There's a nutritionist in Britain, Jacqueline Stordy, Ph.D, who examined dyslexics and realized that they were night blind, and when she treated them with fish oil, the night blindness went away. I think what we're dealing with is a whole spectrum, which is closely connected with night blindness in one parent or another G alpha defect, which appears to result in a language disorder, such as dyslexia and ADHD, or autism, where attention for verbal social interaction is severely impaired. We do know for the RAR/RXR receptors in the middle brain, that the strongest gene activation occurs with the DR3, 4, and 5 tissue types and that the family histories are positive for many diseases associated with those three tissue types. These retinoid receptors are members of the superhormone family of receptors, sensitive to vitamin D and thyroid calcitonin, secretin, and retinoids ' we call them the nuclear receptor super family. RAR beta, as a vitamin A retinoid receptor, is hooked at one end and the message goes through that receptor and then attaches to the G-protein inside the cell. The G protein itself is divided into three major parts ' alpha, beta, and gamma. The changes that I've been talking about occur in close proximity to where the retinoid receptors attach to the G proteins. I have seen these children respond so quickly to vitamin A supplementation. I've tried to figure out why. Apparently, the RAR beta-receptors are highly responsive to retinoic acid induction. The profiles of some of these children suggest severe metabolic disorders.

Many, many had type II A hyperlipidemia profiles with high cholesterol and high VLDL. Forty-eight of the 60 families gave a history of elevated cholesterol high enough to treat in either the parents or the grandparents ' that's 80 percent. In the children, 14 out of 24 tested had cholesterol over 170, which is 58 percent. In a smaller sample, 7 out of 19 children had elevated VLDL. We need to ask if we are turning on lipoprotein lipase and can't turn it off, and as a result, these families are at risk for heart disease later on. It was interesting that of the cases where the autistic child had a normal VLDL and cholesterol, 4 out of the 7 had too low HDLs. So, many, many of these children have abnormal lipid profiles. The other thing I noticed was widely varying blood sugars'from 50 to 150. Some of the children were symptomatically becoming irritable and jittery if they weren't fed right away when they became hungry. If you look at glucose metabolism, what's happening is that the cells are being flooded with cAMP if you activate the "on" signal, (i.e. Gs alpha where you'd block inhibition of Gi alpha inhibiting the stimulation for the G protein). The cAMP floods into the cells and you have breakdown of glycogen and gluconeogenesis.

Seventy eight percent of the families have adult-onset Diabetes Mellitus (AODM) or juvenile-onset Diabetes Mellitus (JODM) in a parent or grandparent. Intracellular glucose transport, recently identified as a cause for insulin resistance in AODM, is a G protein modulated function. For a long time, I have felt that their peripheral sympathetic nervous systems are in an imbalanced state. Put quite simply, I think there is sympathetic overdrive. It's very interesting'in both the liver, skeletal muscle and adipose tissue'(that's just smooth muscle and bronchial smooth muscle)'you have an epinephrine effect by increasing intracellular cAMP so they are probably getting epinephrine poured into their system. Many of the mothers of these children have had their gall bladders removed and there is a history of diarrhea around 15 to 18 months. Intermittent and severely delayed toilet training out-of-proportion to delays in other adaptive skills occurs in autistic children. Children with dyslexia and ADHD often don't "get the signal" and have incontinence and/or encopresis. I tried to think of something we could use to increase parasympathetic stimulation without cardiac effects to help these children with their GI dysfunction. So, I tried Urocholine, which is an alpha-muscarinic agonist, after weeks of vitamin A supplementation, with normal daily doses (all < 5,000 IU vitamin A/D) and in some of these children, it has acted like a switch.

One child in particular, who, last week on Friday, and every day at recess, had gone out and filtered sand between his fingers, and not interacted with any of the other children, on Monday at recess, after having started the Urocholine over the weekend, ran outside and said: "Hey guys, wait for me!" These children are waking up and it's been a blocked pathway! In other words, one ten-year-old I treated, when I walked in the room three weeks after starting him on treatment, this child, who never talked, was telling his mother not to help him because he could get up on the table by himself. So the early adolescents are waking up developmentally and with the understanding of what you'd expect of a ten-year-old who has developed normally. There is also a high association in endocrine disorders in the family histories of these children'in 53 percent, in either a parent or grandparent; there was a history of adult onset diabetes. Could this be related to breaking down glycogen and gluconeogenesis, which is turned on and not turned off? Juvenile onset diabetes is associated with HLA DR3 tissue type. We found three in 60 children who had a sibling with juvenile onset diabetes, or 5 percent. Family history of thyroid problems reflected 7 out of 60, or 11 percent. In the autistic children,

