The Doctor's Corner

AUTISM: WHERE ARE WE, WHAT CAN BE DONE?

by NOHA's Professional Advisory Board member Jon B. Pangborn, PhD, ChE, Syracuse University, who is a fellow of the American Institute of Chemists; a certified nutrition counselor; founder and president of Bionostics, Incorporated; author or coauthor of nine patents and more than 200 publications; and recipient of the 1991 Herbert J. Rinkel Award from the American Academy of Environmental Medicine "in recognition for excellence in teaching the techniques of environmental medicine."

Significant progress in understanding and treating autism is being made by organizations and medical centers who have focused on metabolic and biomedical aspects of autism. We have an alphabet-soup assortment of parent groups which started as education and support groups (ASA, CAN, DAN!, NAA, NARR, TAAP, etc.). While they still do this, their fervor for doing something about this epidemic has produced useful financial, political, and legal incentives. A medical center alliance that is in the planning stages is the Autism Treatment Network (ATN). Executives of the ATN expect it to be up and running by midyear 2006, with an eventual goal of having a treatment center within driving distance of all major population areas of the US. Initially, there will be six (possibly seven) centers: Mass General Children's Hospital and the medical centers at Columbia, Baylor, Oregon Health Sciences University, the University of Washington, and the Cleveland Clinic.

We have an alphabet-soup assortment of parent groups which started as education and support groups (ASA, CAN, DAN!, NAA, NARR, TAAP, etc.). While they still do this, their fervor for doing something about this epidemic has produced useful financial, political, and legal incentives. A medical center alliance that is in the planning stages is the Autism Treatment Network (ATN). Executives of the ATN expect it to be up and running by midyear 2006, with an eventual goal of having a treatment center within driving distance of all major population areas of the US.

In addition, several university-affiliated medical centers are already active in research on environmental/genetic causes of autism. Research on acquired, altered genetic expression ("epigenetics") is underway at Baylor University Medical Center. Arkansas Children's Hospital Research Institute (ACHRI, Little Rock) is performing controlled clinical studies on measurable biochemical abnormalities in autistic children. Mass General in Boston (affiliated with Harvard Medical School) has an up-and-going treatment program that merges gastroenterology, other medical and nutritional strategies, with behavioral and learning regimens.

As a cofounder of the Defeat Autism Now! (DAN!) effort, I'm best acquainted with the advances made by this group. It includes inputs from key staff of Harvard and Mass General (Martha Herbert, MD, Timothy Buie, MD), and ACHRI (Jill James, PhD). Autism often is treatable and the Autism Research Institute (ARI, directed by NOHA Honorary Member Bernard Rimland, PhD) has at least 1000 documented cases of recovery. In October 2004, ARI's DVD of interviews of some of the formerly autistic kids "Recovered Autistic Children" won a gold award at the Worldfest-Houston International Film Festival.

The list is long [of environmental insults that affect methionine methylation and adenosine metabolism adversely] but includes mercury and antimony compounds, organophosphate chemicals (many pesticides) and many solvents and petrochemicals. Combinations of these may have synergistic detrimental effects that greatly exceed those of a single toxic substance.

What do we think the cause is? For the vast majority of our autistic population, it's something that has gone really wrong during the last 20 years and especially during the 1990s and into the years after 2000. Autism is the result of acquired toxic and infectious insults added to metabolic weaknesses possibly of genetic origin. This is a nice generality, but specifically, what metabolic weaknesses, and which insults?

Metabolic Weaknesses
In the early years of life, children's brains go through a process of self-assembly, in which separate and developing neuronal networks are interconnected. The interconnecting neurons, "interneurons," are rich in attention getting and message transmitting systems, including "receptors" and G proteins , which are regulatory proteins that work with cell receptors to transfer messages from outside the cell to the apparatus that responds biochemically inside the cell. The message transfer process requires energy, which comes from guanosine triphosphate (GTP) becoming the diphosphate (GDP). The guanosine or "G" gives the G-protein its name. These molecular systems require both energy and synchrony in their operation. The network-connecting process allows distinctions in shape, color, texture, sound, etc. to be integrated into coordinated thought, organized responses, and expressive speech. If the interconnections are deficient, some neuronal networks may become overdeveloped but isolated. For some, this results in exceptional skills (music, mathematics, art, working puzzles) while other skills, such as self-expression and sociability are underdeveloped for all with deficient interneuronal connections.

How does this neuronal interconnection deficiency tie into metabolism problems, genetic and acquired? Unfortunately for humans and animals in general, one metabolic process is central to three physiological functions that have gone awry in many with autism: energy supply (amplitude modulation of neurons), methylation (frequency modulation or synchrony)¹, and inflammation. The faulty metabolic process is that of the essential amino acid methionine. As S-adenosylmethionine, "SAM," this amino acid provides a chemical part (methyl group, CH3) needed for many purposes in body tissues, including assembly of the energy carrier molecule called creatine. In brain tissue, creatine carries phosphate, the metabolic currency of energy, to neuronal receptors. If SAM can't methylate adequately, then creatine phosphate is deficient and so is neuronal energy.

