Autism, Pigments and the Immune System
Immune System Regulation of Pain and Stress: evidence for the
utilization of chiral substances.
Natural pain killers in the autist.
by Sandra J. Desorgher and Max
Desorgher (c.1999 revised 2001)
First published online at Autism99 Online conference
Introduction "Autism is a
movement disorder at the cellular level"
Circadian
Rhythm "The relationship of pigment metabolism to circadian and
circannual rhythms"
Transthyretin
and xanthophils (lutein)
Correlates
of pathogenesis in autism "The connection between
movement, pigment and known
scientific data on autism"
Part One: Autism and
Affective disorders: New findings in neurochemistry
Galanin "Galanin
may thus be involved in the manifold functions hitherto ascribed to
ascending 5-hydroxytryptamine neurons"
Kynurenine
"A number of neuroactive compounds, the kynurenines, are metabolites
of tryptophan"
Autism a hypoglutamatergic
disorder?
Tetrahydrobiopterin
"Severe tetrahydrobiopterin (BH4) deficiency is a naturally
occurring model of cerebral catecholamine and serotonin shortage"
Galanin & Epilepsy "hippocampal galanin acts as an endogenous anticonvulsant
via galanin receptors"
Autism & Anorexia Nervosa "deregulation of the
serotonergic neurotransmitter system as a common underlying mechanism"
Autism,
Trichotillomania & Seasonal Affective Disorder (SAD) "Oils
and pigments leaving the body through the hair
and hair follicles may be responsible for the
biological responses which result in trichotillomania"
Part Two: Autism - Evolutionary
Perspectives "Syndromes with autism show
purine synthesis defects and/or pigmentation defects"
Brain Structure
"The size of the brain stem and cerebellar
vermis are anatomically altered in autistic children"
Pellagra
"Altered mental status is common in
pellagrins"
The
cytochrome P-450 pathway and its relevance to autism "Lutein is
an aldehyde and an immune response to lutein
could produce a similar interference in P450
lipid peroxidation"
NMDA and NO
The
pterin
factor
Cathepsins
Part Three: Natural pain killers from our immune system "In the autist the substances released back into the body when the macrophage engulfs and removes the pigment can be epoxides, carboxylase and potentially mu opioids."
References
Introduction
Part One & Part Two
Part
Three
Autism is a movement disorder at the cellular level,
involving the immunomodulation of pigment metabolism. At
the cellular level pigments are moved about through a
complex system which explains the relationship of
pigmentation and movement (1); “both pigment
aggregation and maintenance of the CPM
(central pigment
mass) are dynein-dependent processes.
” (2) “dynein is
localized in Purkinje cells of cerebellum
and axons of
central and peripheral nervous systems.”
(4)
“Two of the
most consistently observed biological findings
in autism are increased serotonin levels in
the blood and
immunological abnormalities. A positive
relationship was
observed between elevated serotonin levels
and the MHC
types previously associated with autism.”
(10)
The predominant pathogen that I have identified in my
research as creating a hapten-type immune response is
lutein, I suggest that it is being engulfed and removed
from the body by the cytokine reaction, leading to a
cascade of metabolic responses which is dependent
upon the individual’s genetics, diet and environment (13).
To support this hypothesis, five years of research has
taken place with diagnosed autists from around the world
implementing an individualized lutein free diet. The results
of these efforts are the basis of this paper.
As the full potential of an immune response to a pigment
of this nature is elucidated, it becomes clear that the
co-occurring disorders associated with autism may or may
not involve the immune response. However, these
disorders most often do have a connection to the pigment
metabolism or pigment genetics. (53)
Included in either the evaluation criteria or research on
autism have been behavior, movement, handedness, (29)
speech pathology, eating disorders(32), hearing
differences (33), visual anomalies (60) as well as the
alternative diagnoses of Prader-Willi Syndrome (40), Rett’s
Syndrome and the co-occurring disorders of
Hypomelanosis of Ito (34, 35, 36), Angelman Syndrome
(37,38,39), Anorexia (30, 31), Tuberous Sclerosis (41),
Usher’s type I and type II, trichothiodystrophy (45), light
chain storage disorder or Scotopic Sensitivity Syndrome,
abnormal tryptophan metabolism (46), circadian rhythm
disturbances as in sleep disorders, Circannual rhythm
disturbances as in Seasonal Affective Disorder (47),
trichotillomania (47), blindness and retinal abnormalities
(48,49), ear discharge (52), vitiligo, adenylosuccinate
lyase deficiency, xerophthalmia, auto-immunity, Raynaud’s
phenomena, Hartnup’s Disease (50), Phenolketonuria (59),
Cytochrome P450 (P for pigment) abnormalities as well as
diseases with some similar clinical as well as laboratory
findings such as Xeroderma pigmentosum (42).
The relationship of pigment metabolism to circadian and
circannual rhythms was first described in our book (13):
‘Many parents of autistic children are now
familiar with
the pineal gland for its role in melatonin
secretion. Less
familiar is the pineal gland’s function as
a regulatory gland
to environmental stimuli, metabolism,
immunity, adrenal
glands, behavior and brain chemistry. The
pineal gland
could be the connecting link in current
theories, research
and treatments for autism. A very important
feature to
note about the pineal gland is that the
pineal gland is not
protected by the blood brain barrier.’
I have mentioned
that ‘carotenoids are not essential to the human diet’ ref
(AA) however, the pigments perform regulatory actions
which can include the role of lutein as the serotonin
regulator. Serotonin and melatonin are both indoleamines.
‘John Panskepp Ph.D. in his article “Melatonin The Sleep
Master”shares with us the role of melatonin to coordinate
our “SCN Clock”. “This clock-like control
center is situated
in two small clusters of neurons at the
base of the brain
called the suprachiasmatic nuclei (SCN)
which, as the
name implies, are situated directly above
the optic
chiasm, the place where half the nerves
from each of our
eyes cross over to the opposite halves of
our brains. The
many output pathways from the SCN control
practically all
behavioral rhythms that have been studied,
from feeding
to sleep. When both nuclei are destroyed,
animals scatter
their behavior haphazardly throughout the
day instead of
maintaining a well-patterned routine of
daily activities.”’
(55)
‘An unrecognized type of receptor in the
eye's retina must
detect light and help set the body's
circadian rhythm
clock.(BB) Two proteins found in the retina
may be those
previously unknown receptors, which help
regulate daily
rhythms of sleep and activity, hormone
release, appetite,
and other functions. A team of researchers
report in two
papers published that mice lacking normal
rods and cones,
types of light-sensitive receptors on the
retina, are still
able to use light to reset their circadian
clocks. (CC)
‘Researchers led by Dr. Gijsbertus T.J. van
der Horst of
Erasmus University in Rotterdam, the
Netherlands, began
their research by studying two retinal
proteins, the
“cryptochromes”Cry1 and Cry2. These
proteins
are very
similar to proteins that regulate the
day/night cycle of
plants. The team theorized that they might
also play a
role in establishing circadian rhythm in
animals. Mice
deficient in both Cry1 and Cry2 displayed a
complete loss
of normal daily rhythm, according to the
investigators.’ “In
mammals the retina contains photoactive
molecules
responsible for both vision and circadian
photoresponse
systems. CRY1 is expressed at high level in
the SCN and
oscillates in this tissue in a circadian
manner. These data,
in conjunction with the established role of
CRY2 in
photoperiodism in plants, lead us to
propose
that
mammals have a vitamin A-based photopigment
(opsin)
for vision and a vitamin B2-based pigment
(cryptochrome)
for entrainment of the circadian clock.”
(61)
Transthyretin and xanthophils (lutein)
"Transthyretin (TTR) in plasma is
associated with yellow
compounds. Their properties differ, and in
the chicken
protein a major yellow compound has
recently
been
identified as a carotenoid, lutein, also
called xanthophyll.
The human TTR derivative has
chromatographic
and
spectral properties identical to a yellow
photochemical
degradation product of biopterin and a
spectrum like that
of the pterin aldehyde.”(62)
“Histologic, biochemical, and spectral
absorption data
suggest that the yellow color is due to a
xanthophyllic
pigment, lutein, that is distributed in all
retinal layers
internal to the outer nuclear layer, with
greatest
concentration in the outer and inner
plexiform layers.
