Although our conversation was short in duration, I was fascinated by the work she is doing and a model she has developed relating to autism and potentially other childhood brain-related dysfunction. It was a "goose-bump" experience for me and I thought it would be useful for the audience of Functional Medicine Update' to hear what Dr. Megson has to say. Mary, I would like to introduce you to our audience at FMU and thank you for making some time available for us today. Would you tell us a little bit about how you wound up in the field of autism and brain chemistry?

MM: I trained in Developmental Pediatrics for three years after residency and worked only with children with developmental disabilities, such as learning disabilities. When I saw the show on television about secretin, I thought that most people would be thinking about secretin and how it affects the brain as a neurotransmitter- like we found in substance P. I went in a different direction and asked myself what secretin would do in the gastrointestinal tract. It stimulates CCK (cholecystokinin), which stimulates bile production, and if patients are not making any bile or are in liver failure, it's very important to supplement these people with the fat-soluble vitamins. I began to ask questions related to deficiency of fat-soluble vitamins. My practice deals largely with autism, or communication disorders. I found that in 54 out of 60 families (90%) I've studied, night blindness was present in one parent, and four more had retinitis pigmentosa in the mother. I heard this again and again. Then, within one week, I had no history of nightblindness in three families in a row but in all cases one parent had been recently treated for a pituitary adenoma.

JB: This is fascinating, and I think it speaks nicely to the question we were left with after interviewing Dr. Jeffrey Kopelson who talked about the experience he's had with the use of secretin in autistic children. Then, we had Dr. Michael Lyon speak about ADHD and some of the things he's observed with brain chemistry and behavior. It sounds like we're taking the next step with you. Tell us something about this interrelationship between a signaling molecule like a retinol or retinoid, like vitamin A, and how that could interrelate to what is observed with these brain chemistry problems in autism.

MM: Several years ago, Margaret Bauman at Massachusetts General did research looking at cellular differentiation in the hippocampus. She had autopsy studies from children at 11 or 12 months of age, and the cells were small. There were problems of connections. But they were not so differentiated. Then she looked at a population of children who had abnormal language development and the cells appeared the same at age three. In children with normal language development, there was a dropout of connections and more branching of synapses. I started to think about vitamin A and cell growth and differentiation'this is all ectodermal tissue. I started to get more thorough family histories that reflected again and again the same sorts of medical problems ' hyperthyroidism, night blindness, rheumatoid arthritis, and even gold nephropathy. Most of these diseases are associated with major histocompatibility complex tissue type DR3, DR4, DR5. Direct repeat sequences are known to have high affinity for retinoid receptors.

JB: I am reading the abstract from a paper you recently submitted in which you report in 36 families a parent of the autistic child, usually the mother, gave history of night blindness and difficulty driving in dim light at dusk, in the rain, at night, or in fog, and that this clearly indicates a potential for vitamin A insufficiency. However, if you do diet-recall studies on these individuals, I presume that you would find that they were "adequate in vitamin A from their diet." So, there is something else genetically related to either the absorption or utilization of vitamin A, I presume, that you're describing.

MM: Yes, you're exactly right. I looked at vitamin A metabolism to try to figure out how these children were absorbing it, because they did not consistently present with a malabsorption picture'fatty stools, etc. And the children appeared to be growing normally. So I asked myself how these well-nourished children offered a variety of foods could have a vitamin A deficiency emerging before 30 months of age. What I found in my research was that if you have gut mucosal damage, the enzyme that helps split vitamin A palmitate is in the microvilli of the gut, and if the child has a single adenoviral or rhinoviral infection before fifteen months of age, the mucosal cells are sloughed off so that enzyme might not be available for use. Vitamin A palmitate has to be in the presence of bile, and the right pH for absorption. Gut mucosal integrity is damaged. At 15 months they get a MMR vaccine. The measles antigen crossreacts with intermediate filaments which are important in gap junctions and tight junctions. Mucosal cell integrity is also important for absorption of CoA, which is the critical enzyme when choline is converted to acetylcholine. The precursor for this reaction is s-adenosyl methionine (SAMe), now touted as the "cure all" nutrient. If the CoA pathway is blocked, choline is diverted to production of homocysteine. Are we effectively blocking G-alpha inhibitor of G stimulatory alpha pathways increasing cAMP cells causing lipolysis, and blocking production of acetylcholine? Many of these patients have elevated cholesterol and VLDL/LDL. These are two-year-old children eating three fruits and two vegetables, and chicken nuggets with serum cholesterols over 200 mg/dl.

JB: Would you expect that this vitamin A malabsorption would also come concomitantly with malabsorption of some of the other fat solubles such as D, E, or K, or do you think that we are looking at selective transport insufficiencies for vitamin A?

MM: They have low levels of other fat-soluble vitamins.

JB: With vitamin A, because we see it as a little bit different than the other vitamin fat-soluble members because of its cell signaling capabilities as a progenitor of the retinoids, I suspect that your model would have it interwoven with some of the other signaling trans-membrane messenger molecules. I know you've talked a little bit about G proteins. Would you tell us how the vitamin A insufficiency might interrelate to altered cell signaling?

MM: Yes. The second problem I noticed in these families was sluggish gut and light-colored stools in many of the parents. Then I looked at vitamin A metabolism and saw that the form of vitamin A they could absorb without the presence of retinylester-hydrolase bile salt dependent in the presence of gut inflammation in the cis form of the molecule. Most of us are ingesting vitamin A palmitate, which is not the naturally occurring form. The naturally occurring form is found in milk, liver, kidney, and cod liver oil. There is a history of hypercholesterolemia in a lot of these families, and at two years of age, these children are being taken off whole milk and put on lowfat milk. Formula has vitamin A palmitate added.

