Dr. Steve Hinder Consultant Psychiatrist April 23rd 2008.

Dr. Steve Hinder

Consultant Psychiatrist

April 23rd 2008

Sulphate and Autism

10 years ago, very few biological markers

↑ platelet serotonin in 30%

Proxy for reduced serotonin brain function

Borne out by success of SSRI’s and Risperidone

Rosemary Waring found low sulphate as a marker in autistic children

Pursued links with Allergy Induced Autism group, finding migraine in mothers

Foods that worsen behaviour contain PHENOLS

Phenols are metabolized by Sulphation, catalyzed by Sulphotransferase enzyme (PST)

PST is low in migraine

RESULTS INAUTISTIC CHILDREN

Very low Sulphate levels (10% of normal)

High Cysteine levels PST very low in individuals with food reactions

PST normal in other children

CYSTEINE AND SULPHATE VALUES IN AUTISTIC ADULTS AND CONTROLS

Mean

CysteineMean FreeSulphate

Ratio

Autism(n=20)

0.58 0.30 1.93Severe LD

(n=10)1.41 0.91 1.55

Mild LD(n=7)

1.57 0.94 1.68Controls(n=60)

0.37 6.34 0.06

METHIONINE

S-Adenosylmethionine

S-Adenosylhomocysteine

HOMOCYSTEINE

Cystathionine

Serine

CYSTEINE

Cysteine Sulfinate(3-Sulfino alanine)

3-Sulfino pyruvate

SO22-

SO32-

SULPHATE

Food + Protein Catabolism

Cystine

Taurine b-mercaptopyruvate

ThiosulphateFood

Catabolismof sulphate

macromolecules

Thiocyanate Cyanide

minorpathway

Rhodanese

CysteineDioxygenase

SulphiteOxidase

Glutathione

Adenosylhomocysteine

hydrolase

Cystathionase

CystathionineSynthase

B6

B6

B6

B6

B6

Molybdenum

SulphiteReductase

Mn2+

B12Folate

Methyl-transferase

Betaine

Dimethyl-Glycine (DMG)

Methyl-transferase

Polyamines

Homocysteicacid

(TMG)

Gaining New Knowledge

Autism Research Unit

Durham conferences

Allergy Induced Autism

Hyperactive Childrens Support Group

Informal networking

Andrew Wakefield

Developmental histories

Taking parents more seriously

Dietary history

Immunity

Vaccines

Eventually brave enough to give advice !

People Practice

OPIATE EXCESS THEORY OF AUTISM

Reduced crying when isolated Decreased pain sensitivity Insistence on sameness Increased stereotypical behaviour Fearlessness Abnormal social play Unusual body postures Changes in eating patterns Increase in seizures Social withdrawal Hyperactivity Lack of response to sensory stimuli

All signs ofopiate addiction

or withdrawal

EXOGENOUS OPIOIDS

Intact peptides can cross mucosa (Gardner, 1983)

Gluten and Casomorphin fragments have opioid activity

Peptide peaks in urine of autistic patients have opioid activity (Shattock, Reichelt)

Abnormal intestinal permeability in autism (D'Eufemia et al, 1996)

Effect of gluten and casein-free diets?

CAUSES OF LEAKY GUTSTrauma CytokinesImmunodeficiency/AllergyGut flora imbalance or CandidaAnkylosing Spondylitis or ArthritisLow GlycosaminoglycansMeasles/MMR ?? Learning disability?

GLYCOSAMINOGLYCANS (GAG's) + CANDIDA

GAG's required for gut wall integrity Normally sulphated - produces negative

charge Lack of sulphate interrupts normal

production Candida no longer repelled Candida very common in autism Known to deplete sulphate Positive feedback ?

Recent Trends

- Increased incidence, was 1 in 2000 now 1 in 100- majority feel due to better diagnosis and wider definitions, but significant minority feel genuinely increasing- “Active but odd” group now more prominent ?- Less LD than you would expect (20% rather than 80%)- Children with autism seem to be making extraordinary progress

If autism is increasing, what might the cause be ?