In the early years of life, children's brains go through a process of self-assembly, in which separate and developing neuronal networks are interconnected. . . . If the interconnections are deficient, some neuronal networks may become overdeveloped but isolated. For some, this results in exceptional skills (music, mathematics, art, working puzzles) while other skills, such as self-expression and sociability are underdeveloped for all with deficient interneuronal connections.

Professor Richard Deth of Northeastern University and his colleagues have discovered another very important aspect of methylation. Certain receptors in interneurons (dopamine D4 receptors) have methylation capability because they include part of the methionine metabolism sequence.² These receptor systems methylate nearby fatty acids or phospholipids in the membrane (wall) of neuronal cells. Such methylation increases cell membrane flexibility and modulates the response frequency of D4 and other nearby receptors to external messages provided by neurotransmitters (dopamine, glutamate, aspartate). But neurons and networks can be "out of sync" if membrane fatty acids aren't properly methylated.

To summarize, if SAM can't methylate adequately, then both energy and frequency requirements of neuronal function are unfulfilled. One consequence is confused or absent neuronal response to external messages. If this happens between ages one and two, long-lasting learning and communication deficiencies can result.

Do we have physiological examples of creatine (energy) deficit and methylation (synchrony) deficits? Indeed, yes! Three genetic diseases have now been described that result in deficient creatine and the consequent energy deficit in the brain. Deficiency of expressive speech results along with other possible symptoms. And persistent brain infection by paramyxoviruses (mumps, measles) was documented twenty years ago to cause cessation of phospholipid methylation.³. This is important because both childhood and maternal (during pregnancy) measles and mumps infections were linked to autism decades ago.

The faulty metabolic process is that of the essential amino acid methionine. As S-adenosylmethionine, "SAM," this amino acid provides a chemical part (methyl group, CH3) needed for many purposes in body tissues, including assembly of the energy carrier molecule called creatine. In brain tissue, creatine carries phosphate, the metabolic currency of energy, to neuronal receptors.

Besides methylation problems, DAN! researchers are concerned about cell membrane transport mechanisms for cystine (an amino acid needed for formation of glutathione), creatine, taurine, dopamine and other molecules essential to cellular perception, response, and antioxidant protection. These transport processes can be disrupted in some brain cells by toxic, organic mercury.⁵

Toxic and Infectious Insults
What environmental insults affect methionine methylation and adenosine metabolism adversely? The list is long but includes mercury and antimony compounds, organophosphate chemicals (many pesticides) and many solvents and petrochemicals. Combinations of these may have synergistic detrimental effects that greatly exceed those of a single toxic substance. DAN! clinician-researchers also are investigating at the DNA level whether the attenuated measles virus used in vaccines has been contaminated with other (avian) viruses. That's because the vaccine measles strain is grown in chicken eggs.

What about the part of SAM that isn't recycled; where does that go? It goes to make cysteine, glutathione, taurine, and sulfates. That pathway is very dependent on vitamin B₆ coenzyme function—the activity of pyridoxal-5-phosphate (P5P), the metabolically active form of vitamin B_6. This was discovered by Dr. Tapan Audhya, who did controlled studies of vitamin B₆ and P5P chemistry in the blood cells of both autistic and normal children.² The problem here is that cellular formation of P5P has been found to be notably deficient in autistics. So, this route, which leads to antioxidant, anti-inflammatory glutathione, is disabled. It hardly gets started if adenosine is high and it can't proceed with necessary speed for many because of the P5P problem.

The purpose is to route more material to cysteine and glutathione and less to methionine and SAM. Oops! By doing this, the body is reducing methylation further in a futile attempt to use broken metabolism to make more glutathione. It's a real "Catch 22" condition.

Intervenes how? How did ARI and DAN! procedures manage to reverse autism in at least 1000 children (documented cases only)? Reversed means they had a diagnosis of autism but do not any longer. There's no magic bullet for all but there are biomedical options that can be very beneficial to individuals. Improvement is typically gradual because neuronal networking has to be established (or re-established), and this can be promoted by behavioral training such as ABA (applied behavioral analysis) along with or following appropriate biomedical treatments. Here is the track record of nutritional interventions as provided to ARI by parents of autistic children:

1. Supplementing vitamin B₆ with magnesium. The rationale should be obvious from the preceding text; magnesium acts synergistically with P5P, especially in sulfation chemistry.

2. Supplementing trimethylglycine (betaine). This circumvents folate and B12 problems by directly methylating homocysteine to make methionine. No cysteine or glutathione results directly but may result indirectly. Note that the nutrient that is used here is NOT the betaine hydrochloride that might be used for increasing stomach acidification. It is "glycine betaine" or N-trimethylglycine."

