Mary N. Megson, M.D., F.A.A.P.
Developmental Pediatrician
Pediatric and Adolescent Ability Center
Richmond, VA 23226
Autism may be a disorder linked to the disruption of the
G-alpha protein, affecting retinoid receptors in the brain.
A study of sixty autistic children suggests that autism may
be caused by inserting a G-alpha protein defect, the pertussis
toxin found in the D.P.T. vaccine, into genetically at-risk
children. This toxin separates the G-alpha protein from
retinoid receptors. Those most at risk report a family history
of at least one parent with a pre-existing G-alpha protein defect,
including night blindness, pseudohypoparathyroidism or adenoma
of the thyroid or pituitary gland.
Natural Vitamin A may reconnect the retinoid receptors
critical for vision, sensory perception, language processing
and attention. Autism spectrum disorders have increased from
1 in 10,000 in 1978 to 1 in 300 in some US communities in 1999.
Recent evidence indicates that autism is a disorder of the
nervous system and the immune system, affecting multiple
metabolic pathways.
Autism has been defined by DSM-IV criteria as a childhood
behavioral and neurological disorder with onset prior to
three years of age. Autistic children and adults have qualitative
impairments in social interaction and communication, including
either a delay in or complete lack of language development.
Furthermore, many people with autism engage in restrictive
patterns of behavior including rigid adherence to routines
and/or repetitive motor mannerisms such as hand flapping (1).
Autistic spectrum disorders have increased from 1 in 10,000
in 1978 to 1 in 300 is some US communities in 1999 (2).
Recent evidence indicates that autism is a disorder of the
nervous system and the immune system, and it affects multiple
metabolic pathways.
This study of 60 autistic children and their families suggests
that inserting a G-alpha protein defect, namely the pertussis
toxin in the D.P.T. Vaccine, (3) into genetically at-risk children
causes autism. This toxin separates the G-alpha protein from
retinoid receptors. Those most at risk report a family history
of at least one parent with a preexisting G-alpha protein defect,
exhibited in disorders such as night blindness, pseudohypoparathyroidism
or adenoma of the thyroid or pituitary gland (4).
This hypothesis asserts that treating these children with natural
cis forms of Vitamin A may have the effect of reconnecting the
hippocampal retinoid receptor pathways that are critical for
vision, sensory perception, language processing and attention (5).
Many of these especially vulnerable children have tissue types
of HREs DR 3, DR4, and DR5 (6). These particular tissue types
form the tightest bonds with blocked RAR and RXR retinoid receptors (7).
Autism is a true developmental disorder. Many of these children
are exposed to wheat at nine months, followed by exposure to
the measles antigen at 12 to 15 months (8). The human measles
antibody that is produced cross-reacts with intermediate filaments,
which are known to be important for maintaining tight junctions
and gap junctions between cells, gut mucosal integrity and cell
to cell communication (10)(11).
Many of these children, who need natural, unsaturated cis forms
of Vitamin A found in sources such as cold water fish like salmon,
or cod, liver, kidney, and milk fat, are not getting this in the
modern diet. Instead, they are dependent on Vitamin A Palmitate,
found in commercial infant formula and low fat milk. Unfortunately,
absorption of Vitamin A Palmitate requires an intact gut mucosal
microvilli surface at the right PH, in the presence of bile for
metabolism (12). However, many of these children already have
damaged mucosal surfaces due to unrecognized wheat allergy or
intolerances.
The Role of Vaccinations in G-Alpha Protein Defects
When the live viral measles vaccine is given, it depletes the
children of their existing supply of Vitamin A (13), which negatively
impacts the retinoid receptors. Natural Vitamin A, in the cis form,
is important for activation of T and B cells for long-term immune
memory to develop (14) and is necessary for natural killer cell
function (15). Scrimshaw, et al. (1968) reviewed over 50 studies
of infection and nutrition and wrote, "no nutritional deficiency
in the animal kingdom is more consistently synergistic with infection
than that of Vitamin A" (16).
If artificial Vitamin A Palmitate binds the now free G-alpha
protein, it deactivates by 90% the "off switch" for multiple
metabolic pathways, involved in vision and cell growth, and
disrupts hormonal regulation and metabolism of lipids, protein
and glycogen (17). Measles, mumps and rubella titers are either
significantly elevated or negative, in spite of one or two doses
of the vaccine given to many of these children. Fish oils contain
one retinoid metabolite, alpha 14 hydroxyretroretinol that has a
role in T-cell activation, vision and growth of lymphoblasts (18).
