Down Syndrome with Growth Failure Division  
Linda Blevins, Division Director
Down Syndrome and Growth Failure Division Summer Newsletter
June 1996
  Reprinted with the permission of The MAGIC Foundation
1327 N. Harlem Avenue, Oak Park, IL 60302-1376
1 (800) 3 MAGIC 3
(708) 383-0808 Fax: (708) 383-0899

The DS division is sponsoring Dr. Richard Lord, Ph.D. of MetaMetrix. Dr. Lord will be speaking on the metabolic imbalances that occur in all special needs children with a major focus on Down syndrome.
Preparations have long been under way. Jamie Harvey has been working hard to plan all of the many activities. Involved are arranging corporate sponsors, soliciting many items for the silent auction, planning the many child oriented activities, handling hotel arrangements, printing and mailing bulletins and coordinating speakers. Jamie has generated so much time, energy and creativity. They only thing missing is your reservation! Hurry and mail those today. Convention is July 25-28, 1996 at the Ramada Hotel - 0'Hare, Chicago, Illinois.
See you there!!!

Convention is coming. I would like to assemble a photo album of our children. Please send me a photo. If it is difficult to part with a photo, an option to consider is color Xeroxing. These replications are very clear. Help me out and send them soon. Also, I still need your personal stories. It can be a short paragraph to comment on your child's response to GH or it can be a saga, or it can be about a therapy that has worked for your child. I can't wait to start getting those pictures and stories.

Welcome to our new members. Your membership and support is very much appreciated. Continue to share the MAGIC newsletter with other DS parents, professionals, DS groups, therapists, doctors and friends. Remember you can make a difference. Let us share information about the many options of treatment for DS.

What are "free radicals" and "antioxidants"?
They have become buzzwords in our society. Most importantly how do they relate to our Down syndrome children?
The human body is a continuous chain of metabolic reactions. A common spin off of these metabolic processes are molecules called free radicals. Free radicals are charged molecules, which have unbalanced electrons. These free radicals are highly reactive and try desperately to balance themselves. Uncontrolled, free radicals rip electrons from neighboring cells damaging proteins, disrupting DNA and RNA, inactivating enzymes and oxidizing the easiest target of all, fatty tissues in the brain.
Fortunately, the body has internal systems, the antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione (GSH). These enzymes serve a protective role and "scavenge" free radicals. Nutritionally, vitamins such a vitamin A, E, C and minerals zinc and selenium provide free radical protection by trapping these charged molecules and reducing the damage to our bodies.

Are there examples of free radical damage in every day life?
If you slice an apple and leave it sitting on the counter, it will soon turn brown. This is an example of oxidation by free radicals. Now, slice another apple and then dip it in lemon juice or lemon water. The apple will remain white. The vitamin C and the bioflavonoids from the lemon "protect" the apple from oxidation.
If your backyard grill is like ours, it is slowly rusting away. Rusting is another graphic example of the oxidative, free radical process.

How does this relate to down syndrome?
In DS the gene for the enzyme SOD is located on the 21st Chromosome (1,2,3,4), leading to a genetic overexpression of this enzyme. "With over production of SOD, catalase and glutathione peroxidase are challenged to keep up with the accelerated production of hydrogen peroxide. When they don't, excess hydrogen peroxide accumulates in the cells and tissues causing increased oxidative stress, free radical proliferation and accelerated aging" (8).

What do the scientific studies say about DS and SOD?
The SOD genetic overexpression is an area that has solicited much attention. Studies have revealed 50% elevation of SOD levels in the brain and in a variety of blood cells. Italian findings revealed "It has been emphasized that an increased oxidative damage can exist in Down syndrome, and that superoxide dismutase (SOD) seems to play a role in the pathogenesis of this disorder" (3). Another study out of Israel says that this over production of SOD causes increased production of hydroxyl radicals (HO). The study states:

"The most reactive and noxious species is the hydroxyl radical. Its reactivity is so great that when it is formed in living systems, it will react immediately with whatever biological molecule is in its vicinity. One of the major targets is the polyunsaturated fatty acids of membrane phospholipid."(2).
Researchers in the United States have come to the same conclusion. Mary Coleman, M.D., of the Children Brain Research Clinic, published "SOD... has been the most studied of the chromosome 21 genes. Research suggest that high levels of this enzyme could effect membrane fluidity and impair membrane function. ... normal brain function is highly dependent upon membrane interactions, particularly at the synapse."(4).

