silymarin, biotin, activated charcoal, CoQ10, alpha-ketoglutaric acid.

Gastrointestinal healing

• Intestinal permeability and dysbiosis correction (categories 1 & 2): e.g., probiotics, antifungal supplements and medications, antibiotic supplements and medications, digestive enzymes, secretory IgA, intrinsic factor, secretin, L-glutamine, nutraceutical foods, calcium D-glucarate, and other supplements to heal and stabilize intestinal function.
• Gastric reflux correction (categories 1, 2 & 3): e.g., remove food allergens, address inflammatory responses with supplements or medications, utilize digestive enzymes and hydrochloric acid supplements.
• Autistic enterocholitis (categories 1 & 3): low-dose naltrexone and other immunomodulators, corticosteroids, enteral nutrition with medical foods, omega-3 fatty acids, oral immunoglobulin supplementation, probiotics, and other pharmaceutical medications.
• Yeast overgrowth correction (categories 1, 2 & 3): e.g., anti-yeast diet including the elimination of high carbohydrates, high-dose probiotics, antifungal supplements and medications, coconut oil, L-glutamine, oral immunoglobulin supplementation, cellulase digestive enzymes.

Immune dysregulation

• Immune system support to reverse nutritional deficiencies (categories 1 & 3): supplementing vitamins A & C, zinc, omega-3 fatty acids, colostrum (oral Ig supplementation), transfer factor, IVIG therapy.
• Remove immune triggers that cause inflammatory reactions (categories 2 & 3): e.g., remove pathogenic organisms like c. albicans yeast, c. difficile bacteria, or cytomegalovirus with antifungal, antibiotic, and antiviral supplements or medications; and treat IgE-mediated allergies with medications, get allergen-specific immunotherapy to desensitize the immune system, and remove food and environmental sensitivities.
• Break the inflammatory cycle (category 3): use anti-inflammatory supplements like curcumin, stinging nettle, and white willow bark, or anti-inflammatory medications like NSAIDs and agents such as PPAR (peroxisome proliferator-activated receptor) agonists. Spironolactone is a drug with potent anti-inflammatory and immunomodulatory properties that can be useful, along with low-dose naltrexone to address immune dysfunction and endorphin deficiencies.

Detoxification

• Prevent oxidative stress (category 1): supplemental antioxidants and antioxidant coenzymes such as vitamins E, C, and K, zinc, selenium, and omega-3s.
• Support detoxification (catetgory 1): correct methylation and transsulfuration pathways with vitamin B6, TMG or DMG, methyl B12 injections, cysteine, N-acetylcysteine, IV glutathione, alpha lipoic acid, and sulfate in the forms of magnesium sulfate, zinc sulfate, and Epsom salts baths.
• Remove heavy metals (categories 1 & 2): heavy metal chelation using pharmaceutical or supplemental chelating agents such as DMSA (dimercaptosuccinic acid), EDTA (ethylenediamine tetraacedic acid), DMPS (dimercaptopropane sulfonate), R-lipoic acid, or IV glutathione; and supplement extra zinc, selenium, vitamins C, E, and B6 during chelation.

Neurological support

• Remove false neurotransmitters and neurotoxins to eliminate neuroinflammation (categories 1, 2, & 3): e.g., gluten and casein, abnormal gut pathogens, and toxins such as lead, mercury, and organophosphates.
• Modulating neurotransmitters to restore the normal production, recycling, distribution, and destruction and disposal of brain neurotransmitters (category 1): in ASD neurotransmitters are found to be out of balance. Supplements such as trimethylglycine (TMG), dimethylglycine (DMG), 5-HTP, glutamate, GABA (gamma aminobutyric acid), choline and phosphatidylcholine (PC) are all alternatives to pharmaceutical drugs to help stabilize brain chemistry.
• Balance neurohormones to address problems of sleep, oxidant stress, socialization, anxiety and emotions (category 2): neurohormones like melatonin, oxytocin, and secretin, produced in the pineal gland, affect brain function.
• Supply the brain with oxygen to correct decreased blood flow and hypoxia found in autistic children (categories 1 & 3): hypothesis: brain cells exist in an inactive state due to reduced oxygen supply. Treatment: Hyperbaric oxygen therapy (HBOT). Result: improvements in microcirculation and relief of cerebral inflammation.
• Treat seizures caused by abnormal and repeated depolarization of neurons in the brain (categories 1, 2, & 3): Depolarization results from trauma, low oxygen, low glucose, infection, toxicity, and metabolic imbalance, but most are idiopathic (unknown cause). Treat infections, correct metabolic imbalances, relieve hypoxia, temporally administer medications or supplements such as carnosine and remove toxins.

A Case Study
This 43 year old, Caucasian female, diagnosed with AS in 2008 suffered with a chronic sadness, anger, and confusion since early childhood. She believed herself to be evil because she experienced a profound lack of “goodness” in her herself. She was isolated socially and lonely with little or no hope of ever being able to marry. At the mercy of her moods that swung from severe depression and apathy to overwhelming anxiety and mental exhaustion from negative thinking, she was unable to work or study effectively. She would often describe her brain as broken because she could not concentrate and had no enthusiasm for life. Sleep deprivation added to her mental fogginess and poor memory. She engaged in repetitive non-functional behaviors and felt irritable much of the time. In addition to these psycho/neurological symptoms, she had numerous medical problems such as persistent digestive distress, ear, nose, and throat infections, low energy, skin rashes, and headaches.

Throughout her young life she had been treated by psychiatrics and medical doctors with very limited success. She was labeled with ADD, OCD, depression, developmental delay NOS, and bipolar disorder and was tried on a passel of pharmaceutical medications including Prozac, Ritalin, Effexor, lithium, Cymbalta, Serzone, Elavil, Sinequan, Zoloft, Wellbutrin, Desyrel, and Synthroid. The Prozac, Synthroid, and Ritalin helped her to some degree, but only partially, and they did not provide the emotional and psychological stability that she knew could be achieved.

