Nutritional Supplements for Autism

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					Nutritional Supplements for Autism

         James B. Adams, Ph.D.
         Arizona State University
          http://autism.asu.edu

          Tapan Audhya, Ph.D.
           Vitamin Diagnostics
                 Collaborators
•   Tapan Audhya
•   Stephen Coburn
•   Liz Geis
•   Julie Ingram
•   Sanford Newmark
•   Dena Goldberg
•   Warren Tripp
•   Marie Adams

Funded by Autism Research Institute, Greater Phoenix
  Chapter of the ASA, BHARE, Arizona State University

Special thanks to Vitamin Diagnostics and Doctor’s Data for
  discounted/free testing
                Outline
• Vitamins and Minerals
• Amino Acids
• Essential Fatty Acids
           Basics of Nutrition
The essential major components of human nutrition
  are:
• water
• carbohydrates (for fuel)
• vitamins and minerals
• amino acids (from protein)
• essential fatty acids
A deficiency of any of these results in disease, or
  even death in extreme cases
Examples of Nutritional Deficiencies
 • Lack of vitamin C -> scurvy
 • Lack of iron -> anemia; mental retardation in
   children
 • Lack of calcium or vitamin D -> rickets

 Children with autism are not classically deficient,
   but most are low in some essential vitamins,
   minerals, amino acids, and fatty acids .
 “Children with Starving Brains” by J. McCandless
     Why consider vitamin/mineral supplements
             for people with autism?
1) vitamin/mineral deficiencies common in general population
2) often restricted diets (“picky eaters”) -> limited vitamin/mineral intake
3) poor digestion (25% have chronic diarrhea, 25% chronic constipation);
    Endoscopies by Wakefield, Buie, Krigsman show damage to gut
     -> limited absorption of nutrients?
4) Rosseneu, Shaw research: overgrowth of harmful bacteria in GI tract:
          fewer “good” bacteria which actually produce several vitamins
5) 18 studies demonstrated benefits of vitamin B6/Mg
6) 1 study showed vitamin C was beneficial in autism
7) Prof. Megson: cod liver oil (with high levels of vitamin A, D, and essential fatty
    acids) helped with gaze aversion, behavior
8) Dr. Rimland’s set of parent-reported case studies on benefits of
    vitamins/minerals
Goals:
1) Evaluate nutritional status of unsupplemented
children with ASD vs. unsupplemented typical
children, age and gender matched.
2) Check for correlations of symptoms of autism
with nutritional levels


Participants:
Enrolled: 48 ASD, 35 controls
Age: 3-9 years
All children from Arizona.
No use of vitamin/mineral supplements in 2 months
  prior to sample collection.
                            Vitamins
             % diff-avg     %diff - med      % < RR % > RR
Vitamin A              -3             -3           13     13
Carotenes             -12              0            5      0
Thiamine               -7            -10           40      4
Pantothene             -4             -6           12     12
B6                      3            -12           20     24
Folic acid              0              2            6     25
B12                    16             -5           25     18
Vit C                  -4             -9           18     18
Vit E                   2              0            9      7
Vit D3                  2             -3           11     20

Ref Range (RR) defined as between bottom 15% and top 15%
Only small differences in vitamin levels between autism and controls
(not statistically significant)
ARI Survey of Parent Ratings of Treatment Efficacy

                %       % No     %        Number
                Worse   Change   Better   of
                                          Reports
   Vitamin A    2%      58%      41%      618


   Folic Acid   3%      54%      42%      1437


  Vitamin B3    4%      55%      41%      659


  Vitamin B12   4%      33%      63%      192


   Vitamin C    2%      57%      41%      1706
Why do children with autism benefit from vitamins if
  levels not very different from typical children?


    1) Typical children do not eat 5 servings of fresh
       fruit and vegetables each day, so the level of
       vitamins in typical children is not optimal.
    2) Several studies show children with autism are
       under increased oxidative stress, suggesting a
       need for increased levels of antioxidants.
   Vitamin B6 and Magnesium
• Over 20 studies, including 11 double-blind,
  placebo-controlled studies, found that high
  dose vitamin B6 (8 mg/pound bodyweight)
  with Magnesium (3-4 mg/pound
  bodyweight) resulted in wide range of
  behavioral improvements
• Only 2 negative studies: one with very few
  subjects, and one with half dose
• Overall, very safe, and helps 50% of
  children and adults.
                 Vitamin B6 levels
First Study
Autism (n=35) 56 +/- 13 ng/ml
Controls (n=11) 36 +/- 9 ng/ml ttest = 0.00002

Second Study
Autism (n=47) 62 +/- 41
Controls (n=33) 53 +/- 27         not significant

Combined First and Second Study
Autism (n=82) 72 +/- 32
Controls (n=44) 52 +/- 25       p= 0.05

Conclusion: Some children with autism have unusually high levels of B6,
  and a few have unusually low levels of B6 -
Explanation: study by Dr. Tapan Audhya found that 4 enzymes for
  conversion of B6 are defective in autism, such that conversion rate is
  much lower than normal
         Substrate Requirement for Maximal
         Activity of P5P-Dependent Enzymes
                  Controls (n=16) v. Autistics (n=8-17)

