Autism, Mercury, and Vaccines: A Total Health Approach Parris M. Kidd, PhD

An earlier version of this document appeared in Alternative Therapies in Health and Medicine, Volume 9 issue 5, 2003. For a more in-depth, 2 part series on the medical management of autism, click 1 or 2

In 1943 the psychologist Leo Kanner published case histories of a childhood developmental disorder he called autism. He defined three symptom patterns: (1) failure to use language for communication, (2) abnormal development of social reciprocity, and (3) desire for sameness, as seen in repetitive rituals or intense circumscribed interests.1 These were termed Kanner’s triad, and usually manifest by age three. Autism is developmental, but need not involve mental retardation.2

Symptoms of autism can become evident as early as 4 months after birth. In a minority of cases, after developing normally a child regresses into autism. Clinically, neurological abnormalities usually dominate the symptomatology. Brain imaging has revealed zonal brain hypoperfusion and underresponsiveness, localized mainly in the fronto-temporal cortex (reviewed in Kidd3). Abnormalities in other organ systems add to the disorder’s severity, and dictate a fully diversified approach to its medical management.4

Autistic children and their parents face great challenges. Autistics score consistently low on measures of adaptive or life skills.3 As adults, their life outcomes range from complete dependence to (rarely) successful employment. Autistics also have abnormally short lifespan.5 Death most often comes from seizures, nervous system dysfunction, drowning, or suffocation (rates more than 3 times the general population). Epilepsy occurs in at least one-third of autistics,3,6 and deaths due to epilepsy are some 24 times that of background.

Autism has become epidemic in the industrialized societies.3 In the United States, autism was relatively rare until the early 1990s, after which its prevalence increased by at least double, and more likely by 3-5 times. A similar steep increase occurred in the United Kingdom. The gender ratio is around 3-4:1 boys to girls.

From the clinical-biological viewpoint, autism is a complex and multifaceted spectrum of disorders. Kanner's “classic” autism, termed autistic disorder or AD, is now included with the other autistic disorders into the category autistic spectrum disorder or ASD, less commonly termed PDD (for Pervasive Developmental Disorders).3 It is not uncommon for more than one of these disorders to co-occur within the same family.

At least 25-30 percent of autistics have co-morbid conditions, most often epilepsy, sensory impairment (blindness and/or deafness), tuberous sclerosis, and neurofibromatosis, all of which predominate in the most severely mentally retarded. Blaylock has presented a hypothesis whereby endogenous, environmental, or food-derived excitotoxic factors interact with brain hypoperfusion, seizure tendencies, or an overactivated immune system, to produce ASD symptomatology.6

FACTORS PREDISPOSING TO AUTISM: AN OVERVIEW

Autistic spectrum disorder is almost surely multifactorial.3,7 Autism has been variously linked with inborn errors of metabolism; genetic abnormalities such as fragile X syndrome; rubella and other pathogens; thalidomide exposure; and many other factors. There is a striking co-incidence of autism with modern intensified vaccination and the toxic mercury in many vaccines. Genetic predisposition, metabolic abnormalities, and abnormalities of the gastrointestinal, hepatic, and immune systems are almost certainly all involved.3,4,7

A Strong Genetic Predisposition
The evidence for genetics having a prominent role in autism is incontrovertible.3 The degree of genic determinism is strong, probably not sufficient to be classed as an inborn error but more than sufficient to be a predisposing factor.8 Classic twin studies indicate autism’s heritability is high. The chance for co-occurrence among siblings is 50-100 times higher than the general population. This degree of genetic conditioning likely exceeds other known genetically-conditioned diseases such as Alzheimer's, asthma, diabetes, and schizophrenia.3,8

Findings from several genome-wide gene screening studies concur that ASD is multigenically determined, with probably 3 to 20 genes involved.3 Korvatska and collaborators8 suggested the effectiveness of genetic analysis might be improved by dividing the ASD population into more strictly homogeneous phenotypic subgroups and conducting separate analyses on each of these.

A small proportion of autistic individuals (around 10-15 percent) have coexisting genetic conditions, including tuberous sclerosis, neurofibromatosis, X-linked gene mutations such as fragile X syndrome and the MECP2 of Rett's disorder; and other chromosomal abnormalities.3 But without doubt the majority of ASD cases have suffered some non-genetic triggering event(s) that precipitated their symptomatology.

Developmental/Teratologic and Inborn Metabolic Contributions
Several lines of evidence implicate injury in utero as contributing to autism.3,9,10 One example: minor physical anomalies of the ear are found in about 45 percent of autistic children. A chemical model for such teratologic insult is the drug thalidomide10: Exposure of human fetuses during neural tube closure (gestation days 20-24) caused some 30 percent to later develop autism symptoms, along with ear anomalies, hearing loss, facial paralysis, and poor eye abduction.

Congenital enzymatic weaknesses (inborn errors of metabolism) can mimic or contribute to ASD symptomatology. The most prominent among these are phenylketonuria (PKU) variants, histidinemia, adenylosuccinate lyase deficiency, purine synthesis deficiencies, inosine phosphate dehydrogenase weakness, Lesch-Nyhan Disease, adenosine deaminase deficiency, and ADA binding protein weakness. Biochemical analysis11 uncovers their presence, following which specific corrective metabolites can be administered.