Clinically absent in newborns, the pigment
gradually
accumulates from dietary sources and
appears
to serve
both as an optical filter, by absorbing
blue light and
reducing chromatic aberration, and in a
protective
capacity, preventing actinic damage.”
(64)
“Transthyretin, a protein synthesized
and
secreted by the
choroid plexus and liver, binds thyroid
hormones in
extracellular compartments. This binding
prevents
accumulation of thyroid hormones in the
lipids of
membranes, establishing extracellular
thyroid hormone
pools for the distribution of the hormones
throughout the
body and brain”. (66) (69)
“Localization of retinol binding protein
(RBP) and
transthyretin (TTR) may indicate a role in
the transport
and distribution of retinol and thyroid
hormone,
respectively, from yolk to embryo prior to
establishment of
the circulatory system.” “Protein
proportions
(transthyretin and transferrin) increased
until about 3
years of age and decreased from then on.”
“Studies
on the physical-chemical properties of
these hybrid TTRs
will help to understand the pathogenicity
associated with
TTR.” “A low molar ratio of retinol binding
protein to
transthyretin indicates vitamin A
deficiency
during
inflammation.”(71-74)
“Carotenol esters in human skin may be
formed by
reesterification of xanthophylls (lutein)
following
absorption. Also, very small amounts of
esters may
circulate in the blood and subsequently
accumulate in
tissues such as skin."(75)
Small blister-type eruptions and mosquito bite like bumps
on the skin have been reported with picture
documentation from autistic children beginning the lutein
free individualized dietary protocol. It is my hypothesis
that these prurigo type eruptions are simply agglutination
of carotenol fatty esters being removed naturally through
the skin. That the elimination of the pathogen, lutein,
allows for the utilization of these same type fatty esters
which are entering the digestive system with
non-pathogen containing carbohydrates thus accounting
for the alleviation of the blister-type skin eruptions
reported consistently in those who had experienced this
occurrence.
Correlates of pathogenesis in autism
As we consider the results of an immune response which
identifies a pigment such as lutein as non-self and
produces a cytokine reaction we can follow the
possibilities for outcome of this reaction to the area of
the brain referenced in the autism research., “ loss of
cerebellar Purkinje and granule cells
occurring early in
brain development and an immature
development of the
limbic system.”(14) To fully
identify
the possibility of this
immune system response and state that autism is a
manifestation of symptoms brought about by this reaction
the connection between movement, pigment and known
scientific data on autism must be shown. Therefore the
relationship between the purkinje neuron cells, dynein and
pigment must exist. “Immunohistochemical
experiments
have demonstrated that dynein is localized
in Purkinje
cells of cerebellum and axons of central
and peripheral
nervous systems.”(4) This coupled
with the data which
‘show that dynein is involved in the homogeneous
distribution of dispersed pigment’ (2) should be adequate
to justify the potential of the hypothesis.
“Microtubules
serve as a rail on which motor proteins,
such as kinesin
and dynein superfamily proteins, convey
their
cargoes.”(15)
There must also be shown the relationship between these
factors, purkinje cells and pigment, and their relationship
to the immune system. “Polypeptide
subunits
from these
microtubule-based motility factors were
detected on
phagosomes.”(16)
This information must fit within the knowledge database
thus collected in relationship to autism. “Ahlsen
says that
GFAP is elevated in all cases of autism or
autistic-like,
whether child or adolescent. This was 47
out of 47 cases,
which to me means 100%. In autism the
levels
remain at
sometimes three times the normal level.”
(13,17,18) “Aryl
sulfatase works chemically rather opposite
PST, and I had
wondered last year if maybe a problem in
aryl sulfatase
would lead to not enough sulfate around to
power the
PST enzyme, which is the scenario described
by Rosemary
Waring’s study of PST in autism.”(13,18,19,20)
It has been indicated that neurofilament antibody is a
consistent marker for autism. The neuroglial cells are of
three types: astrocytes and oligodendrocytes (astroglia
and oligodendroglia), which appear to play a role in myelin
formation, transport of material to neurons, and
microcytes (microglia), which phagocytize waste products
of nerve tissue. Called also glia. (21) So, if the types of
neuroglial cells associated with myelin formation are not
effected, as can be indicated by CSF testing, then we are
left with the neuroglial cells which are associated with
phagocytosis. One type of phagocyte cell is the
macrophage. In the brain this is called myelinophage, in
the liver kupffer cells. The primary function of these cells
are to break down and remove substances the immune
system marks as ‘non-self’. In studies dating back to 1952
(22) carotenes, bilirubin, methemoglobin and the levels of
these and other pigment wastes in amniotic fluid have
been used as a marker to determine the fetal
environment. Elevated bilirubin is a consistent marker in
infants later diagnosed with neurological impairment.(23)
Bilirubin is said to remain in the brain once it has reached
this destination. However, I believe that with the autist,
the immune trigger is pigment and that the phagocytosis
is the immune system’s attempt to remove the hapten
from the brain through the Cerebral Spinal Fluid, thus loss
of granule cells (14). Research into the phagocytosis of
the pigment metabolites (pterins, carotenoids) and the
improvement for many using dietary intervention removing
the pigments from their diet leading to improvement and
‘symptom free’ results (13) has produced some of the
most dramatic case histories available. (24, 39)
Additional evidence to support the linking of this data can
be included from further research on autism and the
co-occurring disorder tuberous sclerosis (25) “Altered
patterns of gangliosides in the CNS might
reflect
important correlates of pathogenesis in
autism.” (27) This
information also has the potential to elucidate the
intriguing connections between the known and suspected
co-occurring genetic disorders and autism, especially
genetic disorders associated with pigmentation. (44) (28)
More recent reports identifying autism as “an affective
disorder treatable with antidepressants
such as Prozac
(fluoxetine)”(1) have failed to
include the information
identifying the co-occurring “abnormalities
in CSF
(cerebral spinal fluid) which have been
reported in
OCD.”(2) “The
prolactin response to d-fenfluramine was
significantly increased in OCD patients
compared with
controls. The disparate results of studies
of 5-HT
(serotonin) neuroendocrine function in OCD
make it
unlikely that disturbances of brain 5-HT
function play a
central role in the pathophysiology of OCD.”
(3) “Results
indicate that galanin exerts an inhibitory
effect via an
increase in K+ (potassium) conductance in
5-hydroxytryptamine neurons by acting on a
postsynaptic
receptor. In addition, galanin at low,
possibly physiological
concentrations enhances the inhibitory
effect of
5-hydroxytryptamine at the cell soma level.
Galanin may
thus be involved in the manifold functions
hitherto
ascribed to ascending 5-hydroxytryptamine
neurons, for
example in mood regulation.”(4)
These factors may finally
be the evidence needed to elucidate autism as an immune
system regulated response. (5, 26, 51, 53)
Galanin
“The effects on 5-HT release in vivo are
most likely
mediated by a galanin receptor in the
dorsal
raphe. The
implications of these findings are
discussed
in relation to
the role of acetylcholine in cognitive
functions in the
forebrain and the role of the raphe 5-HT
neurons in
affective disorders.” “A recent study has
shown
that ventral hippocampal galanin plays a
role in spatial
learning and that it has an inhibitory
effect on basal
acetylcholine release.” “Inhibition of
cholinergic
transmission by cosecreted GAL may be
enhanced under
certain conditions.” “Galanin-like
immunoreactivity and
galanin receptors are found in dorsal root
ganglion (DRG)
cells and in dorsal horn interneurons,
suggesting that this
neuropeptide may have a role in sensory
transmission and
modulation at the spinal level. Expression
of galanin or
galanin receptors in the DRG and spinal
cord are altered,
sometimes in a dramatic fashion, by
peripheral nerve
injury or inflammation.” “Overall, galanin
appears to
have inhibitory effects in the central
nervous system,
causing in most cases a potassium-mediated
hyperpolarization accompanied by a decrease
in input
resistance. Other actions include a
reduction in
presynaptic excitatory inputs and an
interaction with
other applied neurotransmitters. These
effects are robust
and long lasting in most cases.”(5-10)
Some studies already have identified: “The
effects of
fenfluramine (hydrochloride) [an SSRI] on
the behaviors of
autistic children. Videotaped data favored
the subjects
while on placebo. The implications of this
research make it
difficult to recommend fenfluramine as a
treatment for
autism.”(11)
Emotional states and lack of emotional expression in
autism may be a protective measure which cannot be
maintained under conditions of extreme stress, most often
a response to change in routine or environment. Hormones
synthesized from cholesterol: glucocorticoids (cortisol
corticosterone); mineralcorticoids (aldosterone );
androgens (testosterone, estrogens, and progestins).