- “Leaky Gut syndrome”- MMR/other vaccines- Overuse of antibiotics Candida or clostridium- Pesticides or organophosphates- Food additives (Eg. MSG, Aspartame)- Lowered immunity/increased autoimmune disease - Mercury toxicity- Unusual viruses or other infections- Opiate use during delivery- Chemicals in environment

A Model for Causation in Autism

LEAKYGUT

ALTEREDOPIATE

RECEPTORFUNCTION

EARLY INSULTIN DEVELOPMENT

GENETICCONDITION

CLOSELYINTERACTS

WITHSEROTONIN

GENETICALLYDETERMINEDLOW DPP IV ?

CANDIDAMMR

SULPHATE+ OTHERS

ALTEREDIMMUNITY

CO-INHERITEDWITH OTHER

BIOCHEMICALDIFFERENCES

BRAIN MORESUSCEPTIBLETO INSULTS

DRUGTREATMENTS

ALTERED BIOCHEMISTRY

Possible causes of autism

Leaky Gut Biochemical Causes

Gluten/Casein freeAnti-CandidaSulphate replacementDigestive enzymesSecretinGlutamine

Cod liver oil/vitamin AEvening Primrose oilZinc/mineralsMegadose B6 + MgDMG or TMGAllergiesMSG/Aspartame free

Gluten/Casein-free Combination of both works best May be easiest to start with casein, but often not enough Persevere with casein for at least 2 months ? Persevere with gluten for at least 6 months ? May get “cold turkey”, esp. with casein Constipation/MMR history suggests gluten May previously have craved these substances, or avoided Sunderland urine test can be non-specific May work better in younger children May be less effective if clear genetic cause Improvement in 40% on combined diet ? NEED TOTAL ELIMINATION (in most, but not all) Re-exposure can cause severe behaviours

Sulphate

• No blood test available• May be low in 90% of children• Causes diarrhoea if taken orally• Can try slowly increasing epsom

salt baths• Glucosamine sulphate• Cranberry juice• Cut out citrus fruit, apples,

vinegar, tomatoes• Avoid paracetamol• Overlap with Feingold diet for

hyperactivityEpsomSalts

Treating Candida

• Suggested by early antibiotic use• Difficult to test (we all have it)• NYSTATIN oral drops• Low sugar• Capryllic acid + other natural products• Probiotics (acidophilus, Lactobacillus, Bifidus)• Possibly low yeast diet• Can get massive die-off reaction

Essential fatty acids

• Cod liver oil, may be vitamin A, omega 3• Evening Primrose oil, omega 6 (GLA)• Flaxseed (Linseed) oil• Zinc may aid absorption• Good for hyperactivity/concentration• May improve eye contact• Caution with EPO in epilepsy

Other supplements

• Good evidence for high dose B6, Magnesium• May tie in with sulphate pathways• DMG/TMG may have additive effect

METHIONINE

S-Adenosylmethionine

S-Adenosylhomocysteine

HOMOCYSTEINE

Cystathionine

Serine

CYSTEINE

Cysteine Sulfinate(3-Sulfino alanine)

3-Sulfino pyruvate

SO22-

SO32-

SULPHATE

Food + Protein Catabolism

Cystine

Taurine b-mercaptopyruvate

ThiosulphateFood

Catabolismof sulphate

macromolecules

Thiocyanate Cyanide

minorpathway

Rhodanese

CysteineDioxygenase

SulphiteOxidase

Glutathione

Adenosylhomocysteine

hydrolase

Cystathionase

CystathionineSynthase

B6

B6

B6

B6

B6

Molybdenum

SulphiteReductase

Mn2+

B12Folate

Methyl-transferase

Betaine

Dimethyl-Glycine (DMG)

Methyl-transferase

Polyamines

Homocysteicacid

(TMG)

Other supplements

• Good evidence for high dose B6, Magnesium• May tie in with sulphate pathways• DMG/TMG may have additive effect• Can all improve core social symptoms• Digestive enzymes promising (CCK connection,

DPP IV)• Secretin not yet safe• Other vitamins/minerals may help• Glutamine can heal leaky gut?• Monosodium glutamate/Aspartame important• MANY OTHER THINGS BEING TRIED (Methyl B12,

Glutathione)

Things to consider

• Early treatment probably best• Interventions can also help ADHD/LD• Is mercury important?• Are UK and USA children different? – cysteine

levels seem paradoxical• DAN protocol – Is it humanly possible?• Dilemma re single versus many treatments, as

may be synergistic• Do not take lightly (do have biological action),

but give dietary interventions a try• Therapeutic alliance with parents