Dr. Capone at the Down Syndrome Clinic at the Kennedy-Kreiger Center in Baltimore writes, "Elevations in SOD activity and increased lipoperoxidation are observed in Down syndrome brain as early as 15-20 weeks gestation. Alterations in the antioxidant defense system have been hypothesized to play a role in AD pathology observed in older persons with DS." "The manifestations of elevated SOD activity and therapeutic strategies to counter this effect will continue to be an important area of research".

Does oxidative stress effect I.Q. levels in DS?
There is a very interesting study that was conducted by Jérôme Lejeune. Lejeune is considered the father of modern genetics and the discoverer of the extra chromosome in DS and Fragile X syndrome. Lejeune was the first to discover amino acid imbalances in DS.

This particular study found:

"A highly positive correlation exists between erythrocyte glutathione peroxidase and I.Q."
Translated, this means the more glutathione the individual has, the more efficiently they can deal with the onslaught of the highly destructive free radicals and protect precious brain cells. The study further states:
"Many features of Trisomy 21 are consistent with increased oxidative damages: 1) rapid aging with decreasing intelligence quotient (I.Q.) 2) histological changes in brain similar to that seen in neuronal degeneration with accumulation of lipofuscin such as observed in Alzheimer disease, and 3) shortened life span of cells in culture".
Is there a way to test antioxidant vitamins?
The past decade has brought increased research and more accurate laboratory tests. One such lab is Pantox, which specializes in oxidative stress testing and has the world's largest database of this information. Recently, Dr. Charles Thomas analyzed the test results of 65 Down syndrome serum samples.

    Vitamin A     Vitamin E     Beta-carotene  
1st quitile < 1.67 um < 23.1 um < 0.2 um
Number obs. 46 37 25
Expected 13 13 13

"In addition, 16/65 (25%) were SIMULTANEOUSLY in the lower quintile for vitamin A, vitamin E and beta-carotene. Random expectation would predict 0.5 individuals. Clearly these micronutrients are being affected as a group" (10). To more clearly state this, preliminary results show that 62 out of 65 DS subjects tested low for vitamin A, 53 out of 65 tested low for vitamin E and 41 out of 65 tested low for beta carotene.

Dr. Thomas states "There can be no question that Down syndrome individuals are under unusual oxidative stress and prematurely display a variety of degenerative diseases" (9).

What are the effects of antioxidant supplementation?
Recently published are the results of a very important study that was conducted at Harvard University. The researchers took fetal DS and age matched normal brain cells and cultured them in the laboratory. They report that "DS neurons subsequently degenerate and undergo apoptosis whereas normal neurons remain viable. Degeneration of DS neurons is prevented by treatment with free radical scavengers or catalase. Furthermore, DS neurons exhibit a three to fourfold increase in intracellular reactive oxygen species (ROS) and elevated levels of lipid peroxidation that precede neuronal death." (7). (Reactive oxygen species (ROS) is another way to say free radicals).

The researchers found that both normal and DS cultures were very similar in the first 5 to 7 days. "From 7 to 14 days in culture, extensive loss of neurons and neurite processes occurred in DS but not in normal control cultures. After 14 days in culture, neuronal viability in DS cultures was markedly reduced to 41% of the value at 7 days whereas neuronal viability in normal cultures did not decline." (7).

The researchers then took another round of neurons and treated them with a variety of antioxidant vitamins and enzymes (vitamin E, N-acetyl-cysteine (NAC), catalase, S-PBN). The treated DS cultures retained 80% to 95% of their viability. The researchers, Buscigilo and Yanker, clearly, scientifically, and medically prove that "antioxidants inhibit the degeneration of DS neurons" (7).

This study is a powerful statement for using targeted nutritional supplementation to manage the gene dosage effect of SOD.
As one looks at Dr Wisniewski's startling research that "the brain shape in DS newborns was the same as in non-DS, but after 3-5 months of age in DS the antero-posterior diameter was found to be shorter than in non-DS (11)". Severe oxidative stress may be the major cause of these dramatic brain alterations and a leading cause of the pathology of DS.
(For me personally this has been the most difficult piece of scientific information to digest. To discover that my child was born with a normal brain shape and brain size and no one told me I could treat my child with vitamins and growth hormone to protect him from this free radical onslaught.)

Several laboratories that have expertise in testing antioxidant status and some of them have a track record in working with DS.

4622 Santa Fe St.
San Diego, CA 92109

test antioxidant status and amino acid profiles.
5000 Peachtree Ind. Blvd.   
Suite 110
Norcross, GA 30071

test antioxidant, amino acids, organic acids, fatty acids, serum chemistries, nutrient minerals.
1414 Key Hwy.
Baltimore, MD 21230
test antioxidant status, hormonal biomarkers of growth hormone, DHEA, melatonin, estrogen, testosterone.

