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Handout for the NAS (Surrey Branch) Conference
University of Surrey, Guildford, 8th June 2002
Paul Shattock; Paul Whiteley, University of Sunderland. England.
The Development of a Logical System for the Implementation of
Biomedical Therapies in Autism Spectrum Disorders
The notion that food derived peptides with opioid activity are involved in the
causation of autism spectrum disorders arose from two main areas.
Panksepp, in 1979, noted the similarities between the symptoms of autism
and those seen in people who had used morphine like substances for a
considerable period of time. Morphine acts by mimicking the activity of
substances which occur naturally in the brain. These substances are peptides
known generically as “endorphins”. These peptides consist of short chains of
amino-acids and it is likely that morphine and its derivatives produce their
opioid activity because they are the same shape as these peptides. They fit
the receptors precisely and stimulate them in the same way as the naturally
occurring peptides.
Many parents had observed that certain foods exacerbated the symptoms of
autism and, as a result, had eliminated them from the diet of their children.
They claimed that this ameliorated their problems. The two foods most
consistently reported were the proteins gluten (from wheat and other cereals)
and casein (derived from bovine and other milks). Proteins are made up of
very long chains of amino-acids which are arranged like beads on a string.
During the process of digestion, the large proteins are broken down into
smaller peptides before being further broken down into the amino-acid
components. Some of these peptides obtained from gluten and casein are
very similar to those endorphins found in the brain. These are known as
casomorphins and glutemorphins and the structures are now well established.
It was hypothesised that these peptides could, under certain circumstances,
be absorbed from the intestines into the blood stream. If that occurs, the
majority would be deposited in the urine where we and other workers
throughout the world have been finding and identifying them for some years
now. The brain is protected from such compounds circulating in the blood by
a “blood-brain-barrier” (BBB). However, this is not totally impervious and a
proportion of these peptides will cross into the brain. They may either have
direct opioid effects there or could form a substrate for the enzymes which
would, under normal circumstances, break down the endorphins once they
had done their job. Either way, the effects would be the same. There would
be increased opioid activity.
These opioid peptides act as neuro-regulators or modulators. They can affect
the function of all the main types of neurones in the brain and cut down (or
enhance) transmission in all the systems. The consequences will include
perceptual and cognitive problems; changes in behaviour, in mood and
emotional response. Opioid peptides are also implicated in the functioning of
the immune system and, at certain times, in brain development and
maturation.
When children are about two years of age, they have many more neurones
than they actually require throughout life. Those that are not required are
“pruned”. This is a part of natural development for many systems which would
have been of use to mankind in past millennia but are no longer beneficial.
The systems which are not employed are destroyed. The main agents
involved in this pruning are the opioid peptides. If the levels are too high at
this critical time, the pruning that occurs will be abnormal. It could be over or
under zealous depending upon the peptide concentrations available. The
abnormalities of structure reported by Bauman and Courchesne are entirely
consistent with this concept. The importance of early intervention, which can
only follow early diagnosis, is obviously immensely important.
However, the brain is much more plastic than had previously been believed.
Although there is little evidence to suggest regeneration of actual cells occurs,
it is clear that the brain is a dynamic entity and that new connections and
circuits do form when the insulting peptides are removed from the system.
Removal of these peptides could also encourage more normal
neurotransmission to occur.
Any use of dietary intervention must, like all other interventions, be seen as a
part of an overall treatment plan. There is absolutely no point in taking the
breaks off the car (removing the peptides) unless there is fuel in the tank (in
terms of intensive education and therapy). The best results are seen in those
children where therapy combines these two elements.
Structures of the Peptides
Some of these peptides have now been isolated from the urine and identified
precisely. Bovine casomorphins and glutemorphins have been shown to be
present using a number of techniques (HPLC; immuno-assays; Mass
Spectrometry etc). These are not human products and, given the quantities
involved, can only have been derived from ingested food.
There are also a number of other closely related compounds which have
been isolated. Reichelt has identified some novel compounds which act as
selective serotonin uptake stimulators; Friedman has identified powerful
opioid substances which could be derived from intestinal bacteria. During our
investigation of these compounds we located a marker compound which was
present in elevated levels in some 80% of people with autism (in the UK) and
associated disorders. This compound, Indolyl Acryloyl Glycine (IAG) is
present in the urine of each of us but people with autism excrete considerably
higher levels.