Serotonin and Other Transmitter Imbalances
Serotonin is a monoamine brain transmitter, one of the earliest to appear in the developing brain. It also plays a role in regulating brain development.12 Elevated blood serotonin is one of autism's most consistent abnormalities, perhaps with a genic connection (chromosome 6). Up to 40 percent of ASD cases feature abnormally elevated blood serotonin, but some brain areas can have decreased concentrations while others are elevated, likely reflecting uneven development of brain networks.

Dopaminergic imbalances are also frequent in ASD: High homovanillic acid in the CSF (cerebro-spinal fluid) and/or urine is a frequent finding, and indicates possible CNS insufficiency of dopamine.3

Variability in its onset, expression, symptom pervasiveness, and progression rank autism among the most perplexing disorders to manage. Yet within the past decade real progress has been made towards helping autistic people become fulfilled and productive members of society. This progress is largely attributable to nutrition-centered, nontoxic, integrative management.

NUTRITION-CENTERED AUTISM MANAGEMENT

Integrative autism management began with the efforts of Rimland9 and the Autism Research Institute,13 then also by DAN! (Defeat Autism Now!)14. Founded in 1995 by Rimland and other scientists, parents, and physicians, DAN! now has an extensive collection of conference reports, practitioner referral services, assessment tools, and intervention protocols. DAN! continues to drive the development of diagnostic and treatment protocols for autism.

Every ASD child has a unique combination of clinical and laboratory abnormalities, making individualized assessment a key requisite. Most often, detailed assessments begin with the parent. Sidney Baker, MD worked with others in DAN! to generate parent protocols for keeping track of medical records.15 Then the first concrete therapeutic step is taken by the parent: to revise the child’s diet.

Dietary Revision, The First Phase
Among practitioners and parents familiar with autism, there is a strong consensus that modifying the diet sets the stage for the success of other treatments and therefore should come first.16 Food additives can be a particular problem—though many of the worst have been banned, others remain in the food supply. For ASD children unusually sensitive to foods, the Feingold Diet is likely to be highly beneficial.15

Sugary foods are an obvious target for dietary revision.15,16 Sucrose and other simple sugars, even artificial sweeteners, have adverse behavioral effects in some ASD children. Urine testing frequently evidences abnormal carbohydrate metabolism, and invariably a sugar-avoidance diet helps the autistic child. Parents can test this diet by slowly removing these substances over three weeks (to avoid withdrawal symptoms), then reintroducing sugar for up to five days and observing the results. Simple sugars in the intestine also support microorganisms (especially Candida fungus) that can produce toxins harmful to the lining, and potentially also to other organs.15

Foods containing casein (dairy products) or glutens (wheat) contribute significantly to ASD.15,16 In various controlled studies, as many as 80 percent of ASD subjects improved following strict dietary exclusion of these proteins (the CFGF, casein- and gluten- free diet).16 Behavior improves, seizure activity is decreased. Gross motor coordination, social contact, eye contact, ritualistic behavior, language all may improve; sleep patterns often normalize. This one dietary upgrade can effect striking improvement in ASD; further, it is an essential prerequisite for implementing other dietary changes.

Since abrupt simultaneous removal of casein and glutens from the diet can cause withdrawal symptoms, a two-step phased removal is appropriate.16 First should come removal of the cow’s milk and other dairy products, whose metabolic dangers are established.17 The benefits can show within 2-3 days in young children or 10-14 days in adults, even though full clearance of casein from the body takes a much longer time.

Consumption of cow’s milk was linked to increased autism incidence among immigrants to Sweden .18 Symptoms of casein intolerance include projectile vomiting; eczema, particularly behind the knees and in the crook of the elbow; white bumps under the skin; ear discharges and infections; constipation, cramps, and/or diarrhea; and respiratory disorders resembling asthma.

Some higher-functioning ASD children voluntarily cease casein intake, apparently sensing it is not good for them. Gluten products, on the other hand, stir strong cravings and children are less likely to refuse them.16 Gluten exclusion requires complete dietary exclusion of the common cereals wheat, barley, rye, and oats. Nonetheless, many other foods contain hidden glutens. Gluten elimination usually takes a minimum of 3-4 weeks, and 3 months is an appropriate trial period. The urinary gluten profile persists for much longer than does the casein profile, and correspondingly the withdrawal effects are usually milder in severity than casein’s but typically more prolonged.

Gluten withdrawal symptoms can persist after fully five months on an exclusion diet.16 In some cases dramatic improvement have emerged 7-9 months after initiating the diet, but maximal improvement can require up to two years of rigid dietary exclusion. Meanwhile, adding glutein and casein foods back into the diet can result in severe symptom resumption. Dietary casein and glutens very likely generate “excitotoxic” damage in the ASD brain,17 but the CFGF diet often effects clinical improvement even when laboratory tests fail to detect such peptides via the urine.