Some symptoms of metabolic problems in the adrenal
glands are: in the medulla - increased secretion of
catecholamines, hypertension, excessive sweating,
blanching or flushing of skin, tachycardia, headache,
weight loss, personality changes, signs of increased
metabolism, constipation, postural hypotension; in the
cortex, when increased secretion of cortical hormones
occurs, one of a variety of syndromes may occur:
Cushing’s syndrome (buffalo hump/moon face), muscle
wasting, osteoporosis, decreased glucose tolerance,
atherosclerosis, and systolic hypertension.
Inositol, like choline, also exists in cells as a phosphatide.
Current research indicates that inositol lipids appear to be
intimately involved in Ca mediated control of cell functions
by hormones and other ligands, in cell proliferation, and in
the attachment of enzymes to the plaza membranes.
Stearic and arachidonic acid esterified represent the
major fatty acids in phosphatidylinositol of mammalian
tissues. And, current research indicates that each form of
inositol may have distinct, unique biologic activity. A list
has been summarized by Mitchell in “Modern Nutrition in
Health and Disease”: Stimuli whose major effects are to
produce rapid physiologic responses include muscarinic,
cholinergenic, adrenergenic, serotonin, histamine
receptors, angiotensin, vasopressin, and those that bring
about long term stimulation of cell proliferation.
Kynurenine
“Approximately 40% of the kynurenine in
brain is
synthesized there, the remainder having
come from
plasma. Tryptophan loading also increases
kynurenine
formation in the brain and in the
periphery.
Because of
the formation of kynurenine, which competes
for cerebral
transport and cellular uptake of
L-tryptophan, and
because of substrate inhibition on
tryptophan
hydroxylase, excessively high doses of
tryptophan may
actually decrease the production of
cerebral
serotonin
and 5-hydroxyindoleacetic acid.”(15)
Protein intake needs to be carefully considered in autism
just as it is in the co-occurring disorder of PKU
(phenylketonuria). It has been my observation that
following the ‘food guide pyramid’ would provide protein at
3 to 4 times the RDA (recommended daily allowance)
which is higher than the RDI (recommended daily intake).
“It can be concluded, that reduction of
D2-receptors is
due to loss of cholinergic and GABA-ergic
cell bodies in
the striatum or may be a response to iron
deficiency. Low
serotonergic and high kynurenergic activity
may be of
pathogenetic importance.”(16)
“Recent studies have revealed that, in
addition to
serotonin, a number of neuroactive
compounds, the
kynurenines, are metabolites of tryptophan.
Of these,
perhaps the most important is quinolinic
acid, a neurotoxin
that acts at the N-methyl-D-aspartate
(NMDA)
receptor
and whose precursor responsiveness to
tryptophan far
exceeds that of serotonin. In the central
nervous system,
kynurenines, and in particular quinolinic
acid, may
modulate excitatory amino acid
transmission,
and may act
as neurotoxic agents implicated in the
pathogenesis of
several neurologic diseases.”(18)
Lab tests often indicate a need for ubiquinone
supplementation. However, the additional supplementation
can lead to additional neurotoxins. I have found that
removing the lutein and balancing the nutrient intake
results in superior outcomes and is the primary method for
reducing natural opioid production.
Autism a
'hypoglutamatergic disorder'?
“Based on 1) neuroanatomical and
neuroimaging studies
indicating aberrations in brain regions
that are rich in
glutamate neurons and 2) similarities
between symptoms
produced by N-methyl-D-aspartate (NMDA)
antagonists in
healthy subjects and those seen in autism,
it is proposed
in the present paper that infantile autism
is a
hypoglutamatergic disorder.” “Increased
glutamatemia
may be dietary in origin or may arise
endogenously for
several reasons, among others, metabolic
derrangements
in glutamate metabolism perhaps involving
vitamin B6,
defects or blockage of the glutamate
receptor at the
neuronal compartment, or alterations in the
function of
the neurotransmitters transporters.
Increments of taurine,
an inhibitor, is likely compensatory and
calcium
dependent.”(19, 23)
Tetrahydrobiopterin
“6R-L-erythro-5, 6, 7,
8-Tetrahydrobiopterin (6R-BH4) is
known as a cofactor for the hydroxylases of
phenylalanine, tyrosine and tryptophan and
also as a
cofactor for nitric oxide synthase. 6R-BH4
acts on specific
membrane receptors to directly stimulate
the release of
monamine neurotransmitters such as dopamine
and
serotonin, independently of its cofactor
activity. In
addition, it indirectly stimulates the
release of
non-monoamine neurotransmitters such as
acetylcholine
and glutamate, through activation of
monoaminergic
systems. In this paper, we briefly review
recent
experimental data, which provide new
insights into the
role of 6R-BH4 as a regulator of neuronal
function. We
also discuss the possibility of treatment
by 6R-BH4 of
neuropsychiatric diseases such as
Parkinson's disease,
Alzheimer's disease, depression and
infantile autism.”(20)
“Severe tetrahydrobiopterin (BH4)
deficiency is a naturally
occurring model of cerebral catecholamine
and serotonin
shortage. …Our data indicate immense
hyperprolactinemia
but few other hormonal disturbances in
severe BH4
deficiency.” “Defects in
tetrahydrobiopterin
and a
deficiency of aromatic L-amino acid
decarboxylase,
tyrosine hydroxylase or
dopamine-beta-hydroxylase are
candidate inborn errors for
neurotransmitter
metabolites
screening. This investigation has to be
considered in any
child with motor retardation and
extrapyramidal
signs.”(20-21)
What percentage of individuals diagnosed with autism
have been screened for inborn errors? Subtle
improvements in behavior and decreased anxiety have
been reported consistently when folic acid
supplementation has been included in an autism
intervention regimen.
“Antidepressant treatment effects differ
according to
many variables, including the pre-existing
state of the
organism (e.g. depressed, stressed or
normal), the
species, the duration of treatment and the
particular brain
or peripheral circuits investigated. These
examples
illustrate the complexity found in attempts
to identify a
unitary mechanism of antidepressant drug
action.” (24)
Galanin & Epilepsy
“Thyroid hormone is required for basal and
estrogen-induced expression of anterior
pituitary
galanin.” “We examined the role of
hippocampal
galanin in an animal model of status
epilepticus (SE). We
suggest that hippocampal galanin acts as an
endogenous
anticonvulsant via galanin receptors.
SE-induced galanin
depletion in the hippocampus may contribute
to the
maintenance of seizure activity, whereas
the increase of
galanin concentration and the appearance of
galanin-immunoreactive neurons may favor
the cessation
of SSSE. The seizure-protecting action of
galanin SSSE
opens new perspectives in the treatment of
SE.” (12,13,26)
“An abnormal circadian pattern of
melatonin was found in
a group of young adults with an extreme
autism
syndrome. Although not out of phase, the
serum
melatonin levels differed from normal in
amplitude and
mesor. There appears to be a tendency for
various types
of neuroendocrinological abnormalities in
autistics, and
melatonin, as well as possibly TSH and
perhaps prolactin,
could serve as biochemical variables of the
biological
parameters of the disease.”(30)
“Growth hormone (GH)-releasing hormone
(GHRH)
stimulates GH and slow wave sleep” “It is
now well
established that the balance between the
neuropeptides
growth hormone-releasing hormone (GHRH) and
corticotropin-releasing hormone (CRH) plays
a key role in
normal and pathological sleep regulation.
In addition to
GHRH, galanin, growth hormone-releasing
peptide, and
neuropeptide Y also promote sleep, unlike
ACTH(4-9),
which disturbs sleep.”(31-32)
“Galanin is an important target for
regulation by many
hormones, and we postulate that as a
cotransmitter,
galanin acts presynaptically to modulate
the secretion of
GnRH and GHRH, possibly by altering their
pulsatile release
patterns, which in turn influences the
release of the
gonadotropins and GH from the pituitary.”