            70
            60
            50
            40
         KM
            30
            20
            10
             0
                 Pyridoxal kinase     Glutamate         Glutamate
                                    transaminase      decarboxylase

                               Controls   Autistics

Autistics often have weak B6-dependent enzymes, so may need very high B6
        Substrate Requirement for Maximal
        Activity of P5P-Dependent Enzymes
         1000
          900
          800
          700
          600
          500
          400
          300
          200
          100
            0
                DOPA decarboxylase     Histidine        5-HTP decarboxylase
                                     decarboxylase

                                Controls    Autistics



Some autistics need high-dose B6 to make important neurotransmitters
                            Autism Treatment Study:
                   Effect of B6 (10mg/kg/day) + Zn (25mg) +
                     Mg (400mg) on Kryptopyrrole Levels
                   120

                   100
micromoles/100ml




                    80

                    60

                    40

                    20

                     0
                         0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
                                          Months of Treatment


                   Conclusion: High-dose B6 very helpful for treating pyroluria
High-dose B6 + multivitamin treatment study (Audhya)

                           184 Volunteers

             1. Unsuccessful with Diet Intervention


             2. Given Daily one centrum advanced formula
                Multivitamin Tablet with food, 25 mg Zn++ (as
                Gluconate and Citrate) and 400 mg Mg ++ (as
                Gluconate & Oxide)


           128 (A)                                              56 (B)
           (95:33)                                              (41:15)
        Pyrindoxine -HCℓ
                                       Pyridoxine – HCℓ & Pyridoxal – PO4
          5 mg/kg/day
                                                      1 mg +4.7 mg/kg/day
          Outcome of the study
89 Volunteers      Substantial Improvement;
                   Almost normal


86 Volunteers      No perceptible change;
                   Behaviorally or physically


9 Volunteers       No improvement;
                 and additional adverse reaction
ARI Survey of Parent Ratings of Treatment Efficacy
                  %       % No     %        Number
                  Worse   Change   Better   of
                                            Reports


   Vitamin B6
                  8%      63%      30%      620
      alone


   Magnesium      6%      65%      29%      301


   Vitamin B6
      with        4%      49%      47%      5780
   Magnesium


  P5P (Vit. B6)   13%     37%      51%      213
       Summary re. Vitamin B6
Some children and adults with autism benefit from high-
dose B6, to make neurotransmitters, glutathione, and many
other important substances
Simple measurement of kryptopyroles in urine determines if
high-dose vitamin B6 (or zinc) is needed (caution –
destroyed by light, so collect in dark).
Doses up to 10-15 mg/kg may be needed (1000 mg max);
takes about 6 months to lower kryptopyroles in urine
Always give at least half as much magnesium (400 mg
max).
                 Vitamin B12
• Methyl cobalamin (methyl form of vitamin B12) is
  most active form of vitamin B12
• Vitamin B12 is very hard for body to absorb orally
• Injectable form of methyl-B12 may help up to 70% of
  autistics per informal reports by Dr. Jim Neubrander,
  at doses of 75 mcg/kg bodyweight, 2x/week, for 6+
  weeks
• Safe, but needs research to verify effectiveness
• Research by Prof. Richard Deth shows it is needed to
  produce glutathione, and to help Dopamine 4 receptor
  function (important for attention)
  Low Cysteine and Glutathione
• Studies by Jill James and Tapan Audhya find low
  cysteine and extremely low glutathione in children
  with autism; glutathione is important antioxidant
  and for detoxification
• Treatment study by Jill James finds that 800 mcg
  of folinic acid and 1000 mcg of TMG over 8
  weeks improve cysteine and glutathione levels
  somewhat
• Addition of 75 mcg/kg of methyl B12 injections
  helps more
• Informal reports of improvement in behavior
                           Minerals
                           %diff - avg % diff-med        % < RR % > RR
Magnesium    whole blood             2          1              33     13
Magnesium    serum                   1          1               2     15
Magnesium    RBC                     2         -2              13     22
Zinc         whole blood             7          9 p=0.05        9     13
Zinc         RBC                     2          2              15     11
Copper       whole blood             1          0               7      2
Copper       serum                  -3         -8              22      7
Copper       RBC                    15         17               2     24

Zinc slightly high in whole blood, but average in RBC
Copper results mixed – slightly high in RBC, slightly low in serum, not
  statistically significant
Disagrees with results by Walsh (possibly due to LabCorp Ref Range
  and age of controls?)
                    Minerals (cont.)
                          %diff - avg % diff-med        % < RR % > RR
Selenium    whole blood             3          4               4     22
Manganese   whole blood            -6         -6              13      7
Iron        serum                 -19         -5 p=0.06       14      0
ferritine   serum                   3         -6              20      9
Lithium     serum                  -3          0               0      0
Calcium     urine                 -29        -28 p=0.04       30      2