Finally, at age 43, her life began to turn around. She obtained SPECT brain imaging scans from the Amen Clinic in California. These scans confirmed some old diagnoses and identified other new ones. The new list of labels included autistic spectrum disorder, seasonal affective disorder, sleep disorder, mild head trauma, hypothyroidism, hyperacusis (sensitivity to sound), and memory disorder NOS. The psychiatric diagnoses confirmed by the Amen Clinic were major depression, recurrent severe; Asperger syndrome, and attention deficit disorder—hyper-focused and limbic subtypes.

New medicines were tried including Cytomel (thyroid), Abilify, Geodon, Trileptal, Nystatin (for yeast infection), and melatonin and Benadryl for sleep. With only minor improvement and the development of paranoia and claustrophobia, these medicines were discontinued. The psychiatrist came to the conclusion that there was likely to be a physical, biomedical issue underlying her diagnoses and referred her to a functional medicine physician.

The functional medicine physician did several initial lab tests based on her history, symptoms, and SPECT brain scans. These included complete blood count (CBC), immunoglobulin panel, IFE (immunofixation electrophoresis), comprehensive digestive stool analysis, saliva cortisol levels, stool gluten & casein sensitivity test, urine toxic metals, vitamin-D test, Kryptopyrrole test, ApoE genetic test (apolipoprotein-e), Lyme disease, amino acid and fatty acid analyses, and vitamin and mineral analyses. Eventually, these led to three further tests: comprehensive metabolic analysis, complete hormones analysis, and a detoxigenomic profile.

The lab tests revealed intestinal dysbiosis, yeast infection, adrenal fatigue, hypercholesterolemia, vitamin B-12 deficiency, hypothyroidism, hypogammaglobulinemia, vitamin-D deficiency, mercury toxicity, progesterone deficiency, intestinal permeability, and hypochlorhydria (low stomach acid). Extensive food elimination trials were instituted to rule out food allergies and intolerances. The food elimination trials led to a diet that excluded gluten, casein (dairy), added sugar (fresh fruit only), processed or refined foods, and grains except rice.

The doctor treated the yeast infection with probiotics, oil of oregano, and Diflucan. These helped effectively clear symptoms of fatigue, cravings, and cognitive dysfunction. The adrenal fatigue was treated gradually over several months with adaptogenic herbs such as ashwaghanda, rodiola, cordyseps, ginseng, as well as vitamins B-5 and B-6 and adrenal extract. This improved stamina and overall energy. The Vitamin-D deficiency was addressed with 5000 IU of vitamin D-3 daily and continues today.

The mercury toxicity was treated by replacing all dental amalgams with non-toxic substances, and several months of chelation therapy with DMSA (dimercaptosuccinic acid) to lower the high mercury levels. She also took glutathione precursor supplements (L-glutamine, trimethylglycine, and N-acetyl cysteine) to support glutathione production—the body’s own main detoxifying agent that can remove heavy metals. This was especially important as she later discovered that she had a glutathione SNP that prevents optimal production of glutathione. After chelation therapy, she mainly noticed an improvement in digestion.

The progesterone deficiency was treated with bio-identical hormone replacement therapy which helped stabilize her mood. The hypothyroidism was treated with selenium and a compounded natural thyroid hormone therapy. This treatment continues today and has improved metabolism, energy, and sleep. The B-12 deficiency was treated with oral methyl-B12 lozenges daily.

The intestinal dysbiosis and permeability were treated by the avoidance of food intolerances, and the use of probiotics, L-glutamine, oral immunoglobulin supplementation (to assist secretory IgA intestinal function), and digestive enzymes (DPP-IV gluten digestive enzyme, serratiopeptidase, protease, lipase, amylase, and cellulase enzymes). Dysbiosis resolved but it is unclear to what extent the permeability improved since symptoms of casein intolerance and food sensitivities still remain, and she cannot benefit from the gold-standard, Ig-based test for intestinal permeability because of her hypogammaglobulinemia.

The detoxigenomic (genetic) profile led her to try a supplement called trimethylglycine for a COMT SNP found in the test. She also tried the glutathione precursor supplements and mitochondrial support supplements like CoQ10 based on this genetic profile. TMG significantly improved her ability to focus and concentrate, and relieved chronic anxiety. Many ASD patients are under-methylators because of the COMT polymorphism, and the TMG will correct this due to its capacity as a methyl donor (this is also the action by which the stimulant drugs such as Ritalin and caffeine do their work—by donating methyl groups in the catecholamine and dopamine pathways of the brain).

After this, another significant treatment therapy—perhaps the most significant one—was started which brought her dramatic improvement. She convinced the doctor to try low-dose naltrexone (LDN) therapy after reading about it. This drug was originally used to treat narcotic addiction, but was discovered by Bernard Bihari, MD to have immunomodulatory properties at low doses in the 1980s when he worked with his addiction and AIDS patients in his clinic. This drug tricks the pituitary gland to produce endorphins and metenkephalins (the neurotransmitters of the immune system) at three times the normal rate for about 20 hours after a small dose is given. It is essentially correcting an endorphin deficiency. It is a safe drug with no known side effects and is inexpensive (see book and website lists for further information). This drug brought the most significant change. It eliminated the sleep disorder, completely normalized her metabolism for the first time in her life, resulting in weight loss, eliminated the hypochlorhydria which has a deleterious effect on digestion and nutrient absorption, completely normalized IBS symptoms (bowel transit and digestion, chronic alternating diarrhea and constipation, and gas and bloating), and stabilized her emotions for the first time in her life. For the first time, she began feeling emotions and feelings that had been absent during childhood and adolescence. Also, the Prozac and Dexedrine were much more effective after starting LDN, and the Dexedrine has been able to be decreased to a very small dose.