It should be noted that the presence of this compound in high levels, although
characteristic of autism spectrum disorders (ASD), is not absolutely
diagnostic. It appears in similar levels in about 20-25% of asymptomatic
controls and in about 50% of first degree family members (UK figures). This
would appear to confirm some genetic significance. It is well known that there
are increased incidences of associated disorders (ADD; ADHD; Speech and
Language problems) in our families and, perhaps, a predisposition to select
certain careers (Engineering; Architecture; Computer Technology etc) and it
may be that some of the milder characteristics associated with autism would
be beneficial in these occupations!
Our theoretical model may be illustrated visually in Figure 1.
Figure 1
In Figure 1, the stars represent peptides. Figure 1A represents the normal
situation. We all produce low levels of peptides when we digest proteins.
Small quantities will pass from the intestines into the bloodstream and thence
on to the Central Nervous System (CNS). Figure 1B represents the situation
where there are excessive levels of peptides in the urine. This could be for a
variety of reasons but the result will be the passage of elevated levels of
peptides to the CNS. There may be, (as in Figure 1C) excessive permeability
of the intestines which will encourage passage of peptides. Some of the
reasons for this are given below but this could also result from a lingering
infection in the intestinal wall. It is suggested that this permeability could be
the result of a sub-acute intestinal measles infection resulting from a
vaccination programme that includes multiple infections with attenuated
strains of the diseases. In Figure 1D, there is excessive permeability of the
Blood Brain Barrier. This could result from physical injury or infectious or
other diseases.
The process by which intact peptides can pass from the intestines to the brain
and affect development and activity may be complex but the notion is, in
itself, comparatively simple.
IAG is an abnormal metabolite of the amino-acid “tryptophan”. The limited
amount of available evidence suggests that IAG itself is comparatively
innocuous (although this may not prove to be the case). As tryptophan is
being converted into IAG, it is converted to Indole Acrylic Acid (IAcrA) and it is
this compound which may have the more serious consequences. It is a planar
and very reactive molecule and could have a variety of effects in the body.
We speculate that it becomes involved in the lipids that make up cell
membranes. It could, by replacing fatty acids, become directly incorporated
into the fats themselves but this is not certain. Alternatively (or additionally) it
could become deposited between the lipid layers that make up membranes.
These would, under these conditions, greatly reduce the flexibility of these
membranes (including those surrounding red blood corpuscles). If these
effects do occur (and work is proceeding to test these hypotheses) the
consequence would be greatly increased permeability of the intestinal wall
and of the blood brain barrier. In the presence of this compound, the passage
of peptides from the intestines to the brain would be greatly facilitated.
There may be other reasons for increased permeability of these membranes.
Deficiencies in sulphation processes would cause this and so would severe
infections with yeasts or some other intestinal parasites. Physical damage to
the intestines could be involved. Alternatively, infections of the intestinal wall
could result in this increased permeability.
Inside the intestines themselves, we should look for deficiencies in the
process by which proteins are broken down into amino-acids. We must seek
reasons for the process becoming arrested at the peptide stage. This could
result from:a) the presence of levels of gluten and casein which are beyond the
capabilities of the digestive process in the individual; (remove from diet).
b) a shortage of the natural peptidase enzymes (supplementation directly with
“bromelain” , “Seren-Aid” or “Enzyme-Aid” or encouraging the pancreas to
produce appropriate levels with secretin).
c) insufficient acid in the stomach (betaine hydrochloride supplementation);
d) insufficient co-factors (supplement vitamins and minerals);
e) presence of intestinal parasites such as yeasts, Giardia or worms
(eradicate).
There are factors which may increase the permeability of the intestinal wall
and which will lead us to a number of interventions which could be used to
ameliorate this problem.
a) incomplete sulphation (sulphate, in the form of Epsom Salts (Magnesium
Sulphate) in bathwater or patches; MSM) (removal of phenolic or salicylate
containing foods).
b) inappropriate acids in the membrane lipids (evening primrose oil followed
by other oils (such as fish and flax oils)
c) insufficient nutrients for intestinal wall (glutamine)
There is little that can be done to increase the integrity of the blood brain
barrier but the advisability of utilising combination vaccines where there are
reasons to suspect immune systems which are compromised by immaturity or
other infections must be questioned.
The Sunderland Protocol
The Autism Research Unit’s main objectives are to investigate the biological
mechanisms, which may underlie autism, and the implications these may
have for the development of therapeutic regimes. In the course of this work
we have obtained clinical information, including urinary peptide analyses on
over 7,500 subjects with ASDs and other related disorders such as Chronic
Fatigue Syndrome; Gulf War Syndrome; Obsessive Compulsive Disorder;
Dyspraxia and others. More often than not, as a result of our investigations,
we are requested to advise parents and carers on appropriate interventions.
We would question the ability or the right of anyone, medically qualified or
not, to make recommendations for subjects they have not seen and that they
know only through a series of clinical notes and chemical tests.