Sources of Possible Excitotoxic Damage
Reichelt, Shattock and others observed clinical correlates between the symptoms of autism and impaired ability to digest proteins from dairy and wheat foods.3,16,17 Incomplete protein digestion results in the accumulation of peptides (amino acid polymers) in place of the monomeric amino acids. Some of those derived from casein and gluten are dipeptides (two-amino acid molecules) or oligopeptides (a few amino acids), molecules small enough to be absorbed and access the brain. These can have endorphin-like, opioid effects on the brain’s dopaminergic, cholinergic, serotonergic, noradrenergic, and GABAergic transmitter systems, so were dubbed exorphins.20,21

The “opioid excess” theory for autism arose around 1979, probably with Panksepp’s suggestion that incompletely digested peptides with opioid activity could precipitate autism.20 By 1981, Reichelt and colleagues detected such peptides in the urine of 22 of 25 autistics they studied17; later Gillberg found excessive levels in the cerebro-spinal fluid.21 Enhanced absorption of exorphins could contribute to autism by way of numerous potential mechanisms.3,6,17,20-23

In 2002, Wakefield's group reviewed “autistic enterocolitis”, an intestinal motility disorder characterized by inflammation of the lining.22 They concluded exorphins were involved, such as gluteomorphin and gliadomorphin from wheat and beta-casomorphin from milk. Their work provides further indication that these GI symptomatologies, present to some degree in the majority of autistics, can be resolved only through near-total elimination of casein and gluten from the diet. This is impossible to fully achieve through food choices. However, a recent advance in digestive enzyme supplementation and probiotic repletion bring this goal closer to attainment.

Digestive breakdown of the small peptides from casein and wheat mostly relies on just one enzyme, the dipeptidyl-peptidase IV (DPPIV). Congenital weakness in DPPIV function is linked to autism,3 and the enzyme is highly sensitive to mercury and organophosphate xenobiotics. Recently, Brudnak, Rimland, and collaborators designed a sophisticated digestive enzyme supplement aimed at supporting DPPIV activity. Their pilot study with 22 subjects documented wide-ranging symptom improvements of between 50-90%.23 The supplement included galactose, as a food source for the “probiotic” bacteria of the intestinal tract. These symbionts such as lactobacilli and the bifidobacteria, produce DPPIV and are able to fully digest exorphins. This innovation has particular clinical promise since there are normally far more probiotic cells housed in the human intestines (over 1011) than there are cells in the intestinal lining.

Brudnak and collaborators also discussed the potential for repleting probiotics in the intestines, using multiple species on a rotating or “pulsed” basis.23 Altogether, a new four-pronged GI approach is emerging, of combining food restriction with potent enzyme supplementation, probiotic substrate support, and probiotic supplementation. This approach represents the current best effort to restore GI function and epithelial lining integrity, thereby to protect the brain against damage from food-derived molecules.

Subtle Relationships of Foods with Symptoms
Once the main sources of food intolerances – sugars, artificial additives, casein, glutens – have been removed from the diet, other foods may emerge as sources of symptoms. Parents can often associate the child’s consumption of a particular food with deterioration in behavior, sleep patterns, or cognitive performance. These symptoms can occur in the absence of classic allergy symptoms such as stuffiness, eczema, wheezing, and itching. Beef, pork, rice, and potatoes are only occasionally implicated; eggs, tomatoes, eggplant, avocados, red peppers, soy, and corn are more often problematic.15 To confirm a food intolerance, the suspect food should be removed from the diet for at least three weeks and any improvements noted. Subsequently , on being reintroduced into the diet it will likely trigger an exacerbation of symptoms.

Hospital-based laboratories often test for food allergy by measuring IgE antibody levels. But the dominant food allergies seen in autism usually are not the IgE-mediated, immediate hypersensitivity type.15 Rather, they take hours or days to develop and often require cumulative exposure to the offending food. This suggests the allergy is mediated mainly by IgG rather than IgE antibodies. Baker and Pangborn conducted two double-blind, placebo-diet controlled studies using IgG-ELISA (Enzyme-Linked Immunosorbent Assay). Both trials demonstrated significantly better symptom reduction in subjects avoiding IgG-reactive foods versus IgG-nonreactive foods.24,25 Systematic dietary elimination of suspect foods is likely to have more clinical value than painstaking laboratory assessments for food allergy.

Perhaps due to wide-ranging difficulties with foods, children with autism are typically "picky" eaters. Further dietary restrictions due to intolerances are likely to result in inadequate intakes of essential nutrients. For these reasons alone, a nutrient supplementation regimen is always appropriate.

SPECIFIC NUTRIENT SUPPLEMENTS FOR AUTISM MANAGEMENT

Controlled research on the benefits of nutrient supplementation for autism has been scant. However, since 1967, the Autism Research Institute (ARI) has collected and periodically published semi-quantitative ratings of various nutrients.13

The ARI Treatment Effectiveness Survey questionnaire solicits from parents a rating of each nutrient, drug, dietary modification, or other biomedical intervention used on their child. Periodically the ratings are tabulated, and a “Better to Worse” score (B:W ratio) derived. Most recently, cumulative nutrient data from 21,500 parents were summarized in April 2002 (available from ARI13). Orthomolecular nutrients – vitamins, essential minerals, and other substances that naturally participate in the body’s metabolic pathways – consistently receive better ratings than do herbals.