(35)
“Changes occur in the GH secretory
pattern under
discrete, pathological conditions, such as
abnormal
growth and dwarfism, diabetes, and
acromegaly, as well
as during inflammatory processes.”(36)
Autism
and anorexia nervosa
“The development of anorexia nervosa in a
high-functioning, early adolescent,
autistic
female is
described. This case raises the issue of
co-occurrence of
childhood-onset disorders sharing the
phenomena of
obsessions and compulsions. The role of
deregulation of
the serotonergic neurotransmitter system as
a common
underlying mechanism in these disorders is
suggested.” “Because of the increase in
public school
programs for severely handicapped children,
teachers are
more likely than ever to be confronted with
serious
medical or psychological problems like
anorexia nervosa. If
programs are to meet the needs of these
children in the
future, service and resource models for the
public school
settings must be developed.”(37-38)
“An example of self-administered gastric
tube nutrition in
a boy aged 15 years with infantile autism
is presented.
The boy would neither eat nor drink in the
normal manner
since the age of eight years and has
gradually
administered tube-feeding himself. This
patient does not
fulfill the international criteria for the
diagnosis of anorexia
nervosa.”(39)
“Most autistic children showed a large
variation of total
sleep time. Forty per cent of subjects
showed 10% or
more on coefficient of variation of total
sleep time. In the
retiring and rising time, many subjects
tended to show
late retiring and early rising.”(41)
Autism,
Trichotillomania and Seasonal Affective
Disorder (SAD)
“Our data indicate that the optical pathway
participates
in prolactin regulation.” “Intraocular
pressure and
prolactin measures in seasonal affective
disorder (SAD).
The SAD women had significantly lower IOP
and PRL
values than the control subjects at all
four time points
measured starting from 4.00 p.m. The
authors
discuss the
implications of the finding of lowered IOP
in relation to
opposing roles of dopamine and serotonin in
prolactin
secretion in SAD.”(43-44)
Both seasonal affective disorder (SAD) and
trichotillomania are reported as co-occurring in autism.
(42) Oils and pigments leaving the body through the hair
and hair follicles may be responsible for the biological
responses which result in trichotillomania.(45)(46) (47)
The hairpulling greatly dimishes with changes in diet and
supplementation. Additionally, changes in hair color and
structure are noted. Eyelash hairs with thick hairbulbs and
dark pigmentation as well as course structure can change
to depigmented hairs. In one instance the symptoms of
co-occurring aldosterism were alleviated in an adult
female autist.
Autism -
evolutionary perspectives
Evolution of the autism disorder most probably is a result
of our own medical breakthroughs. The development of
the original vaccine placing a live attenuated virus inside
a lipid filled chloroplast has forced our immune system to
re-evaluate the potential for a chloroplast (carotenoid
containing plant structure) to harbor a pathogen.
Agricultural changes including the widespread use of
pesticides contributed further to the immune system’s
alert to chloroplasts and pathogens. As the developing
fetal immune system produces it’s first cytokines which
set out to identify a non-self pathogen it is reasonable
that pigments/pterins such as lutein and beta-carotene
are readily available and easily cross the placental barrier.
This would occur at the time of development just past
neural tube closure. Although neural tube closure has
been suggested as a time for the developmental
alterations leading to a diagnosis of autism this slightly
earlier time frame would likely also produce a significant
population with autism and co-occurring spina bifida. This
correlation does not exist. The immune response to a
pigment pathogen would likely result in co-occurring
disorders of purine, pyrimidine, and pigment metabolism.
This correlation does exist.
“Syndromes with autism show purine
synthesis defects
(PSDs) and/or pigmentation defects (PDs)”
. (48) (49) By
continuing to diagnose autism solely on the basis of the
behavioral characteristics we continue to be deprived of
the information which could become available should
screening tests such as that provided to determine PKU
at birth be implemented. This type of diagnostic tool
would further increase the database of information
necessary to establish the connection between autism
and those diseases, disorders and conditions which lead
to inevitable miscarriage, fetal distress and early infant
death. “Disorders in purine and pyrimidine
metabolism may
be difficult to recognize because their
recent description
means many are little known. These
disorders
should be
suspected, particularly where the history
involves siblings,
in anaemia, susceptibility to infection, or
neurological
deficits including autism, delayed
development, epilepsy,
self-mutilation, muscle weakness and -
unusual in children
and adolescents - gout.”(50) “Autism is caused by very
lengthy expansions of (CAG)n, (CGG)n and
(GAA)n
repeats, while schizophrenia results from
much smaller
(CAG)n and (CGG)n repeat expansions.”(48)
Brain Structure abnormalities
“The neuropeptide galanin (GAL) has been
shown to be
located in the pituitary gland and to
modulate the
secretion of several pituitary hormones. In
the human
pituitary, GAL is almost exclusively
located
within
corticotrophs. The possibility exists that
GAL produced by
corticotrophs exerts its action principally
through a locally
mediated paracrine or autocrine mechanism
without being
secreted into the bloodstream.” “Galanin
gene
expression may represent a useful marker for
differentiating the anterior and posterior
cerebellar
lobes.”(51) (52) (53) (54) (55) (56)
“Autism may be one of the first
developmental
neuropsychiatric disorders for which
substantial
concordance exists among several independent
microscopic and macroscopic studies as to
the location
and type of neuroanatomic maldevelopment.
Onset might
be as early as the second trimester.
Discovery of the
etiologies underlying cerebellar
maldevelopment may be
the key to uncovering some of the causes of
infantile
autism.” “The rapid maturation of the
pro-dynorphin
system in the substantia nigra is in
contrast to the
development of the pro-dynorphin system in
the posterior
pituitary where adult-like processing
patterns are not
observed until neonatal day 21”. “The brain
stem
and cerebellar vermis lobules VIII to X
were found to be
significantly smaller in autistic children.
This suggests that
the size of the brain stem and cerebellar
vermis are
anatomically altered in autistic children
and that growth
of the brain stem and cerebellar vermis in
autistic children
is different from normal children.”(11,
58-60)
“Nerve growth factor inhibits
sympathetic
neurons'
response to an injury cytokine: …recent
evidence
suggests that galanin plays a role in
peripheral nerve
regeneration.” “…results suggest that
autism
may
involve a type of structural brain
impairment different from
MR.” “These results suggested that
significant
anatomical changes took place in the
posterior fossa brain
structures in the prenatal period in
autistic children, but
were not progressive.” “Results suggest that
brainstem and vermian abnormalities in
autism were due to
an early insult and hypoplasia rather than
to a progressive
degenerative process.” “Fewer than 35
brains
have
been examined pathologically, none with
modern
techniques. The findings thus far suggest
subtle prenatal
neuronal maldevelopment in the cerebellum
and certain
limbic structures. Abnormalities in
distributed networks
involving serotonin and perhaps other
neurotransmitters
require further documentation.”(62-67)
Pellagra
“The data suggested that ascorbic acid was
rapidly (iron
accelerated) metabolized to
monodehydroascorbate, a
compound that rapidly reacts with tissue
(NADPH) to form
(NADP). This mechanism could reduce tissue
levels of
(NADPH) such that the feed-back control of
tryptophan
pyrrolase enzyme was depressed. The change
in control
level of the pyrrolase enzyme permitted
large quantities of
tryptophan to be converted into the
kynurenine pathway
products, and a smaller quantity for the
serotonin
pathway. This mechanism could contribute to
the
abnormal tryptophan metabolism found in
chronic
pellagrins with dementia.”(70)
“Serotonin metabolism is pellagra:
Altered mental status is
common in pellagrins.” “Particular features
of clinical
pellagra: The follow-up of an important
number of
patients during the last three decades has
shown a
substantial difference between the clinical
description of
pellagra in the 40's (the triad:
dermatitis,
diarrhea,
dementia) and its clinical aspects today:
sun-exposed
teguments revealing erythema and rapidly
becoming
pigmented and parchment like, dried,
parched
lips, angular
stomatitis, lead like sclera fine cornea
vascularization;
gastro-intestinal disturbances:
constipation, unjustified
diarrhea, strange migratory abdominal
feelings
accompanied by ubiquitous dysesthesias.
Other
characteristics of this form of disease
are: unexpressive
look, continuously concerned, thoughtful,
anxious or
frowning, labile mind, headaches, insomnia.”
(71-72)
“Metabolic photodermatoses are diseases
in which
photosensitization reactions, often
revealing, are due to
the accumulation in the skin of an
endogenous
chromophore as a result of a congenital
(porphyria) or
acquired (pellagra) enzymatic disorder.”
