DAN/ Spring 2005 Conference, April 14-17, Boston, MA

Methionine Metabolism in Autistic Children -Individuality and Clinical Options

Nutritional biochemistry does not offer the same reml the Neponset rotary problem) or tunnels to replace the paths where traffic is supposed to pass smoothly. Instead, we are constrained to work within the system nature has provided. That system consists of a flow of traffic in which molecules are transformed as they move along pathways we represent with map-Iike drawings. Such drawings approach the wall-sized charts that Dr. James will illustrate as well as the detailed maps such as Dr. Mumper, Dr. Neubrander and other speakers will show.

As in Boston, rotaries, or in chemistry what we call cycles, are amenities that may both solve and present special problems. Special in a couple of wavs:

In the chemistry of living things -biochemistry -nature has resorted to cycles relatively infrequently. The few cycles are key components of major activities:

As you will have heard from other lecturers by now, the methionine cycle is subject to problems of flow that are perhaps greater than those of Boston traffic. Those problems come out in different children in different ways. Individuality -the overriding theme of the DAN! approach -emerges in ways that demand flexibility on the part of clinicians and parents. The research that has brought us to our current place in our exploration of thiol chemistry in children with autism shows differences in the average values in autistic children as compared to normal children. These average differences provide persuasive evidence for the diagnostic and therapeutic relevance of thiol chemistry .Ok, now find me an average autistic child, and I will know how to treat him or her. Problem is -there is no such thing as an average autistic child or an average anything child. Average is a concept we apply to a group of people whose aggregated measurements of height, weight, blood count, plasma methionine, etc. give values that give us an idea of average. Average remains an idea- around which we can make useful judgments about individuals. But there is no average individual even though we may use the practical convenience of speaking that way about a person whose measurements fall close to the mean.

Jill James has a way of measuring the traffic in and around the methionine cycle. I have sent her blood from my patients with the idea of looking, not at the averages that distinguish them, as a group, from normal children but at individual patterns that we wish to ponder with certain questions in mind.

Can we tell the difference between children who have responded very well to treatment vs. those who have not? Can we predict who will respond to treatment or to a particular treatment?  Can we find patterns that drive therapeutic decisions that differ from what the group average results would indicate?

In other words, how does individuality play in this chemistry? The answer to that question will determine whether in the near future every child should have his thiol chemistry checked or whether his clinician can rest treatment decisions on the average picture that we have formed about the pathology of thiol chemistry in autistic children.

I will show examples of ways in which patterns of thiol results have given answers to the above questions.

For example:

Here are the results of thiol tests done on a boy (Ky) who was about 4 years old at the time of the two tests, one before and the other after a treatment based on the first test.

Now let's take the numbers -as compared with normal -and show them laid out in a north to south orientation like Dr. James' diagram. First, here is the diagram (Figure 3) featuring the methionine rotary in which methionine gives up a methyl group (CH3) and then gets one back as the cyde turns dockwise. That part of the diagram shows the "northern" part of thiol chemistry .

Note that the place where mercury toxicity has its influence in this chemistry is with the part of the cycle in which HC is remethylated to become Methionine again. The remethylation of HC serves two purposes: one is to prevent a build up of HC, which is a very toxic molecule and like an ingot in a foundary , is an essential material that cannot be kept around in quantity or it would burn the place down. "Quenching" and returning HC to become methionine accomplishes the other purpose. assuring a constant supply of methionine independent of meal times.

From homocysteine on down to GSH is the southern part. Then we can simplify it a bit (Figure 4) to make it easier to follow for the main points we want to make.

Then we can put some numbers in this template to indicate different children's patterns based on the values of their results for the measured items. We just have to change the drawing a little (Figure 4) to accommodate the numbers that reflect the ratio between SAM and SAH -because that ratio tends to reflect how well methylation can proceed, and the numbers that reflect the relationship between GSH and the form (GSSH) that it takes when it is "used." There are two helpful ratios fGSH/fGSSG and tGSH/fGSSG (f = free, t= total) which we will call ratios 1 and 2, both reflective of the level of oxidative stress as measured by the redox potential in th~ milieu where the chemistry takes place. Note that GSH is the main substance that establishes good redox potential but a good redox potential is needed for the production of GSH. Hence the set up for a vicious cycle: not enough GSH to have a good redox potential- redox potential not good enough to produce GSH.