I actually diagnosed hypothyroidism in four children out of 29 tested, or 14 percent, although the sample is not very large. There is also a family history of Addison's disease in three out of the 60 families. Other associations such as autoimmune disorders are also connected here. For example, lupus occurred either in the parents or grandparents in 8 percent of the families, and rheumatoid arthritis in 31 percent of the families assessed. We know that the G protein alpha sub-unit, either stimulatory or inhibitory, stimulates the growth of the endocrine cells, and mutations of this will prevent GTPase from stopping the action. In other words, the GIA inhibitory protein would stop the action on adenyl cyclase. This is what floods the cell with cAMP and you would have proliferation of those cells and increased secretion of the hormone.

The other thing I found was that many, many of these children are in negative nitrogen balance. Their BUN-to-creatinine ratios are very high. Perhaps we're turning on a pathway through the G protein that is not being turned off. As I look at this more closely, this really is a developmental disability in that. I think these children are genetically at risk and then they face a series of situations, the first of which is the inability to absorb and/or utilize vitamin A palmitate, which leads to a devastating neurobehavioral syndrome. Even if absorbed, can artificial vitamin A palmitate cross the blood brain barrier? Can this water-soluble substance insert itself in a lipid bilayer? Do you have any questions?

JB: I think anyone listening to this has to be overwhelmed. You have advanced the model and given both good historical explanation for the mechanism and then some clinical outcome from the test to the hypothesis that revolutionizes our thinking. Let me do a good and quick summary. What you've said is that there is a genetic sensitivity that may be locked into the HLA DR3, 4, or 5 that makes these children and their family siblings more sensitive to things like gut infections, allergy, or even things like MMR vaccinations.

MM: Yes, in retinoid research there is the "1-2-3-4-5 Rule:" the strongest gene activation by RAR and RXR receptors occurs with HREs direct repeats of the core sequence AGGTCA with 1, 2, 3, 4, or 5 spacers. These receptors, DR3 DR4 DR5, are the preferred response elements for these vitamin D thyroid and retinoic acid receptors. I think the large biological response I am seeing in these children reflects activation of retinoid responsive genes involved in lipid, fatty acid, and carbohydrate metabolism because of auto regulation or small increase in Retinoic Acid increases the receptors and their activation creating a large biological response. These primitive retinoid receptors were recently identified as involved in thyroid disease in NEJM. I've diagnosed hyper and hypothyroidism in seven autistic children in the last two months. RAR receptors were originally discovered in hepatocarcinoma cells. The hepatitis genome inserts itself into the genes for retinoid receptors. This relationship needs to be studied. Is this another oncogene being turned on? Thirty to 50 percent of breast, lung, and GI cancers contain RAS protein, which is G alpha protein, modulated. Yes, I think that many of them go into the MMR vaccine immunosuppressed. We treat severe measles with IV vitamin A. For years in Africa in countries where the measles mortality rate is >1%, the WHO has been giving not the MMR vaccine but 200,000 IU vitamin A per year because this is the best way to improve morbidity and mortality from measles. T cells, B cells and natural killer cells have retinoid switches and can't be turned on. With Vitamin A deficiency, the nonspecific branch of the immunization system is turned on and can't be down-regulated.

JB: From that then, it may explain why secretin was helpful in some of these autistic children because it improved some of the aspects of gut function related to the absorption of fat-soluble nutrients like vitamin A. The increased absorption of vitamin A then influences G protein signaling in various tissues, one of which is the hippocampus which has receptors for vitamin A, and that may explain why therapeutic administration in the form of cod liver oil has been successful, in your experience, with some of these children who have autism. Is that what you've said?

MM: Yes, and I'm giving a normal daily dose, the RDA. I'm not giving any extra. I'm very careful to explain effects and side effects of that, but just on a normal daily dose, they've done well.

JB: Is that somewhere around 1500 IUs in children. Is that the dosage you have been using?

MM: Depending on their weight.

JB: That may obviously then interrelate with other tissue specificities that explain some of the general endocrine abnormalities you've seen with thyroid and adrenal and some of the autoimmune disorders, as well.

MM: One interesting association I found was that in the families tested, 26 percent had a history of adenocarcinoma of the colon and there's a G protein that turns on a ras gene, which is an oncogene. We know that 30 to 50 percent of people with adenocarcinoma of the colon have this gene. Are we taking this high-risk population and giving a second defect in the G protein with the pertussis vaccine? Has it lost its off-switch and that's why we wind up with adenocarcinoma? In terms of cancers of the whole GI tract, and secretory organs, there were 62 cases in 60 families.