       Iron: slightly slow in serum, but serum ferritine is
          more relevant and is “normal”
       However, some children with exceptionally low
          serum ferritine (10 with < 10 mcg/l)
       Calcium: low in urine, possibly due to low intake
          (GFCF diet)
         Toxic Elements in Hair
                 %Diff-avg %Diff - med    P-value
        Al              -38           -37      0.002
        Sb               -7           -23
        As               -3           -11
        Bi              -15           -55
        Cd              -11           -27
        Pb              -25           -34
        Hg              -15           -24
        U               -11             0
        Ni              -26           -13       0.06
        Ag               -9           -23
        Sn              -39           -48      0.003
        Ti              -15           -12
• Most toxic elements are lower in autism, suggesting an
  overall problem with excretion; aluminum, tin, and
  possibly nickel are statistically significant
                    Sulfhydryl-Reactive Metals
                                Autism
                                Control
                                                           Arsenic, cadmium,
             70                                            lead, and possibly
             60                                            mercury are lower in
             50                                            hair of young autistics
Mean Ranks




             40
                                                           (ages 1-6 yr) than
             30
                                                           typical controls),
             20
                                                           suggesting problem
             10
                                                           with excretion.
              0
                  Arsenic   Cadmium       Lead   Mercury
                                  Metal




Kern JK, Grannemann BD, Trivedi MH, Adams J.
Sulfhydryl-reactive metals in autism. Toxicology and
Environmental Health, Part A., 2007;70:1-7.
           Essential Minerals in Hair
                           %Diff-avg %Diff - med
              Ca                   14         67
              Mg                    1         55
              Na                   44          3
              K                   -17        -19
              Cu                   22          4
              Zinc                  5          8
              Mn                  -47        -32         0.005
              Cr                   -4          4
              V                    23          0
              Mo                  -17        -15           0.06
              B                   -19        -36
              I                     4          3
              Li                  -29        -38           0.04
Manganese, molybdenum, and lithium are low in hair.
Manganese slightly low in blood, partially consistent with hair.
Low lithium is consistent with previous study.
   Essential Minerals in Hair (cont.)
                  %Diff-avg %Diff - med    p-value
         P                 1            -2
         Se               -8             1       0.05
         Sr              -11            67
         S                 2             3       0.07
         Ba               -4            12
         Co              -30           -25       0.07
         Fe              -20           -13       0.02
         Ge                3            -1
         Ru              -18           -39
         Zi              -17            -7
Low iron and possibly low cobalt. (iron not reliable in hair)
Slightly low selenium.
Possibly slightly high sulfur.
Lithium – previous ASU study

The only abnormality in mothers of children with
  ASD was low levels of lithium:
   all ages: -40%, p=0.05
   mothers of children ages 3-8: -56%, p=0.005 (highly
      significant!)
Similarly, children with ASD had lower levels of
  lithium
   all ages: -15%, not significant
   ages 3-6 yr: -30%, p=0.04
          Importance of Lithium
• Hair is a reliable measure of lithium
• Lithium is probably an essential mineral (not well studied)
• Study of goats on lithium-deficient diet found:
   – decreased activity of monoamino oxidase, which is of particular
     importance to manic-depression, chronic schizophrenia, and
     unipolar depression.
   – lowered immunological status, and suffered from more chronic
     infections (may explain why children with autism had more ear
     infections)
• Lithium concentrations highest during first trimester, and
  highest in the brain, so a deficiency of it could affect early
  fetal development, including early brain development
             Lithium - continued
Several studies have show low lithium correlates with:
• schizophrenia
• neurosis
• suicide
• behavior problems
• crime (homicide, rape, burglary, theft, drug use, juvenile
  runaways)


 Finally, a four-week placebo-controlled study of 24 former
  drug users found that 400 mcg/day of lithium resulted in
  steady increases in mood scores, especially in
  subcategories reflecting happiness, friendliness, and
  energy.
                       Lithium
• Not included in most nutritional supplements, or in
  prenatal supplements
• An estimated RDA is 1000 mcg/day, and people in the US
  consume only about 500 mcg/day
• Extremely high doses of lithium (1,000,000 mcg/day) are
  used as a psychiatric medication, primarily for
  “calming/mood stabilization”, especially for bipolar
  disorder; nearly toxic at that dose

• RECOMMENDATION: a dosage of 200-1000 mcg/day
  should be safe, and may be beneficial to younger children
  with autism and their mothers
• More research needed
      Essential Minerals - Iodine
• Iodine: 45% lower in ASD than controls, p=0.005 (highly
  significant!)
• in 3-6 yr old group, similar value (-47%)

• Caution: no data showing that iodine in hair correlates
  with level in body (blood is standard measurement)
• iodine is an essential mineral
• major role of iodine in body is in thyroid function
• a deficiency of iodine causes goiter (enlarged thyroid) and
  mental retardation (Cretinism)
• worldwide, the leading cause of mental retardation is
  iodine deficiency, affecting roughly 20 million children
            Iodine - continued

• In early 1900’s, iodine deficiency was up to 30% in
  some parts of the US
• iodine in salt is believed to be sufficient to make iodine
  deficiency very rare in the US/western world
• however, iodine levels in blood have declined 50%
  from 1970’s to 1990’s per NHANES I and III, possibly
  due to decreased salt intake
• many fast foods (fries, chips) use non-iodinized salt
• RECOMMENDATION: take modest iodine
  supplement; measure if suspect problem with thyroid
ARI Survey of Parent Ratings of Treatment Efficacy


                %       % No      %        Number
                Worse   Change    Better   of
                                           Reports