Since moving from California to Arizona, she is now being treated by a DAN! physician in Phoenix, Arizona to finish the work started with the functional medicine physician in California. This new doctor has ordered lab tests to check levels of amino acids, minerals, TNFα (tumor necrosis factor alpha), fatty acids, vitamin D, thyroid, cholesterol, and immunoglobulins. A CBC (complete blood count) panel and a genetic test for the MTHFR (methylene tetrahydrofolate reductase) gene was also done. This doctor is confident that she can eventually transition off of the Dexedrine and Prozac, but is not concerned about the low-dose naltrexone.

There were elevated levels of the heavy metals arsenic, cadmium, and lead but not mercury. Chelation therapy is being recommended if IV glutathione injections do not lower these levels of heavy metals. She has received a course of four IV glutathione injections to help remove these heavy metals. This treatment should improve her suboptimal levels of glutathione caused by her GSH (glutathione stimulating hormone) SNP. Future testing will confirm the degree of improvement of these levels of heavy metals and determine the extent of needed chelation therapy.

The amino acid profile showed deficient levels of most of the proteins measured. This confirmed what is called a protein enteropathy, or diminished ability to metabolize and absorb proteins, as well as the conditions of intestinal permeability and a secondary immune disorder. The vitamin D test was normal and continued use of a daily vitamin D3 supplement to maintain this level was recommended by the doctor.

The MTHFR and TNFα tests were both normal as well as thyroid levels. The fatty acid profile was excellent, and the cholesterol levels good and under control despite having a positive test for the ApoE-4 SNP and the diag-nosis of hypercholesterolemia. This was achieved by using a red yeast rice supplement to bring down choles-terol levels with natural statins that are present in this supplement. Because she had to follow an anti-yeast diet for a period of time, the red yeast rice was stopped, and the cholesterol levels increased slightly despite having an excellent diet that is devoid of cholesterol-forming fats and an excellent fatty acid profile in January. The doctor will be monitoring her cholesterol levels to decide if the red yeast rice should be started again.

5-methylenetetrahydrofolate (also called methylfolate), phosphatidylserine, and taurine have been started to address certain nutrient deficiencies observed from functional lab test results. Some issues the methylfolate is addressing are serotonin and dopamine production, glutathione synthesis, purine synthesis, and dopamine receptor function. The phosphatidyl-serine is an amino acid that can help with cognitive function, and the taurine is an amino acid that is key to thyroid and neurotransmitter function. She is currently taking these supplements to improve level and function in these areas. Tests in the near future will determine if there is improvement, and that will be combined with symptom improvement to discern if further treatments are necessary. These supplements so far have only had a subtle continued improvement in clarity and energy.

The doctor has diagnosed a strain of yeast different from the previous year that has been causing a skin rash on her left foot, mild memory impairment and mental fog. This was treated with super high-dose probiotics, Diflucan, colon hydrotherapy, and an anti-yeast diet. Despite faithful adherence to an anti-yeast diet and the other treatments, this rash would not heal and it would require the treatment of her primary immune disorder before this infection could heal.

The immunoglobulin tests showed very low levels of IgA, IgM, and IgG subclasses 3 and 4. The IgE levels were undetectable, while the other two IgG subclasses 1 and 2 were at the very low end of the normal range. On the basis of the results from these lab tests the DAN! physician referred her to an immunologist to get an official diagnosis for the hypogammaglob-ulinemia (low immunoglobulin levels). Immunoglobulins are also known as antibodies. The immunologist confirmed the diagnosis of a primary immune disorder called common variable immunoglobulin deficiency (CVID) that is treated with intravenous immunoglobulin (IVIG) infusions. The immunologist stated that it can be a genetic disorder or an acquired disorder, but says it is likely to be genetic in her case, based on her history. Instead of monthly IVIG infusions with Privigen (human immunoglob-ulin), she is doing an alternate treatment on a weekly basis that can be done at home using Hizentra (human immunoglobulin) in a subcutaneous infusion (technically called SCIG), which is slightly different than an intravenous infusion.

Both doctors stated that the SCIG treatments should improve protein absorption and distribution, decrease inflammation, strengthen immune responses, and improve intestinal permeability. As levels of immunoglobulins (which are proteins made up of amino acids) improve with the treatments, her low protein resources can be redistributed to other metabolic processes needing these proteins to function optimally. Recent tests have shown the Hizentra to have raised all four subclass levels of IgG. Subclasses 3 and 4 are barely in the normal range now, but the immunologist may adjust the dosage of the Hizentra in the future. The Hizentra treatments mainly provide human IgG antibodies, and only provides very little, if any, IgA, IgM, or IgE. From the most recent lab work her levels of IgA and IgM have only increased very slightly and remain very low, and the IgE is still undetectable.
The Hizentra has finally allowed the skin yeast infection on her left foot to slowly heal and this is no longer an issue. It has also significantly improved her life-long post nasal drip. These sinus issues are not likely to be allergic reactions because her IgE levels are undetectable and therefore her immune system cannot mount an IgE-mediated allergic response. Though one can still mount an allergic response that is mast-cell mediated, it is possible that the histamine response causing the life-long post nasal drip is from underlying viral infections (which trigger histamine responses) that her immune system could not fight off. She has also noticed that her intense craving for dietary protein is gone since starting the Hizentra treatments, as well as stabilization in energy and fuel (food) supply–-she no longer experiences a sudden onset of hunger or low energy throughout the day.

A low uric acid level has indicated a suboptimal purine metabolism that is being treated with the supplements triacetyluridine and NADH(nicotinamide-adenine-dinucleotide-hydride). If uric acid is low, this is an indication that uridine levels are low, which is a further indication of a suboptimal purine synthesis. There are numerous genetic disorders involving purine production, some of which impact ASD. Improving uric acid levels in ASD patients (in general) has stopped self-injurious behavior, improved language and communication, and noticeably improved mental clarity and cognitive function, among other things. These two supplements have brought her improvements in energy, dreams, sleep, Theory of Mind issues, as well as multitasking abilities. Uric acid levels will be checked again at a future appointment.