Multiple Vitamin-Mineral Supplements
Individuals with autism typically exhibit poor status of many nutrients. Many have poor digestion; approximately 25 percent have chronic diarrhea; 25 percent have constipation. Still others have others have more subtle inflammatory conditions that limit absorption.22 Often the probiotic (beneficial) bacteria in the intestines are depleted by antibiotic treatment for food-allergy related ear infections, and fewer vitamins are being produced by these populations (vitamin B12, biotin, and vitamin K, in particular). Thus every autistic child is likely to benefit from a multivitamin – mineral supplement, with one caveat: copper is one mineral they often have in relative excess.26

In 2000, Vogelaar reported on the nutrient status of 20 autistic children.27 More than half had abnormally low vitamins A, B1, B3, and B5, and biotin; essential minerals selenium, zinc, and magnesium; essential amino acids; and essential fatty acids. In a double-blind, placebo-controlled trial a multivitamin-mineral complex was given to 16 autistic children for three months.28 Blood levels of vitamins B6 and C were significantly increased, and sleep and bowel patterns (parents' scores) were significantly improved.

Vitamin B6 and Magnesium4,29-31
This nutrient combination is the archetype for nutritional ASD management: many cases of remarkable improvement have been documented.29-32 Vitamin B6 is an essential cofactor for a majority of neurotransmitter systems, including serotonin, gamma-amino-butyric acid (GABA), dopamine, epinephrine, and norepinephrine. Rimland, a pioneer in this area, notes that in 1968 Bonisch reported vitamin B6 (100-600 mg per day) improved behavior in 12 of 16 autistic children; and supposedly three of Bonisch's subjects spoke for the first time while participating in this open trial.30

Magnesium is an essential macromineral for literally hundreds of enzyme-catalyzed metabolic reactions. When combined with vitamin B6 it further increases the B6 clinical benefit.29-31
In the 1970s, after conducting an exploratory, non-controlled study Rimland did a small double-blind, crossover trial on 15 children with autistic symptoms.30 Each child received either a placebo, or vitamin B6 at 2.5-25.1 mg/kg body weight/day (75-800 mg per day) and magnesium at “several hundred” mg per day . Statistically significant benefits included better eye contact, less self-stimulatory behavior, more interest in surroundings, fewer tantrums, and better speech.

In the early 1980s, LeLord and colleagues did further research and concluded that the combination vitamin B6 and magnesium was a breakthrough for autism.31 Urinary homovanillic acid (HVA) levels fell, indicating dopamine metabolism was improved; and average evoked potentials, a measure of sensory processing ability, also were improved.

Rimland recently reviewed 18 studies on high-dose vitamin B6 for autism.29 Eleven were double-blind, placebo-controlled trials. The one small study with negative outcome was earlier condemned for its “obvious bias,” since its design included a crossover yet no washout period was allowed.
Taken together, the studies establish that vitamin B6 benefits as many as half of children and adults with autism, also that combining B6 with magnesium further improves its efficacy and safety. None of these studies reported any significant adverse effects, even with vitamin B6 doses as high as 1,000 mg per day. Vitamin B6 intakes went as high as 30 mg/kg/day (equivalent to 2,100 mg for a 70 kg adult); administered with 10 mg/kg/day of magnesium lactate to 11 autistic children for eight weeks, with no evident adverse effects.4,29 The latest ARI parent ratings in 2002 reported a B:W ratio for vitamin B6 used alone of 4.1:1, for magnesium alone 5.2:1, and for the combination of vitamin B6 plus magnesium, 11:1.13

Cases of hereditary impairment of pyridoxine metabolism have been described, sometimes manifesting as seizure disorder and autism symptomatology.6 Enzymatic activation of vitamin B6 (pyridoxine) to the fully active pyridoxal –5 –phosphate (P5P) can be hereditarily impaired, and P5P supplementation may work for these cases although hyperactivity is a possible adverse effect. Nonetheless, the cumulative data are consistent with vitamin B6 and magnesium having impressive efficacy for autism, superior over either nutrient alone.3,29-32

Dimethylglycine (DMG)
DMG is a nutrient orthomolecule involved in methylation reactions, widely required in metabolism. Having two methyl groups, it is an important methyl donor to support cell growth and renewal. It also has antioxidant character. Early feedback from parents promoted interest in DMG for autism; to date three small studies are available.4

Rimland29 reported that Kun administered DMG to autistic children aged 3-7 years, for three months; 31 of 39 benefited (80 percent). Kern and collaborators did a four-week, double-blind, placebo-controlled trial on 37 children aged 3-11 years.33 The DMG and placebo groups both improved but were not significantly different. The trial period may have been too short. Similarly, Bolman and Richmond34 conducted a small, double-blind, short-term trial with low-dose DMG (125-375 mg/day) and found no significant results. The ARI parent B:W ratio for DMG is currently 5.9:1, from 4,547 questionnaires.13

The nutrient TMG (trimethylglycine; betaine) has a third methyl group and could be a better methylator than DMG. To date its parent B:W ratio is less favorable, at 3.1:1 (182 questionnaires). Both DMG and TMG are best taken earlier in the day, to avoid the rare possibility of interference with sleep.