    CalciumE:   2%      62%       36%      1378


   Magnesium    6%      65%       29%      301


      Zinc      2%      51%       47%      1244
         Summary of Minerals
Low iron in some children – supplement only if low.
Low calcium in some children (esp. if dairy-free)
Low lithium in children and mothers, which can
  affect behavior
Low iodine is a leading cause of mental retardation,
  and should be supplemented
Low toxic metals in hair suggests problem with
  excretion of toxic metals.
          Research Study of
  Multivitamin/mineral supplement

• 3 month study of Spectrum Support
     (by Brainchild Nutritionals)
• Double-blind, placebo-controlled
• Dosage is slowly increased to maximum
  over first 2 months, then held constant
• parent ratings of changes
• small study - 20 children only
   Vitamin C results (at end of study)

                range        average
Placebo:        0.9-1.4      1.03
Suppl.          1.0-2.0      1.33
typical child (age 3-8)      1.45


Placebo children are 2 standard deviations below average
   value
500 mg raised vitamin C to near-normal levels, but more
   may be better (1000 mg)
                   Overall Results
Based on parent evaluations on final day of study

7 point scale
   1=much worse
   2=worse
   3=slightly better
   4=same
   5=slightly better
   6=better
   7=much better
                    Overall Results
Category               Placebo        Supplement      Difference
Sociability            5.1            5.3             +0.1
Expr. Language         5.6            5.9             +0.3
Rec. Language          4.9            5.8             +0.9
Eye Contact            4.9            5.5             +0.6
General Behavior       4.3            5.1             +0.8
Sleep                  3.9            5.4             +1.5
Gastrointest.          3.9            5.4             +1.5

Overall                5.1            5.5             +0.4

Sleep and GI results are statistically significant (p<0.005);
other results positive, and worth further investigation
               My recommended daily dose per 20 pounds of bodyweight,
               up to 100 pounds (i.e., for a 60 pound child, multiply by 3)
                           Take with food, split into 3 doses

Vitamin A          1000 IU           Chromium              20 mcg
Vitamin B1         7.5 mg            Copper                0 mg (most autistics don’t need)
Vitamin B2         7.5 mg
                                     Iodine                30 mg
Vitamin B3         25 mg
(10 mg niacin, 15 mg                 Lithium               0.2 mg
    niacinamide)
                                     Magnesium             120 mg
Vitamin B5         20 mg
Vitamin B6         80 mg             Manganese             1 mg
Vitamin B12        200 mcg           Molybdenum            40 mcg
Folic Acid         50 mcg
                                     Selenium              25 mcg
Folinic Acid       100 mcg
Biotin             100 mcg           Vanadium              13 mcg
Choline            70 mg             Zinc                  5-15 mg
Inositol           30 mg
PABA               5 mg              Calcium: Dosing independent of bodyweight: 400 mg
                                     for ages 2-5, 500-600 mg for older children
Vitamin C          300 mg
Vitamin E          60 mg             Potassium from fruits and vegetables (esp. potatoes,
Mixed Carotenes 3000 IU              avocados), esp. for low muscle tone
      Recommended Vitamin/Mineral Supplements
• Kirkman’s Super Nu Thera – the original high-B6/Mg
  supplement for autism; contains many vitamins/minerals,
  but not a complete formulation; www.kirkmanlabs.com
• Kirkman’s Spectrum Complete: broad-spectrum
  formulation, with moderate B6
• Brainchild’s Spectrum Support: broad-spectrum liquid
  vitamin/mineral supplement with moderate B6;
  www.brainchildnutrionals.com
• D-Plex: broad-spectrum vitamin/mineral supplement with
  some amino acids; www.danplex.com
• Awaken Nutrition: broad-spectrum liquid
  multivitamin/mineral with high B6;
  www.awakennutrition.com
Need extra Calcium with most of above products.
       Homemade Vegetable/Fruit Juice
• Commercial juices are heated (pasteurized), which destroys many
  vitamins and other nutrients.
• Recommend making fresh vegetable/fruit juice, and storing it for up to
  a few days in an airtight glass container.
• Grinding vegetables/fruit one time yields half of the vitamins/minerals.
  So, soak the pulp for 15 minutes in a small amount of pure water, then
  grind the pulp again – this will yield most of the remaining
  vitamins/minerals.
• Small loss of insoluble fiber, but the soluble fiber remains, and that is
  the most important fiber.
• Easy, tasteful way to get healthy nutrients into children who don’t eat
  fruits/vegetables.
• Cabbage, spinach, carrots, broccoli, parsley, oregano, mixed with a
  small amount of fresh fruit for flavor and other nutrients.
• Organic vegetables and fruits preferred - higher amount of vitamins
  and minerals, and less toxic pesticides.
• 8-16 ounces/day enough for most children and adults, depending on
  their intake of other vegetables and fruits.
               Amino Acids
• Protein is composed of long strands of many
  amino acids
• The body needs to digest protein to small peptides
  or individual amino acids
• Amino acids can be measured in plasma (fasting)
  or urine (24-hr best)
• Caution – high level in urine sometimes indicates
  wasting, resulting in low levels in body
     Essential Amino Acids in Urine
                        % Diff-avg        % Diff-med      p-value
    Threonine                        12                  3
    Valine                           -2                  3
    Methionine                        3                -21
    Isoleucine                        3                 -4
    Leucine                           2                 13
    Phenylalanine                     0                  2
    Lysine                           37                 28 p=0.07
    Tryptophan                        7                  8
    Histidine                        17                 15
• Lysine high and possibly significant;
• Methionine slightly low but not significant;
• Histidine slightly high but not significant
Note: high level in urine may mean low level in body
 Conditionally Essential Amino Acids in Urine
                            % Diff - avg        % Diff - med   P-value
       Arginine                            -3               -9
       Asparic acid                        -1               -2
       Serine                              11               10
       Glutamic acid                        1               21
       Glutamine                           -7               -9
       Glycine                             31               17 p=0.04
       Alanine                              3               20
       Asparagine                           3                1
       Cystine                             21               19 p=0.03
       Tyrosine                             5                9
       Proline                             16              -18