Like the LDN treatment, the triacetyluridine and NADH have also given this patient further improvements in emotional development and stability, as well as physical and mental energy that are characteristic of optimal health. Though there is still some room for improvement in mitochondrial function, memory, expressive skills, and Theory of Mind issues, she is feeling emotional, physical, and mental improvements for the first time in her life that are consistent with the quality of life she knew was possible, but had eluded her until now.

To her credit, over a period of many months, she has been vigilant and faithful to the recommendations of her DAN! doctor and has realized significant improvement as a result. She is able to concentrate for long periods of time for the first time in years. Her mental clarity has improved markedly and she. She is calm and happy more often and no longer considers herself to be “evil”. She has enjoyed moments of joy that she hopes will expand and grow with time as she continues to heal. Her improvements are growing with each passing day. She now has aspirations of returning to school and work and eventually, finding a husband with whom to share her life.

Bibliography

• Baker, Sidney M; Pangborn, Jon. Autism: Effective Biomedical Treatments. 2007, Autism Research Institute, San Diego.
• Bock, Kenneth. Healing The New Childhood Epidemics: Autism, Asthma, ADHD, Allergies. 2008, Ballantine Books, New York.
• Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report (MMWR); March, 2012. Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2008.
• James, S. Jill. Impaired Transsulfuration and Oxidative Stress in Autistic Children: Improvement With Targeted Nutritional Intervention. Fall 2003 Defeat Autism Now! Conference.
• Jepson, Bryan.Changing the Course of Autism. 2007, Sentient Publications, Boulder, CO.
• Jones, David S.; Hofmann, Laurie; Quinn, Sheila. Textbook of Functional Medicine. 2010, Institute for Functional Medicine (IFM), Gig Harbor, WA
• Jones, David S.; Hofmann, Laurie; Quinn, Sheila. 21st Century Medicine: A New Model for Medical Education and Practice. 2009, Institute for Functional Medicine.
• McCandless, Jaquelyn. Children with Starving Brains. 2009, Bramble Books.

Internet Videos about ASD & Biomedical Treatments

• 2008 Autism One Conference Powerpoint presentation by Kenneth Bock, MD. Highly recommended.
• 2009 Autism One Conference Powerpoint presentation by Kenneth Bock, MD. Somewhat different from 2008 presentation. Highly recommended.
• 2009 Autism Canada Foundation Conference presentation video by Bryan Jepson, MD. (57 minutes)
• 2011 Autism Canada Foundation video lecture by Jon Pangborn, PhD, “Coupled Dysbiosis and Metabolic Dysfunctions” (55 minutes)
• 2012 ARI video lecture by Sidney Baker, MD. Effective Biomedical Treatments for ASDs. (83 minutes)
• ARI conference video of Bernard Rimland, PhD. “Recovered Austistic Kids, Part 1” (10 minutes)
• 2011 Vaccine Safety Conference video lecture by Richard Deth, PhD. “Oxidation and Methylation in the Human Brain: From Autism to Alzheimer’s” (51 minutes)
• 2008 LDN conference lecture by J. McCandless, MD on low-dose naltrexone. (39 minutes)
• 2008 LDN post-conference interview with J. McCandless, MD about low-dose-naltrexone. (8 minutes)
• 2012 Interview with Jaquelyn McCandless, MD about low-dose naltrexone. (58 minutes)
• Past DAN! conference webcasts that show videos and audio files of lectures at the conference. Highly recommended.

Websites about ASD & Biomedical Treatments

• http://legacy.autism.com/dan/scientificfoundations.htm A compilation of research studies supporting the DAN! protocol of biomedical treatments for ASDs.
• http://www.autismone.org/articles?page=9 Numerous articles about autism and biomedical treatments.
• http://www.immunoscienceslab.com/Articles/A%20Gut%20Feeling%20US.pdf Article by Aristo Vojdani and Jama Lambert: A Gut Feeling for Immune Dysregulation & Neuroinflammation in Autism.
• http://legacy.autism.com/treatable/index.htm Learn about various biomedical treatments at the ARI website.
• http://www.autism.com Defeat Autism Now! (DAN!) and the Autism Research Institute (ARI). DAN! offers a doctor referral service, video presentations, audio files, webinars, and an extensive website. ARI is the sponsoring group of DAN! The ARI conducts research and disseminates information. An extraordinary compilation, highly recommended site.
• http://www.autism.org Center for the Study of Autism. Associated with ARI. Provides an excellent understanding of the biomedical approach to ASD.
• http://www.defeatautismnow.net; Education and resources.
• http://autism-nutrition.com/defeat-autism-now; Nutritional & biomedical support for ASD patients.
• http://www.starvingbrains.com; Jaquelyn McCandless, MD (DAN! doctor)
• http://www.center4autism.org; Cindy Schneider, MD (DAN! doctor)
• http://healingautismdvd.com; Kenneth Bock, MD (DAN! doctor)
• http://toomanytoosoon.org/bock.html; Kenneth Bock, MD
• http://www.rhinebeckhealth.com/rhc; Kenneth Bock, MD
• http://www.healing-autism.com; Kenneth Bock, MD
• http://www.johnson-center.org/blog; Bryan Jepson, MD (DAN! doctor) Information and resources for ASDs.
• http://www.autismone.org; Parent-driven, conferences, outreach, education.
• http://drneubrander.com/blog; Website of James Neubrander, MD (DAN! doctor). Several Powerpoint presentations on various topics like methylation, autoimmunity, diet/nutrition, mitochondrial disorders.
• http://www.safeminds.org; Founded by parents of autistic children. Focuses on heavy metal links to autism. Well-researched, good credibility.

Internet Videos about Functional & Integrative Medicine

• Clips from an episode of the Dr. Oz Show with a panel of 4 functional medicine doctors that Dr. Oz sends his family and patients to.
• 20 minute video summary of functional medicine given by Mark Hyman, MD at 2010 TEDMED conference.
• 18-minute video summary by Dr. Mark Hyman at TEDMED 2012 about modern chronic diseases and functional medicine approach.
• Brief question/answer video as a follow-up to Dr. Mark Hyman’s above TEDMED 18-minute talk.
• IFM 2012 Annual International Conference Opening Video & additional videos.