We have developed a protocol, "The Sunderland Protocol", which consists of
a sequence of interventions that we feel to be logical and which can be used
with a minimal possibility for adverse reaction. The protocol is divided into
three sections and is based loosely upon the Northern Ireland Peace
Process.
We strongly advise the active involvement of an experienced dietitian (UK) or
nutritionist (US) and the support of a medical practitioner when implementing
these interventions. We would also prefer to see allergy testing for possible
Celiac Disease performed before embarking on this process.
We are of the opinion that even without biological testing, there is sufficient
evidence to support the use of these interventions sequentially. There can be
no guarantees that any particular intervention will benefit any one particular
child. We have been proven wrong so many times in our predictions of
efficacy or otherwise that we regularly introduce the following system for
consideration.
There will be those who opt for a different sequencing (DMG or Yeast
removal first for example). We suggest that people revisit a failed intervention
from time to time and that they test the effectiveness of the interventions they
are using as we have found, repeatedly, that the effectiveness of a particular
intervention will alter with development and with the nature and extent of
other programmes.
THE SUNDERLAND PROTOCOL
(Shattock & Whiteley, (2000)
“CEASEFIRE” - Remove source of bullets
1. CASEIN
2. GLUTEN
- 3 weeks
- 3 months
PRELIMINARY AGREEMENT
3. OTHER FOODS - Food diary (Corn; Soya; Tomatoes; Avocado; Beef et al)
4. TESTING
- Vitamins, Minerals, Amino Acids, Allergies (IgG, IgE)
Supplement as appropriate:
Zn, Ca, Mg, Mb, A, C, B1, B3, B6
5. PARASITIC ORGANISMS - Yeasts, Protozoa, Worms, Bacteria
ACTIVE RECONSTRUCTION
6. SULPHATION ISSUES - Epsom Salts (Internal/External), MSM
7. ENZYME ACTIVITY - Betaine Hydrochloride
8. FATTY ACIDS - Evening Primrose Oil, Fish Oils,Cod Liver Oil (Vit. A), Flax
9. L-GLUTAMINE - Correct Imbalance, Intestinal Nutrient
10. ENZYME SUPPLEMENTATION - Bromelain, Seren-Aid, EnZymAid.
_______________________________________________________________________
11. 5-HYDROXY TRYPTOPHAN (5-HTP) 14. MEGADOSE B6 & Mg
12. PIGMENT-FREE
15. DIMETHYLGLYCINE (DMG)
13. SALICYLATE-FREE
16. SECRETIN
Stage 1 - The Cease-fire.
This involves removal of the guns and the bullets, in this case gluten and
casein for an appropriate period.
Stage 2 - The Preliminary (Good Friday) agreement.
Keeping a diary to look for other dietary insults; consideration of vitamin,
mineral, and allergy irregularities; consideration of other intestinal parasites.
It is our experience that testing is best performed at this stage, after the
removal of the smokescreen caused by the gluten and casein products. We
have found that many of the myriad allergies detected before the exclusion of
these products disappear at this stage whilst others become unmasked.
Similarly, we have found that vitamin and mineral status irregularities may
have dissipated as the intestinal function returns.
Stage 3 - The Active Reconstruction Process.
The ultimate intention must be to re-establish the efficiency of the processes
of digestion and absorption. If this can be achieved, it is conceivable that
dietary regimes could be much less severe. The sequence we propose can
be found on the accompanying page.
This section includes a number of possibilities some of which (DMG and High
doses of Vitamin B6 and Magnesium) have an excellent record. Also included
are other therapies (secretin, for example) which certainly appear promising,
as well as safe, but for which medical support is essential. The use of
severely exclusive diets devoid of phenols (pigments) or salicylates are
placed at this stage purely because they are more intensive and obtrusive
into a normal lifestyle.
Stage 4 – Other Interventions.
We would never suggest that these interventions are the only possibilities.
Many other interventions, which initially seemed ludicrous or without scientific
validation are being utilised by parents who report benefits. Chelation;
Organic Diets; Cranial Osteopathy and many other therapies may yield
benefits.
Some Additional Notes
The use of any of these interventions must be seen as part of a total
programme for each individual child. Such programmes should include
educational, social and health inputs. These interventions are complementary
not alternative.
Do not cease other prescribed medication without the authorisation and
approval of the prescribing physician.
For
further
detailed
information:
visit
our
website
at
http://osiris.sunderland.ac.uk/autism and check out the Sunderland Protocol.
This article is reproduced by kind permission of the author
© Paul Shattock 8th June2002
© for the NAS Surrey Branch 2002.