(73)
“Pellagra was once a major cause of
three
behaviorally
different mental disorders -
schizophreniform,
manic-depressive-like, and phobic neurotic
- plus drying dermatoses, autonomic
neuropathies, tinnitus, and fatigue. In
this preliminary
study all three of the corresponding
present-day mental
diseases are found to exhibit,
statistically, the same
pellagraform physical disorders but to
ameliorate not so
much with vitamins as with supplements of a
newly
discovered trace omega-3 essential fatty
acid (w3-EFA),
which provides the substrate upon which
niacin and other
B vitamin holoenzymes act uniquely to form
the
prostaglandin 3 series tissue hormones
regulating
neurocircuits en block. Since present-day
refining and
food selection patterns, as well as pure
corn diets,
deplete both the B vitamins and W3-EFA, the
existence of
therapeutically cross-reacting homologous
catalyst and
substrate deficiency forms of pellagra are
postulated, the
first contributing to the B vitamin
deficiency epidemics of
50-100 years ago, the second to the more
recent
endemic ‘Diseases of Western Civilization’
which express in
certain genetic subgroups as the major
mental illnesses of
today.”(74)
“About 1900, modern food selection and
processing
caused widespread epidemics of the B
vitamin
deficiency
diseases of beriberi and pellagra which,
for genetic
reasons, often expressed as different
diseases ranging
from bowel and heart disease to dermatoses
and
psychoses. But the B vitamins merely help
convert
essential fatty acids (EFA) into the
prostaglandin (PG)
tissue regulators and it now turns out
that, through
hydrogenation, milling and selection of
w3-poor southern
foods, we have also been systematically
depleting, by as
much as 90%, a newly discovered trace
Nordic
EFA (w3)
of special importance to primates and sole
precursor of
the PG3(4) series, even as a concurrent
fiber deficiency
increases body demand for EFA. Since
substrate EFA is
processed by many B vitamin catalysts, an
EFA deficiency
will mimic a panhypovitaminosis B, i.e., a
mixture of
substrate beriberi and substrate pellagra
resembling
vitamin beriberi and pellagra but
exhibiting
as even more
diverse endemic disease. It is an
assumption
that our
dominant diseases are unrelated to each
other.” (75)
“Although one of the first biological
treatments of a major
psychiatric disorder was the dietary
treatment of pellagra,
the use of diet and dietary components in
the study of
psychopathology has not aroused much
interest. …data
indicate that low serotonin levels alone
cannot cause
depression. Folic acid deficiency causes a
lowering of
brain serotonin in rats, and of
cerebrospinal fluid
5-hydroxyindoleacetic acid in humans. There
is a high
incidence of folate deficiency in
depression, and there are
indications in the literature that some
depressed patients
who are folate deficient respond to folate
administration.
Folate deficiency is known to lower levels
of
S-adenosylmethionine, and
S-adenosylmethionine is an
antidepressant that raises brain serotonin
levels. These
data suggest that low levels of serotonin
in some
depressed patients may be a secondary
consequence of
low levels of S-adenosylmethionine.”(76)
“A 9-year-old girl presented with a red
scaly rash
confined to sun-exposed areas which started
at 2 years
of age and had the appearance of pellagra.
Investigation
of urinary tryptophan metabolites following
an oral
tryptophan load, showed increased excretion
of
kynurenine and kynurenic acid but reduced
excretion of
3-hydroxy-kynurenine, xanthurenic acid and
N1-methyl
nicotinamide. These results indicated a
defect in the
hydroxylation of kynurenine, an important
reaction in the
synthesis of the nicotinamide nucleotide
coenzymes, NAD
and NADP, from tryptophan. The patient went
on to
develop severe colitis and psychological
changes. All her
symptoms responded to treatment with
nicotinamide.” (77)
The Cytochrome P
(Pigment)-450 pathway and its relevance to autism
Ascorbic acid is a requisite in the diet of man. It may act
as a reducing agent in enzymatic reactions, particularly
those catalysed by hydroxylases. Vitamin C is a water
soluble vitamin crucial for the maintenance of connective
tissue, wound healing and scar formation. Deficiency is
known as scurvy and symptoms include dry skin, bleeding
and swollen gums, bone pains, dental cavities and mouth
sores.
The effects of scurvy are due to a failure of the
hydroxylation of proline residues in collagen synthesis and
the consequent failure of fibroblasts to produce mature
collagen. Problems with collagen synthesis are not
associated with autism or the primary conditions
co-occurring with autism. This absence of problems with
collagen synthesis is likely a result of certain advantages
which may be afforded the autistic population based on
the immune diversity which results after the immune error
(lutein reaction) occurs. Other advantages may include that
autists do not present with the manifestation of specific
conditions or diseases for which they have been identified
as 'at risk' based on current genetic studies. How the pigment
pathways are altered individually and for the population
have resulted in need for identifying supplements which
can improve outcome. Common supplements such as
ascorbic acid and niacin may result in unexpected adverse
reactions for this 'abnormal' population. Closer study should
reveal that supplements designed to address the specific
needs of this population may include NADH, SAMe and
some hormones (VIP, galanin), enzymes and medications
(oral tiaconazole) not yet available.
“At all concentrations of ADP and collagen
used
the
autistic children consistently exhibited
diminished platelet
aggregability; the differences, however,
did not reach
statistical significance.”(78)
“To determine the role of major
chromophores of the
human retinal pigment epithelium (RPE) in
photooxidation
of ascorbate, we monitored
spectrophotometrically rates
of ascorbate depletion, induced by blue
light, in
suspensions of human RPE melanin,
melanolipofuscin and
lipofuscin and in preparation of pigmented
and
nonpigmented bovine RPE cells. The results
clearly show
that melanin is the key retinal pigment
responsible for the
photosensitized oxidation of exogenous
ascorbate.
Because in the absence of oxygen, no
measurable
oxidation of ascorbate is observed, it can
be concluded
that melanin acts as an electron transfer
agent. Biological
implications of this study remain unclear;
however, the
formation of oxygen-reactive species that
accompany
melanin-mediated photooxidation of
ascorbate
may
represent a potential risk to the RPE that
should be
minimized by yet unknown cellular
mechanisms.” (80)
“The role of NADPH--cytochrome P450
reductase and
cytochrome P450 in NADPH- and
ADP--Fe3(+)-dependent
lipid peroxidation was investigated. The
results suggest
that NADPH- and ADP--Fe3(+)-dependent lipid
peroxidation involves both
NADPH--cytochrome
P450
reductase and cytochrome P450.”(81)
“polyunsaturated fatty acids are
initially reduced to form
alkoxyl radicals, which then undergo
intramolecular
rearrangement to form epoxyalkyl radicals.”
(82)
“The inactivation of cytochrome P450 2B4
by aldehydes in
a reconstituted enzyme system requires
molecular oxygen
and NADPH and is not prevented by the
addition of
catalase, superoxide dismutase, epoxide
hydrolase,
glutathione, or ascorbic acid. We conclude
that
inactivation of P450 by aldehydes occurs
via homolytic
cleavage of a peroxyhemiacetal intermediate
to give an
alkyl radical that reacts with the heme.”
“Using a
reconstituted system comprised of purified
NADPH-P450
reductase, P450 and isolated microsomal
lipid or pure
L-alpha-phosphatidylcholine diarachidoyl, a
mechanism
has been proposed for the iron-independent
microsomal
lipid peroxidation and its prevention by
ascorbic acid.
Apparently, ascorbic acid prevents
initiation of lipid
peroxidation by interacting with P450
Fe3+.O2.-.” (84)
“SOD activity has increased in the
mammals which is
accompanied by a decrease in the
L-gulonolactone
oxidase LGO activity. In fact, there has
been an inverse
relationship between LGO and SOD in the
progress of
evolution. SOD activity is markedly high in
the guinea pig,
flying mammal, monkey and man, the species
those lack
LGO. The inverse relationship between LGO
and SOD is
also observed in rats during postnatal
development, that
is when the new born rats are exposed to
high
concentration of atmospheric oxygen. Recent
results from
our laboratory indicate that ascorbic acid
is specifically
needed for protection of microsomal
membranes against
cytochrome P450-mediated lipid peroxidation
and protein
oxidation, where SOD is ineffective. Data
presented in this
paper also indicate an apparent
tissue-specific correlation
among LGO activity, P450 level and O2.-
production
during phylogenetic evolution.”(85)
Lutein is an aldehyde and an immune response to lutein
could produce a similar interference in P450 lipid
peroxidation thus identifying the need for the minimal
intake of vitamin C in the autist and the abnormal or
detrimental effects of megadosing with vitamin C.