Websites about Functional & Integrative Medicine

• http://www.functionalmedicine.org; Institute for Functional Medicine: practitioner & patient resources, CMEs.
• http://www.acamnet.org; American College for Advancement in Medicine
• http://www.drhyman.com; Mark Hyman, MD (Functional Medicine physician)
• http://www.nutritionworkshop.com/register.php; Discover how your medications and vitamins interact.
• https://www.functionalmedicine.org/home/Affordable_Care_Act; Article about the Affordable Care Act and Functional and Integrative Medicine.
• https://www.functionalmedicine.org/home/Dietary_Supplement_Controversy; Article about the Dietary Supplement Controversy.

Books on ASD and Biomedical Treatments and Functional Medicine:

• Autism: Effective Biomedical Treatments
  Sidney M. Baker, MD and Jon Pangborn, PhD. A highly detailed account of biomedical therapies for autistic spectrum disorders. Highly recommended.
• Children With Starving Brains
  Jaquelyn McCandless, MD. An early classic, documenting the need for biomedical intervention. A must- read for proactive parents. Highly recommended.
• Changing the Course of Autism
  Bryan Jepson, MD. An excellent summary of biomedical treatments for ASD in clinical practice. Also provides a good description of the underlying science and biochemistry. Highly recommended.
• Healing The New Childhood Epidemics: Autism, Asthma, ADHD, Allergies
  Kenneth Bock, MD. Another excellent summary of biomedical treatments for ASD in clinical practice. Highly recommended.
• Recovering Autistic Children
  Stephen M. Edelson and Bernard Rimland, editors. , A compilation of case examples of recovery, and articles covering biomedical treatments by numerous contributing authors. Highly recommended.
• Biomedical Treatments for Autism & PDD
  William Shaw, PhD. A scientific description of various biochemical issues affecting children with ASD and how to treat them. Well written. Highly recommended.
• Cutting-Edge Therapies for Autism
  Ken Siri and Tony Lyons. Numerous therapies currently being used to treat ASDs.
• Could It Be Autism?
  Nancy D. Wiseman. A mother’s moving, inspiring, and helpful story of successful early intervention. Highly recommended.
• The DAN! Conference Proceedings
  These are written accounts of the presentations by doctors and others at DAN! conferences. They are published twice a year. To receive them, contact DAN!. These highly detailed accounts offer the best overview of current research and clinical findings. Strongly recommended.
• Unraveling the Mystery of Autism and Pervasive Developmental Disorder
  Karyn Seroussi. One of the first and best books on autism. Well-informed and very readable. Strongly recommended.
• Dietary Interventions in Autism Spectrum Disorders
  Kenneth J. Aitken. Comprehensive information about the various restricted diets that can help those with ASDs.
• The Natural Medicine Guide to Autism
  Stephanie Marohn. A thorough source for ASD therapies that do not involve pharmaceutical drugs.
• Evidence of Harm David Kirby. The most well-documented account of vaccination risks. Excellent science and objective presentation. An important book. It is not anti-vaccine, but pro-research and pro-choice.
• The Promise of Low-Dose Naltrexone Therapy
  Elaine Moore and Samantha Wilkinson. Most thorough documentation of LDN research and potential and descriptive science underlying its effectiveness. Highly recommended.
• Vaccine Epidemic: How Corporate Greed, Biased Science, and Coercive Government Threaten Our Human Rights, Or Health, and Our Children
  Louise Kuo Habakus, MA, Mary Holland, JD. Focuses on the debate surrounding individual and parental vaccination choice in America, and the ethics and constitutionality of vaccination mandates. It is not anti-vaccine, but pro-research and pro-choice. Excellent comprehensive overview.
• Honest Medicine
  Julia Schopick. Documentation of four separate but effective and safe treatments not utilized by the medical establishment that could save lives. An amazing accounting of dismissed effective treatments.
• Detoxification & Healing
  Sydney MacDonald Baker, MD. Detoxifying the body from a functional approach.
• Enzymes for Autism and Other Neurological Conditions
  Karen DeFelice. A good account of dietary enzyme supplement use as a therapy for ASDs.
• Building Wellness with DMG
  Roger Kendall, PhD. Description of the nutritional benefits of DMG (dimethylglycine) supplementation.
• Genetic Nutritioneering
  Jeffery Bland, PhD and Sara Benum, MA. How our diet impacts our genetic expression.
• The Road to Immunity
  Kenneth Bock, MD. How to strengthen the immune system from a functional approach.
• Up The Creek With A Paddle: Beat MS and All Autoimmune Disorders with Low-Dose Naltrexone
  Mary Boyle Bradley. One woman’s experience with LDN therapy.
• Could It Be B12? (2nd Edition)
  Sally M. Pacholok, RN, BSN and Jeffery J. Stuart, DO. A thorough accounting of the epidemic of misdiagnoses in mainstream medicine that are actually genetic or acquired vitamin B12 deficiencies.