Rimland recommends children be started on DMG at a low intake (60 mg per day with breakfast), then titrated up to 500 mg per day.29 He asserts that speech is most consistently benefited but behavior also can improve. DMG helps ameliorate seizures, an important consideration for the estimated one-third of ASD subjects who have epileptic involvement; Blaylock suggests this proportion could be higher.6 Occasionally an ASD child will experience transient hyperactivity with DMG; administering it together with folic acid and vitamin B12 lessens this likelihood.35

Folic Acid
Folic acid is essential to numerous metabolic pathways. Frequently it is deficient when B6 and vitamin B12 are deficient. Its current B:W ratio is 11:1, from 1,100 questionnaires.13 Folic acid consistently benefits autism associated with fragile X syndrome. LeJeune pioneered this treatment and, according to Rimland,30 obtained favorable results on non-fragile X autistic children using relatively large doses (0.5-0.7 mg/kg/day).

Calcium
Calcium and magnesium deficiency is common in autistic children, around 22 percent in one study.35 ARI parents gave calcium a B:W ratio of 14:1 (988 questionnaires).13

Vitamin B3 (Niacin/Niacinamide)
As with vitamin B6 and folic acid, this vitamin supports numerous pathways that sustain and renew the body's tissues. The current B:W ratio is 9:1.13

Vitamin C
Vitamin C has an aptly-deserved reputation for its involvement in a plethora of metabolic pathways, and is a cofactor for neurotransmitter synthesis. In a double-blind trial over 30 weeks, multigram intakes (8 g/70 kg body weight/day) improved total symptom severity and sensory motor scores.36 Its current parent B:W ratio is an excellent 16:1, from 1,306 questionnaires.13

Zinc
Participating in numerous metabolic pathways, this essential mineral is crucial to organ development and maintenance. Serotonin synthesis relies on zinc-activated enzymes, and zinc is also central to antioxidant enzyme function. Breeding experiments with rodents indicate maternal zinc deficiency can negatively influence immunity and brain development.38 Zinc currently has a very favorable B:W ratio, 17:1 from 835 questionnaires.13

Zinc operates in a “yin-yang” relationship with copper, i.e., often when zinc levels go down copper levels go up. Walsh reported abnormally elevated blood copper:zinc ratios in 85 percent of 318 ASD children39; a smaller sample of 22 subjects had 100-percent incidence of abnormally high, unbuffered blood copper (unbound to ceruloplasmin proteins) – about four times normal. Walsh's findings corroborate the recommendation that supplements for autistics should exclude copper. Zinc is a key nutrient in Walsh’s protocol to support metallothioneins, circulating proteins which buffer heavy metals.

Essential Fatty Acids (EFAs)
Essential fatty acids are pro-homeostatic constituents of cell membranes, helping to relay signal information from outside the cell to its interior. EFA also are precursors for cell-to-cell messenger molecules (eicosanoids, “prostaglandins”). The longer-chain, 20- and 22-carbon species are crucial for brain development and maintenance.40

Some adults can generate longer-chain EFA from the shorter-chain fatty acids, with poor efficiency, but infants have practically zero conversion capacity. Significantly, the C22:6 omega-3 (docosahexaenoic acid, DHA) and the C20:4 omega-6 (arachidonic acid, AA) occur in ample quantities in breast milk and at a fixed ratio (around 4:1 omega-6 to omega-3). This strongly suggests dietary essentiality for long-chain EFAs in postnatal development.40,41

Essential fatty acids, particularly the omega-3s, are deficient in ADHD, dyslexia, and dyspraxia. These neurodevelopmental conditions have a striking degree of overlap with the autistic spectrum.41 Abnormalities of fatty acid and phospholipid metabolism could help account for many features common to these conditions.

Studies on EFA deficiency in autism are few, but with consistent positive outcomes. Vancassel and collaborators reported DHA 23-percent reduced, total omega-3s 20-percent reduced, and omega-6s unchanged in plasma phospholipids.42 Hardy and Hardy studied 50 children with the more inclusive diagnosis Pervasive Developmental Disorder (PDD), and reported almost 90 percent omega-3 deficient via red cell analysis.43

Prospective trials to assess EFAs for their role in autism are sadly lacking. Still, physicians report autistic patients benefit from omega-3 supplementation. According to the ARI, “fatty acid supplements” (exact composition unspecified) currently have a parent B:W ratio of 12:1.13 The long-chain omega-3 fatty acids are potent anti-inflammatories, though sometimes months of dosing are required to fully attain efficacy. They deserve exploration against the coagulation abnormalities and occasional vasospasm seen in autistic patients.

Vitamin A
Vitamin A is especially important for cell growth and differentiation, especially in epithelial tissues of the gut, brain, and elsewhere. Megson reported on 60 case histories of children to whom she administered cod liver oil (CLO) for three months or longer.44 Some may have benefited within days; core autism symptoms, such as language, eye contact, ability to socialize, and sleep patterns, all supposedly improved. Megson noted that the natural vitamin A found in CLO is about 12-percent “cis”, a molecular configuration absent from synthetic vitamin A (all “trans”). She hypothesized this cis-vitamin A may be “unblocking” brain retinoid receptors linked to cell membrane signal transduction.