"Human cytochrome P (pigment)450's are
pro-oxidants in
iron/ascorbate-initiated microsomal lipid
peroxidation.” (86)
“Excessive cystine and histidine
increased serum
cholesterol and alpha-tocopherol. Excessive
cystine and
methionine increased liver and kidney
alpha-tocopherol
and ascorbic acid. Excessive tyrosine and
phenylalanine
caused a marked increase in serum copper and
ceruloplasmin activity, whereas excessive
cystine,
methionine, and histidine caused a decrease
in the
ceruloplasmin activity. Excessive histidine
increased liver
cytochrome P-450, whereas excessive
tyrosine
markedly
decreased liver cytochrome P-450.”(87)
Recent investigations into the use of diet as a therapy for
autism has resulted in high numbers of children with
autism being placed on restrictive diets. Abnormal levels
of cystine and histidine are common in their lab profiles
prior to implementing the lutein free diet.
“There are extreme contradictions in the
question of an
optimum intake of vitamin C. Ideal RDA
should be based
on studies with increasing vitamin C doses
in which the
efficiency of the ascorbate-dependent
systems would be
correlated with the vitamin C concentration
in the target
tissues. On the basis of correlations of
the hepatic
vitamin C levels in guinea pigs with the
rate of cholesterol
degradation and the activity of microsomal
detoxification
systems, it is suggested that such intake
of ascorbic acid
is optimum that ensures a maximum body pool
and
maximum steady-state levels of vitamin C in
the tissues.
It is probable that in healthy adults, such
a dose ranges
from 100 to 200mg and that in stress
conditions, it
exceeds 200mg per day.”(88)
“Long-term or high-dosage consumption of
vitamin C may
play a role in calcium oxalate kidney stone
formation. …
Oxalate excretion increased by about 350%
during
ascorbate ingestion before haematuria.
Ascorbate
concentrations also increased dramatically
but appeared
to reach a plateau maximum. Increasing
calcium excretion
was accompanied by decreasing potassium and
phosphate
values. Clinicians need to be alerted to
the potential
dangers of large dose ingestion of vitamin
C in some
individuals.”(92)
"Ascorbic acid inhibits lipid
peroxidation but enhances DNA
damage in rat liver nuclei incubated with
iron ions: In this
report we studied DNA damage and lipid
peroxidation in rat
liver nuclei incubated with iron ions for
up to 2 hrs in order
to examine whether nuclear DNA damage was
dependent
on membrane lipid peroxidation. The
chain-breaking
antioxidants butylated hydroxytoluene and
diphenylamine
(an alkoxyl radical scavenger) did not
inhibit DNA damage.
Hence, this study demonstrated that
ascorbic
acid
enhanced Fe(II)-induced DNA base
modification which
was not dependent on lipid peroxidation in
rat liver
nuclei.”(93)
It has been my experience with the implementation of
individualized dietary intervention and autism that
excesses are equally as deregulating as deficiencies.
Some individuals do require higher intake and/or
supplementation of specific nutrients based on lab work
and testing identifying individual exposures to toxins, such
as heavy metals. From the case files, a significant
regression has been observed with an excessive
consumption of vitamin C. In one instance an 8 year old
male child reached symptom free status and was
declassified. Almost 2 years later symptoms returned. The
only change identified was an increased intake of dietary
vitamin C. With a return to the RDI levels of vitamin C (up
to 60 mg supplementation with additional dietary intake of
50 to 150 mg) his symptoms were once again alleviated.
(22)
NMDA and NO
“Cytokines and NO production could play a
role in
regulation of the blood-ocular barrier
function and of the
development of ocular inflammation.”(94)
“The data from purification, ligand
binding, reconstitution
and immunochemical studies indicate that
there is a group
of small molecular size proteins (30 to 70
kDa) that form
what appear to be NMDA receptor complexes.
Based on
cell biological studies of the expression
and localization of
one of the subunits of this complex, the
glutamate-binding subunit, it appears that
this putative
NMDA receptor plays a key role in neuronal
sensitivity to
NMDA and in neuronal survival in early
development.
However, brain neurons quite clearly
express
another
family of proteins which have all
functional
characteristics
of an NMDA receptor plus a great degree of
variability
that can account for the varieties of NMDA
receptors
found in brain. If brain neurons are indeed
expressing two
very diverse families of proteins that
function as
glutamate/NMDA receptors, this must be an
indication
that either there is a very selective
expression of one of
these forms in specific neurons or neuronal
compartments,
or that one of these forms of the receptor
plays an
important role in unique functions of the
cell, such as
synaptic plasticity or neurodegeneration.”
(95)
“This study determined if hippocampal
AMPA and NMDA
subunit immunoreactivity (IR) in temporal
lobe epilepsy
patients was increased compared with
nonseizure
autopsies. In humans, these findings
support
the
hypothesis that glutamate receptor subunits
are
increased in association with chronic
temporal lobe
seizures, which may enhance excitatory
neurotransmission
and seizure susceptibility.”(96)
“N-methyl-D-aspartate (NMDA)-activated
glutamate
receptor subunits are invariably expressed
in neurons,
although NMDA-activated currents have been
recently
described in Bergmann glia. To date, the
NMDA receptor
subunit 2B (NMDAR2B) was thought not to be
expressed
in adult cerebellum. Our findings suggest
that Bergmann
glial cells contain the molecular machinary
to synthesize
the NMDA receptor 2B subunit. The role of
physiological
NMDA receptors in the interaction between
Bergmann glia
and Purkinje neurons is not yet known.”
(97)
“Our findings suggest a common mechanism
for galanin
and NOS (NADPH-diaphorase activity)
expression.”
“When galanin (10(-8) M) and the
cholinergic
agonists
muscarine and nicotine (10(-6) M) were
tested on the
same astrocyte, all three compounds induced
a
hyperpolarization, suggesting a
colocalization of functional
galanin and cholinergic receptors on the
glial
membrane.”(98-99)
“NMDA induces NO release from primary
cell cultures of
human fetal cerebral cortex: We and others
have
previously reported that
N-methyl-D-aspartate (NMDA)
induces nitric oxide (NO) release from the
rat cerebral
cortex in vivo. It is crucial to determine
if this
phenomenon also exists in human brain
tissue. This is the
first time, to our knowledge, that
extracellular NO
concentration evoked by exogenous NMDA has
been
directly measured from the fetal human
cortical
neurons.”(100)
The behavior associated with NO production in the autist
is maniacal laughter. This symptom can be understood as
the protective mechanism in a metabolism with elevated
levels of free radicals. (101) (102) (103)
The pterin factor
The combination of elements which make up the simplest
pterin and simplest amino acids are nearly the same.
When we consider the additional carbons and hydrogens
(isoprenoids, oil residues, PUFA fats) which are part of the
metabolites of the fruits and vegetables, then the
complexity of the plant storage system and the response
of the human immune system to these foods becomes
more clearly understood. The most understood immune
system responses are to amino acids. Recently there have
been carbohydrate receptors identified. (105). The
carbohydrate receptor is located on the C5a amino acid
chain cytokine present on cell walls which is an immune
component which can trigger many immune system
responses. It may be significant that serine has been
identified as part of the cytokine amino acid chain. It is
possible that the similarities between the identified pterin
[of which there are many i.e. biopterin, neopterin: pterin
is the simplest] and the structure of the cytokine could
provoke an immune system glitch (like a computer virus).
The immune system is needed to identify ‘self’ or ‘not self’
and ‘not self’ is then removed. By identifying a substance
which is nearly identical to the amino acids contained in
the cytokine there could be the consequence that the
immune system determines “Self is not self”and this could
lead to an immune compromised host.