Books Specifically about Functional & Integrative Medicine:

• 21st Century Medicine: A New Model for Medical Education and Practice
  David S. Jones, MD; Laurie Hofmann MPH; Sheila Quinn (IFM). Download this pdf document free: http://www.functionalmedicine.org/listing.aspx?cid=34. Highly recommended.
• Textbook of Functional Medicine
  Institute for Functional Medicine, 2010 Edition.
• Clinical Nutrition: A Functional Approach
  Institute for Functional Medicine. Monograph textbook detailing the biochemistry of nutrition.
• The Ultramind Solution
  Mark Hyman, MD. An easy-to-read account about FM and its application. Highly recommended.
• Digestive Wellness
  Elizabeth Lipski, PhD, CCN, CHN. An excellent source for diet, nutrition, and associated disorders from a functional approach.
• Ultra Prevention
  Mark Hyman, MD. Dietary and nutritional recommendations from a functional approach.
• Case Studies in Integrative and Functional Medicine
  Kara N. Fitzgerald, ND and J. Alexander Bralley, PhD. Highly referenced FM cases from eleven disease categories backed by science-based medicine.
• Complementary and Alternative Medicine Treatments in Pschiatry
  Dan Stradford, Garry Vickar, Christine Berger, Hyla Cass. Download this document free:
  http://www.operationflyingpublisher.com/pdf/FPG_008_ComplementaryandAlternativeMedicineTreatmentsinPsychiatry_2012.pdf

Glossary

Acetylation: A reaction, usually with acetic acid, that introduces an acetyl radical into an organic molecule. Also a phase II detoxification pathway occurring in the liver in which acetyl-CoA combines with metabolic compounds. One of the synthetic biotransformations which operate in the metabolism of drugs in which metabolites are produced that are more readily excreted than the parent drug.

Biochemical Individuality*: the idea that each individual has a unique physiological and biochemical composition, based upon the interactions of his or her individual genetic make-up with the environment—i.e. the continuous exposure to “inputs” (diet, experiences, beliefs, activity, toxins, medications, etc.) that influences our genes. It is this combination of factors that accounts for the endless variety of phenotypic responses seen every day by clinicians. The unique makeup of each individual requires personalized levels of nutrition and a lifestyle adapted to that individual’s needs in order to achieve optimal health. The consequences of not meeting the specific needs of the individual are expressed, over time, as degenerative disease.

Biomarker*: a substance used as an indicator of a biological state. Such characteristics are objectively measured and evaluated as indicators of normal biological processes, pathological processes, or pharmacologic responses to a therapeutic intervention. Examples of cancer biomarkers include prostate specific antigen (PSA) and carcino-embryonic antigen (CEA).

Biotransformation*: the modification(s) of a chemical compound made by an organism. Such compounds include, but are not limited to, nutrients, amino acids, toxins, heavy metals, or drugs in the body. Biotransformation also renders nonpolar compounds polar, so that they are excreted and not reabsorbed in renal (kidney) tubes.

Catalyze: a biochemical reaction in which an enzyme transforms one compound to another, and that enzyme is not consumed or altered in the process.

Conjugation: the process of combining two or more chemical compounds to produce another compound.

Cytochrome P-450 enzyme system: a collection of enzymes that use oxygen to modify toxic compounds, drugs, or steroid hormones. Many lipophilic (fat soluble) drugs must undergo biotransformation to more hydrophilic (water soluble) compounds to be excreted from the body. Drug biotransformation reactions consist of Phase I (e.g., oxidation, reduction) or Phase 2 (e.g., conjugation) reactions that occur primarily in the liver. The most common Phase I reaction is oxidation, which involves the insertion of an oxygen atom into the compound to form a polar hydroxyl group.

Functional Medicine*: a systems-based, science-driven approach to individualized medicine that focuses on uncovering the underlying metabolic causes of disease & dysfunction instead of suppression of symptoms.

Functional Medicine Matrix*: the graphic representation of the functional medicine approach, displaying the seven fundamental clinical imbalances, the patient’s known antecedents, triggers, and mediators, and the salutogenic factors that promote health. Practitioners can use the matrix to help organize their thoughts and observations about the patient’s health and decide how to focus therapeutic and preventive strategies.

Genomics*: the study of the whole genome of organisms, including interactions between loci and alleles within the genome. Research on single genes does not fall into the definition of genomics unless the aim of this functional information analysis is to elucidate the gene’s effect on the entire genome network. Genomics may also be defined as the study of all the genes of a cell, or tissue, at the DNA (genotype), mRNA (transcriptome), or protein (proteome) levels.

Inducible gene: a gene whose expression is either responsive to environmental change or dependent on the position of the cell cycle. An inducible gene is a gene that is expressed in the presence of a substance (an inducer) in the environment. This substance can control the expression of one or more genes (structural genes) involved in the metabolism of that substance.

Intestinal dysbiosis: a state of imbalance of the intestinal flora (bacteria and other micro-organisms), which may lead to the excessive harmful effects of bacterial fermentation in the gut and “autointoxication” from endotoxins (toxins produced by undesirable bacteria within the body). It can be described as being due to either putrefaction, fermentation, deficiency, or sensitization of, and to, food.

Kryptopyrrole or Pyroluria: Its cause is an inborn error in pyrrole chemistry, resulting in a dramatic zinc and vitamin B6 deficiency. Elevated levels of kryptopyrrole produce symptoms including irritability, anger episodes, poor memory, impaired intellectual function, impaired immune function and inability to deal with stress. Patients are easily identified by their inability to tan, poor dream recall, abnormal fat distribution, and sensitivity to light and sound. Treatment is centered on zinc and B6 supplements together with omega-6 essential fatty acids.

Long latency disease*: disease that becomes manifest at a time remote from the initial exposure to disease triggers, or diseases requiring continued exposure to triggers and mediators over an extended period of time to manifest frank pathology. Examples include heart disease, cancer, type 2 diabetes, and osteoporosis.

Methylation: In chemistry, the addition of a methyl group to a molecule. On a protein level, the addition of a methyl group or groups to the amino acid arginine or lysine in a protein. On a DNA level, the addition of a methyl group to a cytosine residue to convert it to 5-methylcytosine. Methylation of DNA occurs at CpG sites, where cytosine (C) lies next to guanine (G). The CpG sites are in regions near the promoters of genes. These regions are known as CpG islands. The state of methylation of CpG islands is critical to both gene activity and gene expression.

Mutation: any change in DNA over the most common sequence, called the wild type. A mutation can come in many forms: a whole section of DNA may be deleted; a large section may be inserted where it doesn’t belong; a small deletion or insertion can also occur. Most of these, if they are large changes, lead to observable differences in structure or function, or even death in utero, and they occur in less than 1% of the population.