Although CLO is unlikely to provide a sufficiently high intake of omega-3 fatty acids to correct the deficiency in these developmentally impaired children, and its high vitamin A content limits its upper dosing level, evidently it still has clinical utility. CLO products must be screened for mercury and other pollutant content, and so also the fish oils. The B:W ratio for CLO is 14:1, and for vitamin A (probably mostly the synthetic form) 22:1.13

Other Nutrients Offering Possible Autism Benefit
Bradstreet and Kartzinel45 have asserted what is perhaps obvious to many practitioners: that close to 100 percent of children with autism have vitamin, antioxidant, and fiber deficiencies. Considering the widespread metabolic compromise this might involve, supplementation with conditionally-essential nutrient metabolites (orthomolecules) such as taurine, coenzyme Q10, and carnitine often also provides benefit, on a case by case basis.4

Carnitine is central to energy generation. It can be synthesized in the healthy body but many individuals benefit from supplementation. Valproate, a drug prescribed for seizures, is known to deplete carnitine. In one open-label study carnitine benefited patients with Rett Syndrome, a developmental disorder that shares features with autism; a small, double-blind trial with 35 Rett Syndrome patients demonstrated clear improvement in well-being.46

The pterin substances, biopterin and its precursor neopterin, are nutrient orthomolecules found naturally in body fluids. During periods of immune activation (as with inflammation or autoimmune exacerbation) their levels in urine are increased.4 Biopterin in its reduced form (rBH4), is a limiting cofactor for biosynthesis of the transmitters dopamine, epinephrine, and serotonin. Autistic children can manifest relatively poor rBH4 status, perhaps because the enzyme that produces it is somehow compromised. In a pilot study, six autistic children were treated with rBH4 for three months - all showed improvement in language, eye contact, and sociability.47

Inositol is a precursor for phosphatidylinositol, a phospholipid that facilitates serotonin receptor function. In one small, double-blind trial no significant benefits emerged.48 The investigators conceded their efficacy measures were crude and suggested inositol be re-investigated.

Magnesium sulfate (Epsom salts) can benefit the autistic child through a novel route of delivery. A parent reported her child's oppositional behavior disappeared overnight after a bath in Epsom salts. Other parents who used the treatment reported improved speech, mood, cooperation, and motor development in their children.4

Correcting Amino Acid Abnormalities
Dr. Jon Pangborn, a prominent autism research pioneer, is expert in this area and has developed diagnostic and therapeutic protocols for normalizing amino acid status in ASD subjects.11,25,50
He reports at least two-thirds of autistics have abnormal amino acid levels, as measured in 24-hour urine or fasting blood plasma. High urine levels of several amino acids (generalized hyperaminoaciduria) almost always indicate toxic chemical exposure and consequent liver damage. Low urine amino acids often suggests malabsorption, as do high urine levels of peptides – incompletely digested proteins.

Sulfur amino acids are often abnormally low in autism, and this has direct implications for the proven impairments of detoxication in ASD. When detoxification capacity is limited, the cysteine/cystine ratio, and methionine, taurine, and glycine levels all tend to be abnormal. Cysteine, important for the formation of glutathione and taurine, often is measured low in young autistics but paradoxically high in those older than five years. Methione levels are occasionally found low, and taurine was reported deficient in 62% of autistic children by urine analysis.25

Glutamine is an energy source for enterocytes of the small intestine, is a glutathione precursor, and contributes to numerous other pathways. Glutamine is low in some autistics, particularly in those with an aversion to meat or poultry. Glutamine is readily supplemented to autistics.

Pangborn has recommended laboratories best qualified to perform amino acid and other assays related to possible inborn metabolic errors, along with the pharmacies that custom-blend formulations: Certain cautions must be observed when prescribing amino acid mixtures.25,50

GASTROINTESTINAL ABNORMALITIES AND THEIR CORRECTION

A majority of ASD individuals have gastrointestinal (GI) abnormalities.3 Maldigestion and malabsorption are common, as is inflammation of the lining. Dysbiosis (depletion and imbalance of symbiotic bacteria, fungal and/or other parasitic overgrowth) also is common. One study of 385 subjects found 46 percent had chronic diarrhea, constipation, or other GI symptoms.51 In a smaller study on 36 ASD children with chronic diarrhea, gas, abdominal discomfort and distension, more than two-thirds had GI inflammation and impaired digestive enzyme activity.3

Integrative practitioners worked closely with independent laboratories to develop the comprehensive digestive and stool analysis (CDSA). This includes measures for digestive function, metabolic function, microbiology, mycology (yeasts and other fungi), and parasitology. The Biomedical Assessment manual from DAN! lists laboratories that offer CDSAs.50
Findings with the CDSA reinforce other evidence for intestinal hyperpermeability or “leaky gut” in ASD.51,55

Nutritional Status and Leaky Gut
The intestinal lining is only a few cell layers thick, so that numerous insults can damage its integrity and increase its permeability. The premier test for GI permeability is based on the differential absorption of two inert (non-metabolized) substances, mannitol and lactulose. D'Eufemia51 found that 43 percent of a sample of autistic children and none of the controls had “leaky gut”. Many differing real-life factors contribute to intestinal permeability breakdown, including nutritional deficiencies; localized food intolerance or allergic responses; viral or bacterial infection, Candida overgrowth, parasites; oxidant or inflammatory xenobiotic toxins; NSAIDs and other pharmaceuticals that damage the protective mucus. This reality makes it imperative that gut integrity be assessed and restored as necessary, prior to exploring oral modalities for autism.