JB: When we look at vitamin A, as it is malabsorbed in these children who may have a predisposition, is there a series of screening tests that one can use to pick up the potential, or do we rely on plasma vitamin A levels?

MM: Plasma vitamin A levels are not extremely reliable, though they can vary somewhat. Levels less that 20 'g/dl, if that's consistent, mean the child is at risk for eye damage. Eighty-five percent of the children have a level less than 30 'g/dl, which is where subclinical vitamin A deficiency occurs, down to 15 'g/dl. After I knew about the vitamin A, I postulated that perhaps there are vitamin A receptors in the hippocampus that have to be turned on for pathways from the left side of the brain (where language is processed), to the right (where image of the object is picked up), to the frontal lobe (where the social meaning and attention is connected to interpretation of the communication), to connect. A month later, I was told about an article published in December 1998 by Ron Evans et al., at Cornell Medical Center. He isolated RAR beta and RXR receptors in the hippocampus of mice. It's fascinating. He had three sets of mice. The normal wild mice go through a maze; he changes it; they learn it. The second set are blind mice. They go through the maze slower than the regular ones, but they do learn it. The third set had RARB and RXRX receptors blocked, and they never sped up going through the maze once it was changed.

They acted as if they couldn't learn and didn't remember once the change occurred in spite of multiple trials and they also acted like they showed significant "visual perceptual deficits." From my research, I also figured out that these children had minimal rod function. There are three articles that have been published in the Ophthalmology literature where ERGs were obtained on autistic children and first-degree relatives. In those studies, these children had relatively flat B waves which reflect decreased rod function, but normal A waves, which reflect normal cone function. This research wasn't taken any further. These retinoid receptors are members of the super hormone receptor system and, in many cases, they attach to G proteins which up- or down-modulate the signal. These are the calcitonin, secretin, thyroid and retinoid receptors. I tried initially to see if perhaps giving a normal daily dose of natural vitamin A to autistic children would help. This was given in the form in cod liver oil. Many of these children started to talk, were more appropriate socially, and improved dramatically on just a normal daily dose of vitamin A in cod liver oil. Since that time, on April 1, 1999, there was an article published on the G proteins in the New England Journal of Medicine in which it was visually shown that the defect for night blindness is very close to where the pertussis toxin is inserted into the G protein in the alpha section next to its binding site to the retinoid receptor in the cell membrane. The G proteins act like switches.

They up-modulate a signal or down-modulate it. For example, to see at night ' with night blindness, you have a one-protein substitution in that G protein. People with night blindness eventually see at night, but they don't see as well. There are certain characteristics they have. They don't accommodate as well. They have flash photophobia. From when the impulse enters the cell to when it leaves, it's supposedly amplified 10,000,000 times when you accommodate for night vision. Light is the signal, which activates rods by setting off a cascade of reactions, one of which is G protein modulated. Adding a second defect in G alpha further inhibits the signal, depressing rod function. Not only is night vision more impaired, these children lose light-to-dark shading in daylight. I started to look at the profile these children present with. First of all, these pathways modulate sensory input and these children have abnormal sensory skills. We often send them to an occupational therapist to do "sensory integration therapy." We know that sensory input is a problem. I noticed in these children that they look away from parents at an angle when they are trying to talk to them, which has been interpreted as avoiding eye contact and socialization.

I think they're trying to get the light through the pupil onto the fovea, which is off-center in the retina where they have the clearest three-dimensional vision. This lateral gaze almost disappears on the natural vitamin A in cod liver oil. As I look through what I'm seeing in the labwork in these children, there are very consistent patterns. I've now studied 60 families and 26% have a history of adeno- carcinoma of the colon in parents or grandparents. Are we stimulating the G protein modulated ras oncogene? G2 alpha defect in transgenic mice is associated with ulcerative colitis and adenocarcinoma of the colon. These children, 22 out of 25 tested, had positive antigliadin IgG antibodies. The problem is the antigliadin IgA is negative and it's hard to get a young child to cooperate with getting a sample for secretory IgA evaluation with saliva. Serum IgA is low normal but one wonders: if they are vitamin A deficient are they producing secretory IgA? Many of these children have had recurrent gastrointestinal and/or respiratory infections, and otitis media beginning at 15 ' 18 months. Adequate vitamin A is needed to produce secretory IgA and to heal ciliated membranes, including those that secrete IgA. I then began to think about their development. Are they fed formula from birth to six months?

Then, do they get a cracker at nine months, which sets up an inflammatory process in the gut secondary to gliadin allergy, which probably makes vitamin A palmitate difficult to absorb? I asked myself what happens to these children with low vitamin A levels and problems with the immune system, who then receive a measles/mumps/rubella (MMR) vaccine. They need normal vitamin A levels in order to turn on T cells and B cells. Is this the immunosupression we see as autism? Another thing is the leaky gut that everyone talks about. There are RAR and RXR receptors that are responsive to natural vitamin A, which is responsible for the production of intermediate filaments important in the gap junction and tight junctions between cells. It's all related to G-alpha proteins. Loss of intermediate filaments could lead to leaky gut. Other consistent findings I've noticed in studying these families are rheumatoid arthritis (that's been reported before ' it's 31 percent of the sample), coeliac disease, IgA deficiency, lupus, gold nephropathy in 5 percent of the families, MS in 3 percent, irritable bowel syndrome, and juvenile onset diabetes. Twenty-seven percent have a history of either irritable bowel syndrome or coeliac disease. What I also found on the profile was that these children would come to me at close to 20 months ' many, many of them had normal cognition and receptive and expressive language until 15 to 18 months ' and that's where they leveled off. That would tend to lead one to assume, unless there's a neurodegenerative process going on, that the hard-wiring is there, but that these children, for some reason, are at greater risk for having autism.

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