Nutraceutical: a food or food product that reportedly provides health and medical benefits, including the prevention and treatment of disease. Health Canada defines the term as “a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease.” Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered foods and herbal products.

Nutrigenomics (or nutritional genomics)*: the study of how different foods may interact with specific genes to increase the risk of common chronic diseases such as type 2 diabetes, obesity, heart disease, stroke, and certain cancers. It can also be described as the study of the influence of genetic variation on nutrition by correlating gene expression or SNPs with a nutrient’s absorption, metabolism, elimination or biological effects. Nutrigenomics also seeks to provide a molecular understanding of how common chemicals in the diet affect health by altering the expression of genes and the structure of an individual’s genome. The ultimate aim of nutrigenomics is to develop rational means to optimize nutrition, with respect to the subject’s genotype.

Oxidation-reduction (redox)*: paired chemical reactions that occur in balance with each other within the body of a healthy individual. These reactions involve the transfer of electrons (or the distribution of electron sharing) and thus require both a donor and acceptor. When this physiological parameter is out of balance, a net accumulation of donors or acceptors can lead to deleterious cellular oxidation phenomena (lipid peroxidation, free radical formation).

Phosphorylation: The addition of phosphate to an organic compound through the action of a phosphorylase or kinase enzyme. The process of attaching a phosphate group to an organic molecule such as a protein, sugar, or other compound. Reversible phosphorylation of proteins is an important regulatory mechanism that occurs in both prokaryotic (bacteria and archaea) and eukaryotic (fungi, animals and plants) organisms. Kinase enzymes phosphorylate proteins and phosphorylase enzymes dephosphorylate proteins. Many enzymes and receptors are switched “on” or “off” by phosphorylation and dephosphorylation. Reversible phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated.

Polymorphism: A difference in DNA sequence from the most common sequence that occurs at a consistent frequency and is maintained in the population. To be considered a polymorphism, a DNA sequence must be present in at least 1% of the population. Many polymorphisms result in proteins that are still active, but the activity is either slower or faster than the most common sequence.

Purine metabolism: Purines are heterocyclic compounds that is the nucleus of the purine bases (or purines) such as adenine and guanine, which occur in DNA and RNA, and xanthine and hypoxanthine. All living cells contain purines as purine nucleotides. They can be synthesized using amino acids, or by salvage of dietary or endogenous nucleotides derived from cell wastage. Purines are produced as end products in the digestion of certain proteins in the diet, but some are synthesized in the body. Purines are guanine and adenine, the “A” and “G” of our genetic DNA structure (A, C, G, T). Purines play many important roles in the body’s metabolism, including:

• As the information molecules in genes, they are used in the process of converting genes to proteins.
• As energy transducers, they convert the energy produced by the oxidation of food molecules to a form which the cell can use to satisfy its energy needs.
• In cellular signaling processes, such as nerve conduction and muscle contraction, they act as messengers.
• As a disposal mechanism, they rid cells of excess nitrogen.
• As antioxidants, they protect the cell from cancer-causing agents.
• When a defective gene causes gaps to appear in the metabolic recycling process for purines and pyrimidines, these chemicals are not metabolised properly, and adults or children can suffer from any one of twenty-eight hereditary disorders, possibly some more as yet unknown. Symptoms can include gout, anaemia, epilepsy, delayed development, deafness, compulsive self-biting, kidney failure or stones, or loss of immunity.

Single Nucleotide Polymorphism (SNP; pronounced “snip”)*: a DNA sequence variation occurring when a single nucleotide—A, T, C, or G—in the genome differs between members of a species or between paired chromosomes in an individual. Compared to single-gene mutations, SNPs are very small changes in DNA that are generally at one base site which alter the function of an enzyme, making it more active or less able to function, but not obliterating its function completely. Variations in the DNA sequences of humans can affect how humans develop diseases and respond to pathogens, chemicals, drugs, vaccines, and other agents. SNPs are also thought to be key factors in applying the concept of personalized medicine.

SPECT Brain Scan: Single photon emission computed tomography (SPECT) is an imaging technique that uses radioactive materials injected through a vein that will pass into the brain generating a high-resolution brain image. It is tomographic imaging of local metabolic and physiological functions in tissues. The image is formed by a computer synthesis of data that is transmitted by single gamma photons emitted by radionuclides administered to the patient. As a research tool SPECT imaging is a sensitive tool to measure blood flow through the brain (cerebral blood flow) in persons who have a psychological disorder such as obsessive-compulsive disorder (higher blood flow) and alcoholism (lower blood flow).

Sulfation: (1) In biochemistry it is the enzyme-catalyzed addition of sulfate to another molecule. The process of a sulfur-containing compound being paired with toxins, residuals of prescription drugs, food additives, bacteria and chemicals from the environment. These compounds are then removed from the body. It often refers to a phase II (detoxification) enzyme reaction. This biotransformation process uses its co-substrate 3′-phospho-adenosine-5′-phosphosulfate (PAPS) to transfer sulfate to a xenobiotic. Most of the time this is effective in rendering the xenobiotic less active from a pharmacological and toxicological standpoint, but sometimes it plays a role in the activation of xenobiotics (e.g. aromatic amines, methyl-substituted polycyclic aromatic hydrocarbons). (2) The replacement of a hydrogen atom of an organic compound with a sulfate (-OSO2OH) functional group, or the replacement of the hydrogen atoms of two molecules to form a sulfate (R-OSO2O-R). (3) The conversion of a compound into a sulfate by the oxidation of sulfur.

Transsulfuration: The transsulfuration pathway is a metabolic pathway involving the interconversion of cysteine and homocysteine, through the intermediate cystathionine. In human beings, the transsulfuration pathway is critical for creating cysteine from the essential amino acid methionine. Methionine is first converted to homocysteine by demethylation, which is then converted to the amino acid cysteine and then finally converted to the antioxidant glutathione via the transsulfuration pathway. While methionine is considered an essential amino acid, cysteine becomes an essential amino acid when the transsulfuration pathway is defective. The production of homocysteine through transsulfuration allows the conversion of this intermediate to methionine through a methylation reaction carried out by methionine synthase.