To correct hyperpermeability requires first, a comprehensive patient history to detect all the agents that could promote damage to the lining. The diet should be redesigned to increase protein and fiber intake and to lower digestible carbohydrates.4 Constipation should be treated. When diarrhea occurs, viral activity should be considered and treated if indicated, but often this improves as reactive foods are eliminated. Gram-level intakes of the amino acid L-glutamine can help the enterocyte cells proliferate to reseal gaps in the epithelium. To ensure the most efficient food digestion and so minimize food allergenicity, digestive enzyme preparations such as that of Brudnak and collaborators23 can be orally supplemented. Oral secretin therapy also is an option.

Secretin to Aid Digestion?
Secretin is a small neuropeptide hormone (27 amino acids), normally secreted by cells of the upper intestinal tract. Secretin helps regulate stomach, pancreatic and liver functions in normal digestion. Its status for autism was recently critiqued.4 To date, several controlled clinical trials have yielded mixed results, though the possibility remains that 1 child in 10 could be a secretin responder.14,15 Oral secretin is well tolerated and adverse effects are usually minor.

ORAL MERCURY DETOXIFICATION AND NUTRIENT SUPPORT

The biochemical profile of autism frequently features heavy metal overload. Often this comes on top of an inherently impaired detoxification capacity.3 The affected detoxification pathways are responsive to rational intervention with nutrients. Also, the heavy metal burden can be reduced by medically supervised oral chelation, supported by nutrient supplementation.4 But for these interventions to have lasting benefit, it is essential that ongoing exposure to heavy metals and other toxins be lowered to as near zero as possible.

The Mercury Threat
Heavy metals continue to be major environmental contaminants. Lead, cadmium, arsenic, and aluminum are deservedly suspect, but for mercury the evidence as a causative factor in autism is simply overwhelming.4,26 Shockingly, until recently vaccinations were exposing young children to mercury at levels that exceed the U.S. Environmental Protection Agency’s (EPA) safe limit by as much as 100 times. 4 The mercury-based preservative thimerosal still contaminates some vaccines52 and other medical liquid preparations. In addition, seafood intake or dental amalgams can load the pregnant woman with mercury, some of which may be transferred to the developing fetus. Practitioners report virtually all their autism cases show improvement following oral chelation for heavy metal removal.26,52

Clearance of mercury from the tissues is a prerequisite for repairing homeostatic balance, detoxification capacity, and overall health status in the ASD subject. To be conducted safely and effectively, oral mercury chelation is best entrusted to a qualified practitioner. Serious adverse side effects are rare but can occur, so professional monitoring and assessment is essential.26

Nutrient Support During Mercury Chelation
The oral mercury chelation process can be taxing on the patient, especially because beneficial minerals are inadvertently removed along with toxic elements.4 These require supplementation for immediate replacement. Further, some nutrients actually assist the detoxification process. Therefore many practitioners recommend hypollergenic multiple vitamin and multiple mineral (without copper and with generous zinc and selenium allowances), B complex with generous B6, and antioxidants (listed in Kidd4). Ascorbic acid (vitamin C) is recommended in gram intakes. It is a weak heavy metal chelator and helps conserve other antioxidants such as glutathione (GSH), the pivotal antioxidant inside our cells. ALA (alpha-lipoic acid) is a potent repletor of glutathione and a nontoxic nutritional adjunct to mercury and other heavy metal chelation. Coenzyme Q10 is, like ALA, both an antioxidant and energy cofactor.

Brudnak has made a strong case that the probiotic lactobacilli and bifidobacteria can assist with mercury detoxification.23 This benefit adds to probiotics’ abilities to assist with peptide digestion and boost immune function.

The DAN! Mercury Detoxification Consensus Group recommends that the supplements cysteine/cystine, N-acetylcysteine (NAC), and chlorella and other algae not be supplied during mercury detoxification.26 They also caution that full benefits from mercury detoxification are unlikely unless GI symptoms and especially dysbiosis are previously corrected.

Liver Detoxification Support Following Mercury Clearance
The removal of the highly toxic mercury burden should allow the body’s detoxification mechanisms to rebound and better manage other sources of toxic insult. The autistic population is proven to have higher xenobiotic pollutant burdens.3 Edelson reviewed the substantial evidence that environmental toxic exposure contributes to autism etiology, and claimed that some patients regain near-normal function following meticulous xenobiotic detoxification.53

The cytochrome “P450” system of detoxification is built into cell membrane systems and is highly vulnerable to oxidative mercury poisoning. Once mercury has been substantially reduced, the P450 enzymes can once again function, given adequate availabilities of their conjugation substrates such as ascorbate, taurine, glycine, and glutathione. This core antioxidant is often deficient in ASD individuals. To best replete liver and systemic GSH, its precursors can be supplied orally. These include L-glutamine, alpha-lipoic acid, and glycine. Phosphatidylcholine also helps protect the P450 system, being the primary phospholipid in hepatic cell membranes.54

A majority of ASD subjects have impaired sulfur metabolism, which is related to GSH deficiency and places further stress on the liver.3 Here, along with GSH precursors the sulfur amino acid taurine could be useful.4 Besides being a potent antioxidant, intracellular buffer, and bile salt constituent essential to digestion, taurine is a secondary P450 conjugating agent. Molybdenum is an essential trace mineral and cofactor for sulfite oxidase, the main sulfation enzyme. One of magnesium’s many metabolic roles is to assist with sulfur metabolism. Also, methylsulfonylmethane (MSM) is a general sulfur source that also is well tolerated.