In August of 1996, lutein pigment was finally identified as
a pterin (pigment) in Stockholm, Sweden. The pterin
connection has been elucidated through the research into
PKU, a disorder of tetrahydrobiopterinhydrofolic acid
metabolism which is listed as one of 5 conditions likely to
precede an autism diagnosis. Viral exposure and vaccine
reactions are additional factors associated with or
possibly leading to an autism diagnosis. High levels of
cytokines (immune components which identify non-self
pathogens) leads to an increase in production of
macrophage cells (the immune components which engulf
and remove pathogens) which produce antibodies to
antigens. So an increased reaction to vaccines and
viruses could be a result of elevated levels of
macrophages, and identifying the reason for the elevated
levels of macrophages (cytokine reaction to a hapten)
and the knowledge that pterins can act as haptens (106)
leads to a scientific theory with supportable evidence for
the removal of specific dietary components to determine
outcome.
The lutein pigment is a carotenoid pigment widely
distributed in fruits, vegetables, meat fats and some
grains. ‘Biopterin is a hapten without
antigenicity’ (107)
The disorders of pterin metabolism most scientifically
investigated to date are PKU, Senile dementia of the
Alzheimer’s type, Methylene tetrahydrofolate deficiency,
Down’s syndrome, Parkinson’s disease, some types of
depression, aluminum and dialysis dementia.
Cathepsins
Just as our gastrointestinal system relies on digestive
enzymes to perform its functions so the immune system
components utilize their own special digestive enzymes
called cathepsins. “Cathepsin B: A
lysosomal
cysteine
proteinase which hydrolyzes proteins, with
a specificity
resembling that of papain. The enzyme is
present in a
variety of tissues and is important in many
physiological
and pathological processes. In pathology,
cathepsin b has
been found to be involved in demyelination,
emphysema,
rheumatoid arthritis, and neoplastic
infiltration.” (108)
“The existence of anomalies of
tryptophan's metabolism is
certainly shown in many diseases, however
the true
physiopathogenetic meaning of these
metabolic
alterations is not yet specified.
Particularly it is not
definite if these alterations are the cause
of diseases,
which they appear in, or if they are
secondary
alterations.”(109)
“The serotonin system has been
implicated
as a factor in
some cases of autism since the finding in
1961(Himwich et
al) of elevated serotonin in the blood of
patients with
autism.”(110)
To date the lack of understanding of the immune systems
role in regulation of tryptophan has been a major problem.
The duel role of tryptophan as a pigment containing amino
acid as well as its role in binding to pigments makes this
substance a target for immune system regulation in a
metabolism which has identified a pigment as a pathogen.
The specific ways in which the immune system
manipulates the tryptophan leads to variations most
commonly referred to as autism spectrum disorders.
Further complications in understanding this interaction
occurs as a result of the hapten nature of the
pigment/pterin lutein.
“Cathepsin G purified from neutrophil
granules triggered
platelet aggregation and serotonin release
independent of
arachidonic acid metabolites and
platelet-activating
factor formation.”(111) Cathepsin G,
similar to
chymotrypsin is one of the cathepsin proteases which
have been proven to function in HLA class II mediated
antigen presentation.
“Because the major neurologic
complication is a peripheral
neuropathy and the causes of this condition
are myriad,
pyridoxine may cause neuropathy only in
patients with a
pre-existing susceptibility to this
condition.” (116) We
have not been given the assessment to identify
individuals with the pre-existing susceptibility. “When
evaluating vitamin B-6 requirements or
status in humans,
protein intake must be considered.”(117)
Favorable reports on B6 supplementation influence
caregivers to utilize this information. Identifying the
nutritional status of the individual could result in a more
positive outcome should supplementation be chosen as a
form of intervention. It has been my experience that
supplementation with B6 could be greatly reduced or
eliminated entirely in individuals diagnosed with autism
who choose to implement the pigment restricted/balanced
nutrient intake dietary intervention. Thus far autism
therapies have primarily consisted of treating symptoms.
The elucidation of a specific cause as well as the
interventions that treat that cause, are likely to produce
superior outcome, whereas attempting to manipulate the
metabolism without considering the nutritional status of
the individual and cause of symptoms can lead to
“diarrhoea, drowsiness, nausea, vomiting and
agitation”(118) as well as itching,
blister type eruptions,
panic, headache, profuse sweating, stress, refusal to eat
etc.
In order to achieve optimal metabolism in the autist the
regulation of amino acids must involve providing the
essential fatty acid interaction. (120) (121) “The data
obtained suggest that kynurenine and
serotonin pathways
of tryptophan metabolism were intensified
in vitiligo.”(124)
“Urinary excretion of
indolyl-3-acryloylglycine (chromogen
of the so-called Kimmig's light band) in 15
normal subjects
was highly significantly increased in
June-September
("summer") against the November-April
("winter")
collection in the same subjects.”(125)
“Many specific gene products are
sequentially made and
utilized by the melanocyte as it emigrates
from its
embryonic origin, migrates into specific
target sites,
synthesizes melanin(s) within a specialized
organelle,
transfers pigment granules to neighboring
cells, and
responds to various exogenous cues. A
mutation in many
of the respective encoding genes can
disrupt
this process
of melanogenesis and can result in
hypopigmentary
disorders. Vitiligo, in contrast, results
from the destruction
and removal of the melanocyte in the
epidermis and
mucous membranes.”(126)
My case history files contain many instances of
co-occurring vitiligo with autism and additionally reports
of familial instances of vitiligo.
“Epoxide carboxylase from the bacterium
Xanthobacter
strain Py2 is a multicomponent enzyme
system
which
catalyzes the pyridine nucleotide-dependent
carboxylation
of aliphatic epoxides to beta-ketoacids as
illustrated by
the reaction epoxypropane + CO2 + NADPH +
NAD+ -->
acetoacetate + H+ + NADP+ + NADH. The
stereoselective
dehydrogenases of the Xanthobacter epoxide
carboxylase
system were able to substitute for the
corresponding
components of the N. corallina system when
using (R) and
(S)-epoxypropane as substrates, and vice
versa. These
results provide the first demonstration of
the involvement
of stereospecific dehydrogenases in
aliphatic epoxide
metabolism and provide new insights into
microbial
strategies for the utilization of chiral
organic
molecules.”(123) This shows the
pyridine utilization of the
bacterium in the manufacture of chiral organic molecules
using epoxide carboxylase. In the autist the substances
released back into the body when the macrophage engulfs
and removes the pigment can be epoxides, carboxylase
and potentially mu opioids. Thus the basic understanding
of how the autist can manufacture opioids such as
dermorphin and deltorphin. Reducing the naturally
manufactured pain killers in the autist requires reducing
the number of immune cells produced in response to the
incoming pathogen as well as dietary opioids. This requires
a lutein free diet.
The peptides generated by the immune macrophage cells
can be opioid peptides. Changes made to the diets of
autistic individuals which may reduce specific food derived
opioids will not eliminate the natural potential of the autist
to manufacture opioid peptides: “In vitro
human
hemoglobin hydrolysis by cathepsin D was
investigated. It
confirmed that hemoglobin could appear as a
precursor of
some bioactive peptides following
proteolytic
degradation.” “Using this method, a kinetic
study of
hemorphins appearance has been undertaken.
In this
paper, we also evidenced the generation of
VV-hemorphin-7 from globin by peritoneal
macrophages.”(1-2)
Increasing the autists potential to produce natural
carboxyl proteinase can result in a decrease in the
production of the immune macrophage generation of
natural pain killers. This can result in a more normal
sensitivity to pain stimuli. To accomplish this the autist
must have adequate digestive enzymes and regulated
intake of dietary protein as well as the removal of the
immune pathogen – lutein. (3)
Immune activation of neuroactive kynurenines directly
effect the availability of essential nutrients revealed as
low or deficiency levels of some B-vitamins, particularly
riboflavin. Dietary regulation of food substances which
increase the conversion of tryptophan to kynurenine must
be regulated. And, adequate intake of B-vitamins will
produce results which are not obtainable with
supplementing the B-vitamins and no dietary regulation.
(4) Elevated levels of free radicals from immune activation
produced by dietary intake of food substances identified
as pathogens in the autist contribute significantly to the
production of toxic and neurotoxic substances. (5)
To accomplish the strategies to augment mitochodrial
function requires that the dietary pathogens be identified
and eliminated, the nitrogen containing amino acids be
regulated and the metabolism functioning at optimal level
with healed mucosal linings and the recognized essential
nutrients present and available. When the pigment
pathogen is eliminated and testing confirms improved
gastrointestinal functioning resulting from dietary
intervention and dietary sources of natural enzymes are
supplied the results are increase in cognitive abilities and
a reduction or elimination of the behaviors which
characterize autism:
“Mitochondria are vulnerable to a wide
array of
endogenous and exogenous factors which
appear to be
linked by excessive nitric oxide
production.