High glycine and high cystine in urine suggests low level in body;
Worrisome that cystine excretion is high
     Metabolic Amino Acids in Urine
                            %diff - avg %diff - med     P-value
       Phosphoserine                  2              -2
       Taurine                       26              40
       Phosphoethanolamine          -11             -14
       Hydroxyproline               -17              -8
       Alpha aminoadipic acid        -4              11
       Beta aminoisobutyric acid     46              76 p=0.1
       Hydroxylysine                 -3               5
       Ethanolamine                   2               1
       Ornithine                     10               6
       3-Methylhistidine              8               2
       Homocysteine                   1              -3
       Creatinine                    -1              -8

Taurine and beta aminoisobutyric high but not statistically significant;
  high taurine probably suggests wasting, and hence a need for taurine
     Summary of Amino Acids
• Some children with autism have low levels
  of amino acids in body
• Recommendation: measure levels, and
  supplement if low
• Also, consider measuring neurotransmitter
  levels in platelets, and then supplement with
  precursors if low (neurotransmitters made
  from amino acids) – more research needed
        Why Sulfate is Necessary?
• To maintain the slipperiness of gut mucins
  which support gut permeability
• Sulfate activates some hormones e.g..
  Cholecystokinine, gastrin etc.
• Necessary for detoxification
  Example:
    Increased dopamine is responsible for
    stereotypic movements and behavior; sulfate
  needed to eliminate it.
                                         TKA 1
                      Primary Source of Sulfur
(I) Sulfur containing Amino Acids. (SAA)
           e.g. Cysteine, Cystine, Methionine, Taurine

(II) Organo Sulfur
          e.g. Allicin, Diallyl Sulfide,
               Isolthiocyanates etc.. Found in garlic, onion
               and other fruits and vegetables.

(III) Other Sources

              Methylsulfonylmethane (MSM), DMSO,
              glucosamine sulfate, glutathione (GSH),
              N Acetyl Cysteine (NAC)
              Magnesium Sulfate

(IV) Foods

           Corn, Sunflower seeds, oats, cashews, walnuts,
  almonds, sesame seeds etc.
                                                               TKA 2
          Sulfate Levels are Low
   in Autistic Children for many reasons
• Low level of Sulfation Enzyme

• Poor oxidation of Amino Acid Cysteine to Sulfate

• Poor absorption of sulfate (only 10-15%) because of
  altered gut permeability

• Increased excretion of sulfate by kidney

• Kidney is unable to recycle sulfate
                                                 TKA 3
   Plasma Sulphates and Glutathione
             in Children
                         Control       Autistic
                         (n 24)            (n 41)
Some autistics had normal levels, but some had
  very low levels:
Sulphate (free)1    1.8-10   0.4-1.9 25% low
Sulphate (total)1 1400-3000 94-310 43% v. low
Glutathione (total)2 3.8-5.5 1.2-4.1 46% low
1 (nmole/mg   protein)    2   (µmole/ml)            TKA 4
 Urine Sulphate Metabolites & Glucaric Acid in Children
                      (µmole/l)

Compound       Control         Autistic    % high
                 (n=24)         (n=41)
Sulphate (free) 1260-3000    2164-6082 28.6
Sulphate (total) 2600-6000   4632-8944 43.5
Sulphite         0.15-1.5      1.3-6.4      62.1
Thiosulphate 6.5-35.5         32.8-87.3 51.6
Thiocyanate 20.4-85.6         11.8-25.3 (-) 40.8
D-glucaric acid
 in µmole/24° 88-280         149.3-416.5 77.6
                                                   TKA 5
         Effect of various Sulfur Nutrient on Plasma Sulfate Level
                            In Autistic Children
                           Age – 4-15 years; N=347
         Level before treatment – 94 -310 (182 ± 21) nmole/mg protein
       Age matched normal children level – 1400-3000 nmole/mg protein
                Sulfur Nutrient                            Total Sulfate Level

1.   1% Mg SO4 Bath with 0.25% bicarb
     100ºF/30 min.                      130-972 (892 ± 84) (n=66) 130min-150min AB

2.   1% Mg SO4 gel patch                112-803 (437 ± 32) (n=14) 8hrs after treatment

3.   NACysteine, P/O 7-10 mg/kg/day     462-1189 (745 ± 16) (n=35) 30 DAT

4.   Taurine, P/O 10-12 mg/kg/day       694-1230 (1140 ± 102) (n=49) 30 DAT.

5.   MSM, P/O 15mg/kg/day               1204-1817 (1694 ± 181) (n=67) 30 DAT.

6.   Glutathione, P/O 10 mg/kg/day      251-535 (416 ± 62)(n=29) 30 DAT

7.   Glutathione cream 300 mg/day *     317-604 (582 ± 89) (n=45) 30 DAT

8.   Methionine, P/O 8 mg/kg/day        302 -743 (611± 103) (n=42) 60 DAT

*With 0.001% ZnCl2 and 0.015% Vit. A    AB – After Bath, DAT – Days after treatment
                                                                                   TKA 6
                      Conclusion
• Sulfur compounds are necessary therapeutically in
  Autism.