As previously established from non-autistic populations, poor sulfation capacity is linked to poor metabolism of dietary phenols. Pangborn11 advises that ASD subjects be shielded from phenolic xenobiotics (e.g., “Lysol” cleaner) and that foods high in phenols, such as bananas, onions, and coffee should be considered possibly harmful.

INFLAMMATORY AND AUTOIMMUNE IMBALANCES

Evidence is rapidly growing that the immune system plays an important role in the pathogenesis of autism, as summarized in recent reviews.4,22,55,56 As much as 35-45 percent of the autistic population may have pervasive problems with immunity.55-58 Humoral immunity can be compromised by IgA deficiency, also known to predispose to autoimmunity. On the cell-mediated side, cell counts can be abnormal and cell activities subpar; among the pivotal CD4+ “helper” cells the TH1/TH2 balance can be abnormal, as reported by two separate groups.3 Cytokine profiles also are off-balance in autism. More than 80% of ASD sample children aged 2-14 years could be overproducing proinflammatory cytokines.57,58 Interestingly, more than one study suggests siblings may share this tendency yet not be clinically autistic.3,58

Autoimmune imbalance is consistently apparent in autism. Autoantibodies to brain have been reported, including antibodies directed against specific neural self-antigens. These include anti-MBP (myelin basic protein) and anti-NAFP (neuron-axon filament protein) in 50-70% of subjects.59,60 Many different inflammation-related mechanisms can be triggered by autoantibodies, including outright demyelination of nerve cells.61

Oral immune-based, orthomolecular treatments for ASD have included transfer factor (TF) and colostrum. Transfer factor is a low-molecular weight mix of molecules produced by white cells. Fudenberg, 62 in an open-label study, treated autistic children ages 6-15 years with TF prepared from parents of children with autism. Fully half of these children had depressed lymphocyte responsiveness to mitogens, and the majority had autoantibodies to myelin basic protein (MBP). Most showed significant symptomatic improvement; their food sensitivities and Candida- associated symptoms also decreased.

Colostrum, the fluid expressed by the nursing breast for the first few days following birth, is another immune support agent under active scrutiny for possible benefit to autism. Colostrum contains a wide range of immunoglobulins that generally boost immunity; antibodies, and other less specific antiviral factors; glycoproteins that inhibit the attachment of unwanted bacteria to the intestinal mucosal lining; significant amounts of the cytokine interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and other potent anti-inflammatory factors; and various growth factors that promote cell growth, lymph node and other immune organ maturation, intestinal IgG production, and tissue repair. Interest in colostrum may be justified by the report of low levels of insulin-like growth factor I (IGF-1) in the CSF of children with autism63 and by other indications.3,4

Certain nutrients that are not strictly immune – specific can potentially assist in immune rebalancing. Primary candidates include the long-chain omega-3 fatty acids, mushroom glycans, phytosterols, and nutrient flavonoids. Controlled studies are urgently needed to explore their potential.

CONCLUDING REMARKS

Autism continues to increase in prevalence, and remains an extreme challenge to medical management. Medically, autism's expression is so individualized that its management requires individualized care that only integrative medical practice can offer. Ethical integrative management supports parents' initiatives to explore options that offer negligible risk and a degree of benefit for the child.

Nutrients predictably have broader effects and better benefit-to-risk profiles than drugs. The integrative practitioner, however, cannot always shun the use of drugs. But as the therapeutic power of nutrients becomes ever more evident, it becomes more appropriate to give nutrients a try before turning to drugs. Furthermore, rational application of nutrients often will ameliorate drugs’ inevitable adverse effects.

The current intensified pace of vaccination is circumstantially implicated in autism causation. Blaylock has analyzed the factors that may be interacting between live, attenuated vaccines that are given frequently and often in multiple combination to the young child. He has presented in-depth suggestions for reorganizing vaccination types and scheduling, as well as for building up the child’s immunity via nutrition prior to imposing vaccination on the delicate immune system.6 These seem worthy of consideration as a kind of vaccine prophylaxis protocol. Such a protocol could help avert autistic regression in a child who has genetic predisposition to autism and/or other impairments that increase susceptibility.

Autism also will continue to challenge basic and clinical researchers. From the nutritional – integrative perspective, research funding is urgently needed. More in-depth study is required for, especially: (1) vaccination and nutritional vaccination prophylaxis; (2) nutritional status of the mother and antenatal contribution to autism risk; and (3) nutritional correction of pro-inflammatory and autoimmune imbalance. Improved understanding in these areas would facilitate stemming the current epidemic and moving established cases into remission.

Despite the inherent severity of their impairments, the ASD population is making steady advances in everyday performance and overall life quality. Autism’s current nutritional – integrative management is successful by any measure and is a model for other disease states. Nutritional and other nontoxic interventions remain at the core of this success story in integrative medical management.

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