Strategies to
augment mitochondrial function, either by
decreasing
production of endogenous toxic metabolites,
reducing
nitric oxide production, or stimulating
mitochondrial
enzyme activity may be beneficial in the
treatment of
autism.”6
Improvements in cognitive abilities and a decrease in
behaviors which are measured to identify autism are the
results of dietary intervention which removes the immune
triggering pathogen. Superior results can be obtained
when additional therapies are used in conjunction with
dietary intervention. Presently under study is the use of
secretin. Further research which confirms the potential for
sources of galanin regulation will increase the opportunity
for including these substances or products in the
therapeutic regimen. One such product which has this
potential is Growth Hormone Releaser.
“Nitric oxide synthase (NOS)-containing
neurons are found
in many loci throughout the central nervous
system,
which include the cerebral cortex, the
cerebellum, the
hippocampus, and the hypothalamus. NO plays
a very
important role in control of neuronal
activity in all of these
areas by diffusing into neurons where it
activates soluble
guanylate cyclase (sGC) leading to
generation of cyclic
guanosine monophosphate (cGMP) and
cyclooxygenase 1
leading to generation of prostaglandins.
Both of these
active agents are involved in mediating the
actions of NO,
the first gaseous transmitter. In the
cerebellum, NO is
extremely important and it is also thought
to mediate
long-term potentiation in the hippocampus.
Various stresses and corticoids have
been
shown in
monkeys and also in rodents to cause
neuronal cell death.
This may be via the stimulation of glutamic
acid release,
which by N-methyl-D-aspartate (NMDA)
receptors causes
release of NO, which can lead to neuronal
cell death. In
the hypothalamus,. NO stimulates
corticotropin-releasing
hormone (CRH), prolactin releasing factor,
growth
hormone-releasing hormone (GHRH), and
somatostatin,
lutenizing hormone-releasing hormone
(LHRH),
but not
follicle stimulating hormone-releasing
factor (FSHRF)
release. In situations of increased release
of NO in the
hypothalamus, it could cause neuronal cell
death.
Following bacterial or viral infections,
toxic products of
the ineffective agents, such as bacterial
lipopolysaccharide (LPS), circulate to the
brain, where
they induce interleukin-1 and iNOS mRNA and
synthesis.
After several hours delay, massive
quantities of NO are
released. Induction of iNOS occurs in the
choroid plexus,
meninges, in circumventricular organs, and
in large
numbers of iNOS neurons in the arcuate and
paraventricular nuclei. The large amounts
of NO released
by iNOS may well produce death not only of
neurons but
also glial. Repeated bouts of systemic
infection even
without direct neural involvement could
result in induction
of iNOS in the central nervous system and
lead to large
fall out of neurons in hippocampus to
impair
memory,
hypothalamus to decrease fever, and
neuroendocrine
response to infection, and could play a
role in the
pathogenesis of degenerative neuronal
diseases of aging,
such as Alzheimers. The largest induction
of iNOS occurs
in the anterior pituitary and pineal
glands.
The damage to
the pituitary could also impair responses
to stress and
infection, and the release of NO during
infection could be
responsible for the degenerative changes in
the pineal and
diminished release of melatonin, an
antioxident, and
consequently, an antiaging hormone, that
occur with
age.”7
Improving the characteristic eating disorders recognized
to accompany an autism diagnosis can be accomplished
with dietary intervention and supportive therapies.
Improving the signals which regulate eating behaviors can
result in superior outcome. Therapies used in conjunction
with dietary intervention such as squeeze therapy,
massage therapy, secretin infusion and GHR 15 may result
in the improved signaling needed to reduce abnormal
eating behavior and increase normal eating behavior.
Sensory integration and behavioral intervention therapies
can play a contributing role in improving the feeding
practices of the autist and therefore increasing the
opportunity for providing a nutrient rich diet.
“Patients with GH deficiency appear to
have impaired
psychological well being and potentially
significant
neuropsychiatric manifestations, such as
lack of
concentration and memory impairment.
However, it
is unknown whether this impairment in
psychological well
being is associated specifically with GH
deficiency or is
due to another factor associated with
hypopituitarism.” 18-19
“Indoloyl-Acriloyl Glycine (IAG) has
many
but not all of the
properties of a peptide. The two major
elements of the
molecule are joined by way of a peptide
bond. One of the
elements (glycine) is an amino-acid whereas
the other
element, the indole part of the molecule,
although almost
certainly derived from the amino-acid
tryptophan is not,
strictly speaking, an amino-acid. The
compound is,
therefore peptide like or “peptoid”in
nature. For the
purposes of our interpretation, we assume
that the other
peaks which appear in our profiles, between
17 and 30
minutes are similarly peptide (or peptoid)
in nature and
that many of these are derived from the
incomplete
breakdown of food.”21
Elevated levels of IAG are also found in Hartnup’s and
SAD. The inconsistency in the diets of the autists and
sometimes very self-limited or intentionally restricted diets
might indicate that a source other than dietary is
responsible for the unusual peptides or peptoids. The
tryptophan component indole is also a pigment and
tryptophan metabolism irregularity is a consistent
biochemical marker for autism.
Neurotransmitter irregularities in the autist is a strong
indication that the ACTH/cortisol axis is abnormal and that
stress and immune function contributes to the altered
metabolism in the autist. (22)
Removing the immune triggering pathogen may be
insufficient to improve GH release or regulation in the
autist. Additional therapies are being used and reported to
influence hypothalamic and hypophyseal regulation. Food
deprivation or the potentially nutrient deficient diets of
the autist following a restricted or self limited diet has not
been adequately researched. (35) The manufacture of
drug-like opioids by the immune system macrophages or
derived from food contribute to the behavioral
characteristics which define the disorder of autism.
“The chimeric peptides C7, M15, M32, and
M40, which
have been reported to antagonize some
actions of
galanin, all produced varying degrees of
depression of
evoked EPSCs.”(40) Stimulating
galanin production with
squeeze therapy or using growth hormone releasing food
supplements in conjunction with decreasing the levels of
naturally produced opioids in the autist should be given
further attention. Dietary intervention is the most
comprehensive tool available for use in treating autism.
(AA) (Modern Nutrition in Health and Disease, 8th edition
Pg. 298)
(BB) April 16th issue of Science
(CC) Imperial College of Science Technology and Medicine
in London, UK,
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7. Possible Association of the Extended MHC Haplotype
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25. Giant cells in cortical tubers in tuberous sclerosis
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Yamanouchi, H., Ho, M., Jay, V., Becker, L.E.; Department
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26. Circulating autoantibodies to neuronal and glial
filament proteins in autism; Singh, V.K., Warren, R.,
Averett, R., Ghaziuddin, M.; Department of Psychiatry,
University of Michigan, Ann Arbor 48109-1065, USA;
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27. Gangliosides in cerebrospinal fluid in children with
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28. I kappaB alpha physically interacts with a
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50. Additional research has identified markers so
consistent that they have been identified in up to 100%
of the study groups, including research by Paul Shattock:
“Some of you are aware that in the last year our listmate,
Paul Shattock, has been able to identify the "peak" that
shows up in urinary profiles performed by his lab and by
Dr. Reichelt's lab in Norway. In a paper presented in
Durham this spring, Paul explained that this substance is
IAG, indolyl-acriloyl glycine. Dr. Reichelt reported finding
this substance in 96% of 200 children with autism he has
tested in the last four years. This peak has been used by
them as a marker for the opiate excess problem, but
curiously, Paul told me that this substance has been seen
before associated with something called Hartnup Disease.”
(From the Internet)
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52. Out of pure curiousity, what does it mean when they
have a constant brownish black discharge.....my son has
had that every since he had tubes put in at 10 months
old. He is almost eight. Even after the tubes were
removed at four or five years old, he still has this
discharge...it's thick and waxy...he has only had two ear
infections in the last 12 months or so,...the ped. never
seems concerned. I always have wondered
about it though. Any idea's? Sincerely, Terry J. (from
the
internet)
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63. The evolution of gene expression, structure and
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