• Sulfur amino acid can be used to promote detoxification
  of foreign chemicals via the sulfation pathway.

• MSM may be effective for pain syndromes, bladder
  disorder and allergy in autistic children.

• Increase in serum sulfate may influence the therapeutic
  effects of GAGS in autistic children.

                                                   TKA 7
                Essential Fatty Acids
Essential Fatty Acids are termed “essential” because they are
  necessary for human life.
The major types of essential fatty acids are Omega-3 and
  Omega-6.
Ancient human diets contained a roughly 1:1 ratio of Omega-3 to
  Omega-6 fatty acids.
However, since Omega-3 fatty acids spoil much faster than
  Omega-6, commercial food processors usually remove them
  or “hydrogenate” them to increase shelf life.
Today, American diets contain a roughly 1:15 ratio of Omega 3
  to Omega-6; in other words, most people in the US are very
  low in Omega 3 fatty acids.
Sources of Omega-3 Fatty Acids

In human diets, the major source of omega-
  3 fatty acids is fish. Fish contain two
  important types of Omega-3 fatty acids,
  EPA and DHA.

Some fish contain much more omega-3’s
  than others.
     Importance of EPA and DHA
EPA is important in reducing inflammation (such
 as in the GI tracts of children with autism).
DHA is critical to brain development, and 20% of
 an infant’s brain is made of DHA.
Both are critical to all cell membranes in the body;
 they regulate nutrients going into the cell, and
 waste leaving the cell.
They also affect the release and reuptake of
 neurotransmitters.
     Common Symptoms of Essential Fatty Acid Deficiency
      ω3                                       ω6


Dry Skin                          Excessive Thirst & Sweating

Impairment of Vision              Frequent Urination

Sticky Platelet                   Dandruff

Tingling in Arm & Leg             Kidney Degeneration

Learning Disability               Drying up Glands

Motor In-coordination             Dry, Dull and Loss of Hair

High Blood Pressure               Rough & Dry Skin

Mental Deterioration              Susceptibility to Infection

Immune Dysfunction                Male Sterility/Miscarriage

                                  Heart/Circulatory Problem

                                  Growth Retardation

                                  Poor Wound Healing

                                  Behavioral Disturbance        TKA 15
                      EFA’s in Autism

A recent study in France found that children with autism had
  normal levels of Omega-6, but their levels of Omega-3
  were 25% below “normal”, and even “normal” is
  probably far from “optimal”.
   – S. Vancassel et al., Plasma fatty acid levels in autistic children,
     Prostaglandins Leukot Essent Fatty Acids 2001 65:1-7.
A study by Gordon Bell (Un. Stirling) of 29 children with
  ASD vs 55 controls found several abnormal fatty acids in
  children with ASD.
       Bell et al. (2002) Abnormal fatty acid metabolism in
  autism and Asperger’s syndrome. In: Phospholipid
  Spectrum Disorder in Psychiatry and Neurology (2nd
  edition)
        Treatment with EFA’s

Supplements of fish oil have been shown to be effective in
  treating a range of psychiatric illnesses, including:
• schizophrenia
• depression
• bipolar
• ADD/ADHD
• dyslexia
• Dyspraxia

Now 4 treatment studies for autism!
Amminger et al. Omega-3 Fatty Acids Supplementation in Children with
  Autism: A Double-blind Randomized, Placebo-controlled Pilot Study. Biol
  Psychiatry. 2006 Aug 22

Design: Open study, 6 week trial,
  1.5 g/day of omega-3 fatty acids (.84 g/d EPA, .7 g/d DHA)

   13 children (aged 5 to 17 years) with autistic disorders accompanied by severe
   tantrums, aggression, or self-injurious behavior.

RESULTS: Substantial improvement in hyperactivity and stereotypy. No adverse
  effects

CONCLUSIONS: Preliminary evidence that omega-3 fatty acids may be an
  effective treatment for children with autism.
                  Tucson Study
• A 90-day open trial of essential fatty acids in 18 children
  with autism, age 3-10 years
• Dosage of 1 ProEFA/day - 247 mg of Omega-3, 40 mg of
  Omega-6.
• Found significant increases in language and learning skills.