Further research is needed to understand the complete role of
these metabolites in the immune system.
At 18 months of age, when the pertussis toxin is added, as
"lymphocytosis proliferating factor," it creates a chronic
autoimmune monocytic infiltration of the lamina propia in the
gut mucosa (19) and may disconnect the G-alpha protein pathways,
leaving some G-alpha modulated pathways unopposed. Consequently,
the non-specific branch of the immune system is turned on, and
without retinoid switching, cannot be down-regulated. The
metabolic consequences could be far-reaching.
These 60 children and their families reveal possible consequences
of losing the "off-switch" in G-alpha protein modulated pathways
through abnormalities in lipid, glucose and protein metabolism
in hormone regulation and in oncogene suppression and autoimmune
disorders.
Case Studies
Our early experience with treatment with natural cis forms of
Vitamin A in Cod Liver Oil (CLO) in these autistic children,
followed by stimulation of blocked acetylcholine receptors for
neurotransmitters affected with a blockage of G-alpha pathways
in the cell, is promising. There are dramatic, immediate improvements
in language, vision, attention and social interaction in some of
these children, as evidenced by the following case reports.
My earliest evidence came from a ten-year-old boy diagnosed with
autism by DSM-IV criteria (20). The patient?s parents suspect
he has been reading since age four but his inability to
communicate made this unverifiable. Over an eight-year period
of regular visits I had never heard him speak. Standardized
IQ tests revealed moderate mental retardation. His mother
developed night blindness and hypothyroidism in college and
had responded well to Vitamin A and thyroid hormone replacement.
The patient?s mother?s sister was diagnosed in infancy with
gluten enteropathy that had improved on a gluten free diet.
She has had lifelong dry eyes and is night blind (treated
with amber glasses.)
For these and other reasons I started the boy on cod liver oil
(5,000 IU of Vitamin A, given in 2500 IU/b.i.d.) and a gluten
free diet. After one week, he began to sit farther from the
television and to notice paintings on the walls at home. He
had always gone out of his way to follow the sidewalk and
driveway to meet the school bus. On Vitamin A, he began to
run across the grass directly from the front door to the school bus.
After three weeks, he was given a single dose of Urocholine,
an alpha muscarinic receptor agonist, to increase bile and
pancreatic secretions and indirectly stimulate hippocampal
retinoid receptors. It has minimal cardiac effect, is FDA
approved, has been used safely in children since the 1970s
for reflux, and does not cross the blood-brain barrier, unlike
secretin (21). It stimulates post-synaptic cell membranes via
receptors for acetylcholine, a neurotransmitter in the parasympathetic
system.
Thirty minutes after administration of the Urocholine, the patient,
who was sitting in a chair, swung his feet over the side, pointed
to a glass candy jar on my shelf and said, "May I have the red
Jolly Rancher® please" He had read the label on the candy in
the clear jar. These were the first words he had spoken in eight
years, and the first proof that he could read. We took him outside
and he said, "The leaves, the leaves on the trees are green!
I see! I see!" When I asked to take his picture he looked at
the camera, smiled and waved. When he left the office I said,
"See you later." He asked, "What time?"
In this childs case, after several weeks of treatment with
Vitamin A in CLO 3500 IU/day, the Urocholine acted like a switch.
When absorbed, he immediately became socially engaged, made
excellent eye contact, hugged his mother tightly and said,
"I love you so much," looking at her face. At that point we
both realized that this child had a blocked pathway. The
change in language and social interaction was dramatic and
immediate. Yet he reverted to the pre-treatment state of
silence when the dose wore off. On lower daily doses of
Urocholine (12.5 mg bid) along with the Vitamin A, his language
and social interactions have continued to progress, albeit slowly.
I discussed the case with Dr. Bernard Rimland, head of the Autism
Research Institute. He called me later to get permission for a
mother in Kentucky to call me. She was frantic because her
fourteen-week-old infant had stopped making eye contact, began
to stare at lights and fans, stopped cooing and laughing and
no longer turned to sound after early normal development. The
mother reported she was night blind and had irritable bowel
syndrome. By mothers report, the infant was weaned and placed
on standard formula, which was tolerated well. An audiological
evaluation revealed normal auditory brain stem responses and
tympanograms. The child went to a pediatric Ophthalmologist,
who stated the child was farsighted. The exam was otherwise
normal. The doctor was unable to get the infant to track in
daylight, but when he placed an amber screen in front of his
eyes he would easily track all objects.