Now let's put in Ky's results to show how they were before and after treatment (Figure 5) The pretreatment numbers are in the hexagons and the post treatment figures re in the octagons to their right. The print size reflects whether value of the result is relatively high or low as compared with normal controls and the shading indicates values that moved from being abnormal to normal.

The message of these results is that, on paper, the treatment worked -with the exception of the methionine level which went from low to lower! What about Ky? Here are his mom's comments:

"Ky started the B- 6 Supplements in mid-July. Within a month we saw a child who comfortably approached strangers, interacted with peers appropriately, began napping again, asking "why" about everything, and even reasoning through problems verbally. These are tremendous improvements and ironically, he is becoming a bit of a dass joker. At circle time last week, as his teacher was discussing baseball as one of her '.favorite things", Ky (with great empathy) stated, "Oh those poor Yankees." Even more wonderful was that he told me this story and at the end gleefully added that all his friends .'thought I was so funny!"

Finding the high* homocysteine. in combination with the low cysteine gave evidence of a traffic jam at the bridge across the river from HC to the southern part of thiol chemistry .There is no river there, but it is as if there is a river because there are no back roads on which to by-pass the jam as one finds in much of biochemistry where nature often provides for alternate routes. Traffic jams in this location may be favored by high doses of vitamin 86 (pyridoxine or pyridoxal 5 phosphate), which is what I prescribed Ky and was associated with a leap in his improvement, which was already moving well after initiation of gluten and casein free diet and antifungal therapies. Once the traffic jam was alleviated and his homocysteine fell to levels that are common in autistic children, his methionine also fell to the low levels typical of autistic children. I took this as a signal to give him methy812 injections. After starting methyl 812 injections his teachers have commented about his energy and his many interesting contributions to circle time. Math became a strong point with both a love of numbers and skills at building stuff with Leggos@ and blocks and he became consistently happy. (Incidentally, is mother tried methyl B12 injections and, among other benefits, regained her sense of smell after the first shot. It had been absent for twenty years).

Clay, who was 7-1/2 at the time of the test, gives us another example of a therapeutic response to treatment guided by thiol studies. In the previous examples one might easily have arrived at the same treatment because B6 and B12 work for many children in the autism spectrum and therefore are always worth a try .For Clay, as in the following case, the treatment would have been more difficult to discover or justify without the test. Here his data (Figure 6) He also done quite well -on antifungal treatment and Specific Carbohydrate Diet. As you can see his homocysteine was high, even though he had been on Methyl B12 and his adenosine was elevated.

Clay took acyclovir and the results reveal an improvement in both the northern and southern regions of his thiol chemistry .A side effect of the antiviral medication, acyclovir (ZoviraX@) is to lower adensine levels, which, when elevated, block the traffic at SAH, which in turn inhibits methylation. The consistency in the changes throughout his chemistry are persuasive especially when considered with his clinical improvement after starting the acyclovir.

Here (Figure 7) is another example, p-Z, a three year old boy, whose data are very much like Clay. His mother reported the following "On acyclovir (now 5 weeks) less hyper, more calm. Spontaneously chased a little girl. Took his uncle's hand. Stopped spinning as soon as he started acyclovir; let me cut his hair. He is now understanding 60% of what is said to him, much more alert and aware, goes to bed, poops are better. Now he responds to "turn your head" "get in bed" "spit it out."

These are only a few examples of non-average results of children in my practice. They encourage us to formalize research based on the pilot studies.

Do the data from my 30 patients show a correlation between the severity of autism or the responsiveness to treatment? A glance a the collected data is sufficient to show that there is no correlation sufficient to judge get a good picture of a child past, present or future, from looking at his or her thiol results. This preliminary conclusion tends to uphold my clinical impression that mercury toxicity. which we believe to be the main environmental factor causing disturbances in thiol chemistry .exerts its effects with an extreme variability. It seems to me that there is not only a wide range of thresholds for mercury toxicity to have its negative effects on different individuals but also there is a wide range of expression of that toxicity in different individuals even when the effects on thiol chemistry are the similar.