JB: Wow. And I noticed from your discussion that you've also implicated, because of this heightened sensitivity that things like gluten may be more problematic in these children, and I would presume maybe even casein, as co-variables that could activate this defective immune regulation system.

MM: Yes, and the G proteins are tied in there. I don't think these children have normal monocyte function. Andy Wakefield, who has done gut biopsies, sees monocytes surrounding antigen antibodies from measles. Pertussis toxin has been called the lymphocytosis-promoting factor. He published an article about that in the Lancet last year. What I think we're setting up is an autoimmune disorder that probably involves the intestinal tract. The measles antigen crossreacts with intermediate filaments important in tight junctions and gap junctions between cells. This might lead to gut inflammation and the "leaky gut" in these children at 12 ' 15 months of age. So, on a chronic basis, once inflammation sets in, these children aren't absorbing the vitamin, as they should be.

JB: Let's talk to the doctor who is going to be giving counsel to the parent of a child, and the parent asks if his child should be vaccinated. If the child has been vaccinated, how do they know if the child is a candidate for this particular difficulty? What kind of recommendation would you make?

MM: That is such a hard question. I've got three families with multiple children involved. The oldest one is dyslexic with ADHD. The next one is autistic, and they have a toddler coming along. All this needs to be scrutinized, and retested and retested. However, I am recommending a vitamin A level and careful family history to look for G-alpha related illness before they receive MMR vaccines. If there's a sibling with autism, even with a normal serum vitamin A level, it's important to make sure that these children are getting the natural form of vitamin A daily.

JB: That would be a preloading to make sure that their plasma and tissue levels of vitamin A were adequate.

MM: Yes, but we also have to go back and look at DPT. This has been batted around for years and years, but it's so impressive that we're putting a second defect one space away from the defect that already exists in the G protein. Is this disconnecting them? In an article in the New England Journal of Medicine on April 1, the comment was made that these proteins have to be in an exact configuration "arranged precisely adjacent to neighboring amino acids of G alpha." Are we changing that precise arrangement just enough to either augment the stimulatory signal or not have an inhibitory signal? It's a very fascinating question. Al Gilman, who won the Nobel Prize for his discovery of G proteins, says "palmitoylation" of G alpha deactivates this protein by 90%. In treating these children by giving them natural forms of vitamin A (liquid at room temperature) and avoiding A palmitate, are we able to avoid the blocked pathway? I see a lot of children who are slow learning language who show significant catch up with normal cognition by age 5, but eventually are diagnosed learning disabled with ADHD. My son is gifted and goes to a local high school for college-bound dyslexics. He asked his friends how many saw headlights like stars. Sixty-eight out of the 70 reported that. One family came to me recently with 2 adolescent children. Mother and both children are nightblind. The 13-year-old has juvenile onset diabetes mellitis, and is home-schooled because of chronic fatigue syndrome. The 11-year-old has dyslexia and ADHD. Both have severe sun photophobia. This needs to be studied more thoroughly.

JB: From your experience, what percentage of parents giving vitamin A in cod liver oil to their children are reporting a positive response?

MM: I ran into one yesterday who didn't. I think that child has been on a placebo for a while. All the rest of them have improved.

JB: Do you think the combination of secretin along with vitamin A will give even better benefit, or do you think vitamin A itself will help with the morphological problems of the GI?

MM: The secretin pathway is one of over 100 metabolic pathways modulated by retinoid receptors attached to G protein. I have treated the children with two months of vitamin A in cod liver oil, normal RDA doses, followed by low doses of urocholine which has been used in children since the 1970s for other reasons, with known effects and side effects. Because this is not in the PDR for autistic children, I observe them in the office after the first dose. Care should be used in treating these children with multiple allergies, as they may get mild bronchospasm and increased mucous secretion. Atropine is the antiodote. Besides, its fun to watch them wake up ' sometimes forty-five minutes after the first dose.Vitamin A helps tremendously. To replace your mucous secreting cells, you need vitamin A. To create secretory IgA, you need those cells healthy and I think these children need vitamin A to rebuild retinoid receptors associated with G protein all over the body. I think a low, normal daily supplement dose is safer than injecting a foreign substance into the body.

Mary N. Megson, M.D., F.A.A.P.

Developmental Pediatrician Assistant Professor of Pediatrics

Medical College of Virginia Hospitals/Virginia Commonwealth University

Pediatric and Adolescent Ability Center 7229 Forest Avenue

Suite 211 Richmond, VA 23226
 
From  [http://articles.mercola.com/sites/articles/archive/2000/01/23/autism-fish-oil.aspx]