• Patrick L and Salik R, The Effect of Essential Fatty Acid
  Supplementation on Language Development and Learning
  Skills in Autism and Asperger’s syndrome.
  Autism/Asperger’s Digest: Research Article – Jan/Feb
  2005.
                Adams et al.
    Essential Fatty Acid Study – 2 month
Open study
Phased in gradually over 2 weeks, continued for 6
  weeks
Ages 3-6: 2 gel caps per day
Ages 7-12: 3 gel caps per day
Ages 13 and over: 4 gel caps/day

ProDHA: 250 mg DHA, 100 mg EPA, 50 mg other
  omega 3 per capsule
                                     Effect of ProDHA on ABC Scores
                 Effect of DHA on High Seafood Consumers                                                             Effect of DHA on Low-Seafood Consumers

             18.00                                                                                               18.00
             16.00                                                                                               16.00
ABC Scores




                                                                                                    ABC Scores
             14.00                                                                                               14.00
             12.00                                                                                               12.00
             10.00                                                                          Start                                                                                              Start
                                                                                                                 10.00
              8.00                                                                          End                   8.00
              6.00                                                                                                6.00                                                                         End
              4.00                                                                                                4.00
              2.00                                                                                                2.00
              0.00                                                                                                0.00
                                                            Hyperactivity


                                                                            Inappropriate
                      Irritability



                                     Lethargy



                                                Sterotypy




                                                                                                                                                               Hyperactivity


                                                                                                                                                                               Inappropriate
                                                                                                                         Irritability



                                                                                                                                        Lethargy



                                                                                                                                                   Sterotypy
                                                                               Speech




                                                                                                                                                                                  Speech
                                High Seafood Consumers (2 or more servings of
                                fish/month)– little effect
                                Low Seafood Consumers - large improvements in
                                Irritability, Lethargy, and Hyperactivity
   Results - Total ATEC Score
            Start       End          Difference
ProDHA      66.7        58.1         -8.6

Changes of more than 10 points:
     8 of 24 improved, 0 worse

Seafood Consumption:
0-1 servings/month: -9.7 change in ATEC
2+ servings/month: -3.1 change in ATEC
So, EFA supplementation is most beneficial to low
  seafood consumers
     EFA Study – 9 months Audhya et al.
• Pre/post measurements of EFA levels in
  children with autism vs. typical children

• Open design (no placebo group)

• Only treating those children with low EFA
  levels
   Biochemical Effect of Fatty Acid in Autistic Children

           N= 347 (261 boys, 86 girls)
                   6 – 12 years old

Dose Given 2g ω3 + 0.5 g ω6
+ 400 mg Ca++ with Vitamin-D (400 iu)

Polyunsaturated/Saturated Fat Ratio = 4.8
Duration of Study 9 – 11 months.
                                                     TKA 21
Metabolic Pathways of the Omega-3 and Omega-6 Fatty Acids
  Omega-3 Fatty acids             Omega-6 Fatty acids
   α-Linolenic acid                         Linoleic acid
        18:3n-3                                  18:2n-6
                        δ-6-desaturase
  Stearidonic acid                          γ-linolenic acid
       18:4n-3                                   18:3n-6



        20:4n-3
                                            Dihomo-γ Lenolenic acid
                        δ-5-desaturase            20:3n-6


 Eicosapentanoic acid
                                            Arachidonic acid
        20:5n-3
                                                  20:4n-6


        22:5n-3                              Adrenic acid
                         δ-4-desaturase           22:4n-6

  Docosahexanoic acid
        22:6n-3                                  22:5n-6
       Fatty Acid Level in Autistic Populations (nmole/ml)
                             6 – 18 years; mean 14 years

                                        Control (n = 56)                Autistic (n = 262)
ά-Linolenic (18:3n3)            1.2 - 4.1 (3.7 ± 1.1)             1.1 – 5.8 (2.9 ± 1.0)
Eicosapentaenoic (20:5n3)                   1.8 - 22.4 (13.2 ± 6.6)           1.2 - 14.8 (8.3 ± 2.7)
Docosapentaenoic (22:5n3)                   23 – 69 (47.4 ± 15.4) 24.5 - 46.7 (34.7 ± 13.9)
Docosahexaenoic (22:6n3)                    30 – 144 (69.4 ± 17.4)21.2 - 70.7 (44.3 ±16.2)

Linoleic (18:2n6)                       64 – 154 (116.2 ± 32.1)            90 - 231 (165.3 ± 29.8)
Gamma Linolenic (18:3n6)                0.9 – 3.0 (1.9 ± 0.10) 2.3 – 8.9 (5.1 ± 2.4)
Dihomo- γ-Linolenic (20:3n6) 18.3 – 41.6 (25.6 ±10.3)          30 – 78 (55.6 ± 20.2)
Arachidonic (20:4n6)                    120 - 247 (179.2 ± 35.0)           167.2 – 300.4 (265 ± 122)
Docosadienoic (22:2n6)                  0.5 – 2.0 (1.1 ± 0.07) 0.8 - 4.6 (3.3 ± 0.4)
Docosatetraenoic (22:4n6)               7.4 – 106 (55.7 ± 16.8)            7.2 – 99.6 (52.6 ± 22.4)

Erucic (22:1 n12)                          2.2–10.5(6.3 ± 1.4)              1.7 – 17.6 (12.4 ± 5.4)
Nervonic (24:1 n15)             28 – 74 (53.3 ± 21.5) 27.6 – 90 (56.5 ± 27.2)