I spoke with the child?s pediatrician who obtained a Vitamin
A level. The value was 26 ug/dl (normal is 30-90 ug/dl). I
instructed the mother to add 0.85 cc of CLO (Vitamins A/D) of
cod liver oil to a bottle that night, and 0.85 cc CLO to a
bottle at 11 am the next day. When the baby woke from his nap,
he was back to normal, smiling, laughing, turning to sound,
and tracking objects. As a developmental pediatrician, I have
followed his development. By his mothers reports, his receptive
and expressive language, cognition, fine and gross motor skills
are all normal for his age of nine months. He has remained on
0.85 cc CLO without significant increase in his vitamin A and
D levels. He has had further immunizations without regression.
In both cases the improvement was so dramatic that it seemed
we were dealing with a blocked pathway, presumably in the hippocampus
or amygdala, with an intact cortex.
Effects of Blocked Retinoid Receptors
In December 1998, Ron Evans et al., at Cornell, isolated RAR-B
and RXR receptors in the hippocampus in mice, which, when blocked,
created long-term potentiation and depression of neurotransmission (22).
The hippocampal pathways are important in spatial learning and memory.
When mice with these blocked receptors were put in a maze, and then the
maze was changed, these mice never learned to accommodate for the change.
However, both normal mice and blind mice easily learned the
new pathway with subsequent trials. Evans reported that these
mutations affected cognitive functions such as learning and
memory and reports that the mice acted as if "they had significant
visual perceptual deficits." (23)
Of note, the hippocampus, on staining and electromagnetic exam,
revealed no anatomic abnormalities. Presynaptic and post-synaptic
responses were normal (24), so the authors concluded that the
changes involved changes in inhibition or potentiation at the
cellular level. The authors suggested that lack of retinoid
signaling did not affect neuronal development (25).
Six of the autistic children I have tested also have had hypothyroidism.
Recently reported was the association of central hypothyroidism
when RXR receptors were blocked (26). These RXR receptors are
nonspecific members of the superhormone receptor system, and
have been identified as calcitonin/secretin, thyroid and retinoid
receptors specific for binding with the short carbon chain cis
forms of Vitamin A, found in liver, kidney, milk fat and CLO (27).
In the cell membrane, in the hippocampus (28) and retina (29)
are G-alpha proteins with RXR and RAR-B receptors that potentiate
or depress the signal in a given cell (30). Congenital night
blindness is caused by a single protein deletion in G-alpha
membrane proteins inside the cell attached to the retinoid
receptors which traverse the cell wall, leading to decreased
potentiation of the signal (29). Normally, the signal is amplified
ten million times from stimulation by the time it exits the
G protein coil, providing night vision in conditions of very
low light. Gi alpha inhibits cAMP synthesis, closes Ca+ channels
and opens K+ channels, while Gs alpha has the opposite effect
(30). Both stimulatory and inhibitory G-alpha proteins modulate
acetylcholine and adrenergic amines, neurotransmitters and
chemokines, all affected in autism (31).
Vitamin A and Urocholine
Autism may be a disorder linked to the disruption of the G-alpha
protein and the resulting effects on the retinoid receptors.
These cell membrane proteins are coils that modulate sensory
input. Cis forms of retinoids may act by replacing these receptors
and by easily penetrating the cell membrane for more direct
effects on nuclear retinoid pathways.
Many children treated with Vitamin A in CLO for two months
followed by Urocholine show an immediate improvement in their
autistic behaviors including improved eye contact, ability to
socialize, and increased language use. Many have been able to
toilet train easily and have begun to sleep through the night.
Postganglionic parasympathetic muscarinic receptors innervate
the bowel and bladder through sacral roots, and the pineal gland
where melatonin is produced, through fibers from the upper cervical
ganglia. This may be why the children are able to improve their
sleep cycles and to toilet train on Urocholine and natural Vitamin A.
One of the first improvements noted on Vitamin A in CLO in children
is the dis-appearance of the "sideways" glance at people and objects.