3. Supplementing dimethylglycine. This provides methyl and one-carbon chemical pieces to the system that involves folate, vitamin B₁₂ and methionine recycle.

4. Gluten/casein-free diet. This reduces the burden on a cell membrane protein which: in the small intestine digests dietary opiate "exorphins"; acts as a lymphocyte receptor for immune cell signaling, CD26; and is the binding protein for adenosine deaminase (an enzyme for metabolizing adenosine). These are all the same protein, which in its food digestion role is known as dipeptidylpeptidase IV, DPP4.

5. Digestive enzymes. These, taken with food, reduce the amounts of undigested carbohydrates and complex sugars and bolster DPP4 digestive activity if DPP4 peptidase activity is included. The DPP4 strategy is digestion of exorphin peptides in the gastrointestinal tract with synthetic (plant-extracted) DPP4 before they can be absorbed. If these exorphin peptides get into the blood, they can bind to cellular CD26 (the adenosine deaminase binding protein), worsening the adenosine situation. Better digestion also lessens amounts of dysbiotic, often pathogenic gut flora that contribute to intestinal inflammation in autism. Decreasing inflammation hopefully reduces the epigenetic influence on reduced methylation. Digestive enzymes complement dietary restrictions, but are not a substitute for such restrictions.

6. Detox therapy or "chelation". While there's a lot of controversy about which agent(s) are best for removal of toxic elements (mercury, arsenic, lead, etc.), the results, as reported to ARI, are excellent, provided that prerequisite treatments have been done. Measures that should be in place for autistics before detoxification include: avoidance (casein, gluten) diets if beneficial; treatment, if necessary, for bacterial/fungal dysbiosis; use of enzymes; and appropriate nutritional supplements, including those described here. The current statistics include both DMSA and DMPS-they are not separate items on the questionnaire. The mysterious thing (in both cases) is that the best results often occur without analytical evidence of toxic element removal (per urine analysis). Are the detoxifying agents actually helping to relieve oxidant stress?

7. Injection of and/or oral use of "megadose" methylcobalamin. This is administration of the methylated form of vitamin B₁₂. Injection via the procedure of James Neubrander, MD⁷ has an excellent track record per clinicians that I've spoken with. While we don't yet have parent responses tabulated from ARI, clinicians report anywhere from 40% to 90% being improved in some behavioral or functional aspect. In Sacramento, CA, The M.I.N.D . (Medical Investigation of Neurodevelopmental Disorders) Institute, which is affiliated with the University of California, Davis, is beginning a controlled study of methylcobalamin for autism.

Summary
In summary, there are remedies for what has become an epidemic in our children (as many as six per thousand births). We understand it better at the molecular level, and when we focus on the chemistry that's measured to be abnormal we do get improvement in the condition. Certainly not all go into remission, but many do, and ARI is working on its second thousand to lose the "autism" diagnosis with documentation.

Those wishing more information on parent ratings of biomedical interventions may contact the Autism Research Institute, 4182 Adams Ave, San Diego, CA, 92116, 619-281-7165, and request ARI Publication 34. Those wanting more information and lots of references for what I've said here can contact ARI or Amazon.com for the book: Autism: Effective Biomedical Treatments, J. Pangborn and SM Baker, 2005. The DVD "Recovered Autistic Children" is also available from ARI.

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¹ Waly M, Olteanu H, Bannerjee R et al, "Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal," Molecular Psychology ,9 (4): 358-70, April 2004.
² Audhya, T., "Laboratory indices of vitamin and mineral deficiency in autism," Fall Dan! 2002 Conference Proceedings, pages 239-44. San Diego, October, 2002. Prints available from Vitamin Diagnostics, Clifford Beach, NJ, 732-583-7773.
³ Münzel, P. and Koschel, K., "Alteration of phospholipid methylation and impairment of signal response in persistently paramyxovirus- infected C6 rat glioma cells," Proceedings of the National Academy Sciences USA, 79: 3692-6, June 1982.
⁴ Stubbs, G., Litt, M., Lis, E., et al, "Adenosine Deaminase Activity Decreased in Autism", Journal of the American Academy of Child Psychiatry, 21: 71-4. 1982.
⁵ McBean, G., Trends in Pharmacological Science, 23(7): 299-302, July 2002.
⁶ Vargas, D.L., et al, "Neuroglial activation and neuroinflammation in the brain of patients with autism," Annals of Neurology, 57: 67-81, 2005.
⁷ Neubrander, J.A., "Biochemical context and clinical use of one specific member of the five-member vitamin B12 family, Methyl-B12," Proceedings Fall DAN! 2004 Conference, Los Angeles, pages 275-86, October 2004.

Article from NOHA NEWS, Vol. XXXI, No. 1, Winter 2006, pages 2-5