Xenobiotics*: chemicals which are found in an organism but which are not normally produced by it or expected to be present in it. This may also include substances which are present in much higher concentrations than usual. The term xenobiotics is very often used in the context of pollutants such as dioxins and polychlorinated biphenyls and their effect on the biota, because xenobiotics are understood as substances foreign to an entire biological system, i.e. artificial substances, which did not exist in nature before their synthesis by humans.

* Source: Textbook of Functional Medicine, 2010 Edition

DAN! physicians in Arizona:

• Center for Autism Research and Education
  Cindy Schneider, M.D.
  Center4 Autism
  4045 E. Union Hill Dr. Suite 116
  Phoenix, AZ 85050
  ph: 602-277-2273
  fax: 602-277-2283
• Alternative Medical Care of AZ
  Geoffrey P. Radoff, M.D., M.D.H.
  2525 West Greenway Rd., Ste. 210
  Phoenix, AZ 85023
  ph: 702-755-6475
  fax: 602-993-0207
• Abram Ber, M.D.
  5011 N. Granite Reef Road
  Scottsdale, AZ 85250
  ph: 480-941-2141
  fax: 480-941-4114
• The Valley Clinic
  Alan K. Ketover, M.D., M.D.H.
  10595 N. Tatum Blvd., Ste. E-146
  Paradise Valley, AZ 85253
  ph: 602-381-0800
  fax: 602-381-0054
• Raun Melmed M.D.
  5040 E. Shea #166
  Scottsdale, AZ 85254
  ph: 602-443-0050
  fax: 602-443-4018
• Matthew Baral, N.D.
  8010 E. McDowell Rd. Ste. 111
  Scottsdale, AZ 85257
  ph: 480-970-0000
  fax: 480-970-0003
• Martha M. Grout, M.D., MD(H)
  Crossroads Clinic
  9328 E. Raintree Dr.
  Scottsdale, AZ 85260
  ph: 480-240-2600
  fax: 480-240-2601
• Paul S. Charnetsky, M.D.
  195 La Mar Blvd., Suite B
  Goodyear, AZ 85338
  ph: 623-932-2200
  fax: 623-932-2242
• Maureen Schwehr, N.D.
  1151 S. La Canada, Ste. 103
  Green Valley, AZ 85614
  ph: 520-399-9499
• Cheryl Harter, M.D., MD(H)
  80 Raintree Rd.
  Sedona, AZ 86351
  ph: 928-284-9777

Functional medicine physicians in Tucson and Phoenix:

• Alexander, Thomas, MD
  480-998-3551
  Scottsdale
• Arneson, David, ND
  602-234-1158
  Phoenix
  Specialty: Detoxification
• Aronson, Mary, FNP
  602-697-7444
  Phoenix
  Specialty: Integrative Medicine
• Auvil, Sandra, MD, MPH
  602-265-7029
  Phoenix
  Specialty: Acupuncturist
• Beeley, Jeffrey, MD, DABMA
  520-586-7559
  Benson
• Bessette, Mark, MD
  520-745-6513
  Tucson
• Chan, Kevin, DO
  480-961-2366
  Phoenix
  Specialty: Family practice
• Christensen, Drew, MD
  928-428-3122
  Safford
  Specialty: Family Medicine
• Climaco, Cesar, MD, MD(H)
  623-878-6784
  Phoenix
• Climaco, Sandra, LPN
  623-878-6784
  Phoenix
• Cochran, Jorge, ND
  520-546-3233
  Tucson
  Specialty: Naturopath
• Dedhia, Param, MD
  520-749-9655
  Tucson
• Grout, Martha M, MD
  480-240-2600
  Scottsdale
  Specialty: Chronic Illness, Cancer, Lyme
• Lim, Ruth Tan, MD, MD(H)
  480- 820-4507
  Mesa
  Specialty: Pediatrics
• Loes, Michael, MD
  Sierratucson
  800-842-4487
  Tucson
• Maani, Sahba, MD
  Healing Pathways az
  520 305 2800
  Tuscan
  Specialty: IM/PULM/Ayurveda
• McManigle, Mark, DO
  480-369-1269
  Phoenix
• Meyerowitz, Arnold, MD
  480-940-0088
  Chandler
  Specialty: Family Practice
• Mills, Roland, CIN, HHP
  602-469-0982
  Goodyear
  Specialty: Integrative Nutrition
• Pettersen, Sonja, NMD
  (480) 502-5398
  Scottsdale
• Powell, Lisa, MS RD
  Canyon Ranch
  520-749-9655 ext. 4284
  Tucson
  Specialty: RD, Clinical Nutrition
• Powell, Margaret, DC
  480-990-0664
  Scottsdale
  Specialty: Chiropractic
• Rosdahl, Dana, PhD
  480-634-7833
  Chandler
  Specialty: Family Nurse Practitioner
• Rula, Heidi, MD
  Integrative Care for Women
  480-699-2508
  Mesa
  Specialty: Family Medicine
• Sahni, Jyotsna, MD
  520-749-9655
  Tucson
• Schoeb, Peter, DC
  480-966-2258
  Tempe
  Specialty: Chiropractic
• Sosnowski, Jennifer, MD
  602-663-0641
  Surprise
  Specialty: Family Physician
• Vallejo, Allison, APN
  928-446-4113
  Anthem
  Specialty: Pediatric Nurse Practitioner
• Yost, Hunter, MD
  Hunter Yost MD
  520-219-5060
  Tucson
  Specialty: Lifestyle Medicine

Where to find a DAN! doctor in the U.S.
Legacy Autism
Autism Today Clinician List

Where to find a functional medicine physician in the U.S.
Functional Medicine Practitioner Search