Arachidic (20:0)                            1.4 – 11.5 (7.6 ± 2.3)           1.0 – 9.6 (4.4 ± 1.6)
Behenic (22:0)                              5.5 – 40.2 (18.2 ± 6.4)          4.3 – 49.4 (28.9 ± 13.0)
Hexacosanoic (26:0)             1.0 - 9.8 (4.1 ± 1.1) 3.9 – 34.6 (23.4 ± 12.4)

                                                                                                 TKA 23
                  Fatty Acid Level in Autistic Populations (nmole/ml)
                               6 – 18 years; mean 14 years

                                     Control             Autistic        Autistic + EFA
                                     ( n = 56)            (n =262)            (n = 260)

Eicosapentaenoic (20:5n3) 1.8 - 22.4 1.2 - 14.8            2.1 – 39.7
                                    (13.2 ± 6.6)           (8.3 ± 2.7)         (20.2 ± 9.7)
Docosapentaenoic (22:5n3) 23 – 69.0 24.5 - 47.6           26.5 – 98.1
                                    (47.4 ± 15.4)          (34.7 ± 13.9)       (70.6 ± 26.4)
Docosahexaenoic (22:6n3) 30 - 144               21.2 - 70.7          44.2 – 146.5
                                    (69.4 ± 17.4)         (44.3 ± 16.2)        (104.6 ± 45.7)

Dihomo Gamma Linolenic 18.3 – 41.69        30 - 78          25.2 – 96.4
       (20:3n6)                  (25.6 ± 10.3)     (55.6 ± 20.2)      (75.6 ± 28.3)


Arachidonic (20:4n6)                   120 - 247 167.2 – 300.4    130.8 – 220.5
                                       (179.2 ± 35.0)      (265 ± 122)      (146.8 ± 50.7)
     Parental Assessment after Treatment with Fatty Acids

Symptoms                                            Improvement

Abnormal Bowel movement                 80% Improvement (88/106)

Hyper Irritability                               35% Improvement (30/106)

Limited Eye Contact                              40% Improvement (27/106)

Social Withdrawal                     30% Improvement (31/106)

Short Attention Span                             20% Improvement (12/106)

Repetitive Movements, such as, Rocking           35% Improvement (80/106)

Speech Regression                   Significant improvement (61/106)


                     Overall, 68% responded to Essential Fatty Acid
Additional Benefit of Fatty Acid Supplementation
 •   Blood Pressure          4.8/2.2 – 6.1/3.0 mm Hg

 •   Heart Rate                         6 – 14 Beats/Min

 •                                     Plasma         11 – 18%

 •   Nor-epinephrine                   Platelet       18 – 26%
 •

 •   Prostacyclin-I-(PGI2) ( Vasodilation)        14 – 21%

 •   Thromboxane A2 (Pro-Coagulation)             8 – 15%

 •   Leukotrienes (Pro-Inflammatory)              19 – 30%

 •     HDL                                              11 – 20%
 •
 •     LDL
                                                     No Change
                        Conclusion
• Most autistic children have low level of ω3 fatty acid.
• Some autistic children have high level of ω6 fatty acid.
• The ratio of ω3/ω6 can be altered by administration of ω3 & ω6
  fatty acid (4:1 ratio) for 9 -10 months.
• The presence of high arachidonic acid (20:4,ω6 ) in some
  autistic children may be due to the hyperactivity of cPLA2
  which has preference for arachidonic acid clevage at Sn-2
  position
• There was no significant change in the concentration of
  cPLA2 enzyme by supplementing the autistic children with
  EFA (n = 26) for 9 – 10 months.
ARI Survey of Parent Ratings of Treatment Efficacy


                %       % No     %        Number
                Worse   Change   Better   of Reports



                                          626
  Fatty Acids   2%      42%      55%
          Recommendation
• Measure EFA levels in RBC membranes,
  especially if GI or sleep problems
• Supplement with 1-2 g/day of omega’s from
  fish oil and 250-500 mg/day of omega 6’s
  in borage oil (younger children at lower
  dose, teens/adults at higher dose)
• Also give calcium to improve absorption
  (500 mg/day)
                         Conclusion
• Some autistic children will respond to Biomedical
  Intervention

• Success will depend on:
     a. How early the intervention is initiated
       b. Degree of damage on brain structure

• Approx. 46% responded to vit. B6, Mg & Zn
          36% responded to Sulphate
          68% responded to Essential Fatty Acid

                                                  TKA 28
                         Summary
• Vitamins – little difference (but probably needed)
• Vit B6 – many studies show that high-dose B6 helps some
  children and adults
• Minerals – many children need calcium supplement esp. if GFCF
   – iron levels similar to “typicals”, but some need iron
   – Lithium supplement may help many children
• Amino Acids – measure levels of amino acids and possibly
  neurotransmitters, and give customized supplement if needed
• Hair: low toxics in hair, suggesting poor detoxification
• Sulfation: check sulfate levels, supplement if low
• Fatty Acids – most children with autism need fish oil (omega 3)
  with some omega 6 (evening primrose oil or borage oil)
                  Conclusion
Children with autism are “Children with Starving
  Brains and Starving Bodies”
• Many need essential vitamins and minerals
• Some need some amino acids
• Many need essential fatty acids

Balanced diets rich in vegetables, fruits, and protein
  are needed
Supplements also needed in most cases, and have
  proven benefit

				
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