By doing this, these children with poor rod function are getting
their best three dimensional view of the object by directing light
through the pupil onto the fovea (32), which is off-center in
the retina, the area of the greatest intensity of red and green
cones and greatest acuity. Improved eye contact is noted almost
immediately in the autistic children on Vitamin A.
Importance of Binding Proteins
Cellular retinaldehyde-binding protein is important in transferring
retinal from the photoreceptor to the retinal plasma epithelia.
This binding protein is found in the retina and pineal gland.
The human genome has sequence similarities with yeast SEC14 protein,
which stimulates secretory activity of the Golgi apparatus (33).*
These Muller cells are Potassium sinks, which are RXR and RAR-B
receptors modulated by G-alpha proteins (34). If depolarization
here is not "intensified" because of a G-alpha protein defect,
this may decrease the stimulus to the brain from the neural retina.
This protein binds only the 11-cis and other di and tri cis isomers
of retinaldehyde to form a stable complex with opsin, the forms
found in CLO (36).
P19 cells are neuron stem cells, which, in their response to
their RXR and RAR receptors being stimulated by retinoic acid,
undergo cell differentiation. As these cells differentiate,
they express characteristics of epithelial cells. Many syndromes
with neurocutaneous markers are associated with autism. These
cells, upon differentiation, have a small voltage outward current,
but when differentiated have large inward sodium, potassium
and CA+ currents. As mature cells they synthesize acetylcholine,
not catecholamines (37). Urocholine stimulates alpha muscarinic
postganglionic parasympathetic acetylcholine receptors. Affected
G proteins, trimeric guanine nucleotide binding proteins, rely
on signals from protons, hormones, odorants, and neurotransmitters
and either decrease transmission, causing less effect when stimulated
by hormones, or increase transmission (38). Sensory abnormalities
seen in these children may be due to a lack of modulation in signal
in the cell membrane, but this warrants further study.
Abnormal Lipid Profiles
Also, there appeared to be a very high incidence of abnormal
lipid profiles in the children. These serum values were drawn
prior to the administration of Vitamin A in CLO, due to the
known effect of retinol and the synthetic retinoids causing
hyperlipidemia. Doses of Vitamin A in CLO in our trial are far
below minimal supplemental doses required to induce elevations
of lipids, especially triglycerides and VLDL. Of note, supplementation
with fish oils with eicosapentenoic acid (EPA) and decosahexenoic
acid (DHA) has been reported to reduce these lipid levels (39).
Blocked Neurotransmission
For many of these children, autism represents blocked neurotransmission
that can be reconnected. Correcting immunodysfunction and their
metabolic disorders will be important for prevention of future
early heart, endocrine and malignant disorders of endothelial
origin.
To quote Alfred Gilman, winner of the Nobel Prize for his discovery
of G-alpha proteins, we have been "barbarians at the gate" of
cellular function in multiple organ systems (40). These children
have been devastated and we have abandoned them and their families
from healthcare and rehabilitative services and appropriate
educational opportunities.
The far-reaching metabolic consequences may be enormous, with
potential links to not only autism, but dyslexia, attention deficit
hyperactivity disorder (ADHD), bi-polar disorder, schizophrenia,
Chronic Fatigue Syndrome, fibromyalgia, Type II hyperlipidemia,
gluten enteropathy, cancer of the mucous secreting glands, and
autoimmune disorders including muscular dystrophy and rheumatoid
arthritis. S-Adenosylmethionine (SAMe), called a supernutrient,
is an enzyme-important in acetylcholine synthesis. Loss of gut
mucosal integrity would decrease by 85% gut absorption of CoA,
shunting choline into homocysteine production. Increased production
of acetylcholine may explain why a continuous dietary source of
this nutrient makes people with multiple disorders feel better.
Increased serum homocysteine levels have previously been associated
with early cardiac disease (41). The incidence of mucous-secreting
malignancies in parents and grandparents of the children in
the study was 62 cases within 60 families. Cases of adenocarcinoma
of the colon alone were seen in 1 in every 4 families when the
lifetime risk is approximately 4 percent (42).
The current clinical trial using Vitamin A in CLO vs. placebo
in a double blind, cross-over study is necessary prior to a trial
using Vitamin A and Urocholine. Data from this trial is important
and will have very broad ramifications, including rethinking
infant formula composition and timing of immunizations. If
this hypothesis is correct, we are one step closer to treatment
and prevention of autism
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