Two companies offer vitamins that are formulated for Down syndrome. These companies utilized the most current medical literature and research in compounding their vitamins.

1303 Richmond Rd.
Ottawa, Ontario
Canada, K2B7Y4

Vitamins for DS (MSBPlus) and ADD, customized vitamins and specialty compounds.
Jason Pharmaceutical
International Nutrition for DS.   
Offering NuTriVene-D

For every family this is a personal decision. As with all things in life, there are no absolute guarantees and no magical silver bullets offering a "cure". But this is a fact, that DS individuals have medically and scientifically documented metabolic disturbances. The real questions and controversy arises in "What are reasonable testing procedures and what are reasonable therapeutic strategies to manage these metabolic disturbances?"

Education is always a good first step towards making informed decisions. Each of the organizations will be happy to supply information. Metabolic and endocrine test results can give you a window into your child's metabolism and consideration for possible treatment options. Networking with other parents can provide personal experience and useful information. Of course you should always include your physician in this process.

  1. G. Capone, Molecular Advances Toward Understanding Down Syndrome, Down Syndrome Papers and Abstracts for Professionals, Vol 15, No. 2 (1992).
  2. Y. Groner, et al., Molecular Genetics of Down's Syndrome: Overexpression of Transfected Human Cu/Zn Superoxide Dismutase Gene and the Consequent Physiological Changes, Journal de Physiologie 84(1) 53-77 (1990).
  3. G. Gerli, et al., Erythrocyte Antioxidant System in Down Syndrome, American Journal of Medical Genetics Supplement, 7:272-273 (1990).
  4. M. Coleman, The Molecular Biology of Chromosome 21, Children's Brain Research Clinic, based upon "Down Syndrome and the Molecular Biology of Chromosome 21" D. Cooper, Progress in Neurobiology Vol. 30. pp. 507-530.
  5. P. Sinet, J. Lejeune, Trisomy 21 Glutathione Peroxidase, Hexose Shunt and I.Q.. Life Sciences, Vol. 24, 29-34 (1979).
  6. G. Annerén, Downs Syndrome - A Gene Dosage Disease Caused by Trisomy of Genes Within a Small Segment of the Long arm of Chromosome 21, Exemplified by the Study of Effect from the Superoxide Dismutase Gene. Ampis Supplement, 40:71-9,1993.
  7. J. Buscigilo, B. Yanker, Apoptosis and increased generation of reactive oxygen species in Down's syndrome neuron in vitro, Nature, Vol. 378 21-28 (1995).
  8. S. Fowkes, Antioxidant Intervention in Down's Syndrome, Smart Drug News Vol 4, No. 10, April 1996.
  9. C. Thomas, Oxidative Stress and Degenerative Disease in Downs, Pantox Pub, 1995.
  10. C. Thomas, Preliminary observation on 65 samples of serum taken from Downs subjects. Pantox communication, 1995.
  11. K. E. Wisniewski, Down's Syndrome children often have brain with maturation delay: retardation of growth and cortical dysgenesis. Am J Med Genet Suppl 1990: 274-281.
Trisomy 21 hosted a medical conference for the DS parents in Los Angeles. The hosting MOM was Juliee Bramson. Featured at the conference were eminent advocates and researchers for DS, Dr. Charles Thomas of Pantox, Kent MacLeod, Pharmacist and biochemist, Steven Fowkes of Cognitive Enhancement Research Institute, Dr. Paul Spurlock who heads up animal research at Tulane and Louisiana State University and Dixie Lawrence-Tafoya, founder of Trisomy 21 Research.
The major metabolic abnormality that was highlighted was the genetic overexpression of the SOD gene and the resulting oxidative stress that DS suffer. Also covered was the Barcelona study conducted in the seventies, comparing the cognitive enhancement drug piracetam with the amino acid 5-hydroxy tryptophan. The results showed that DS subjects experienced "substantial improvement" in many cognitive areas as compared to 5-hydroxy tryprophan. The question was raised as to why Down syndrome organizations and researchers have failed to follow up with additional research in this area.
Several mothers spoke of their positive experiences with using nutritional supplementation and the profound positive changes they had seen in their children . But one area they wanted the scientific community to address further was the metabolic differences in DS, that cause them to be more sensitive to drugs which use the methylation pathway (the SAM cycle). Of utmost concern to these parents was their child's reaction under anesthesia. Each of their DS children had experienced a sensitive reaction to anesthesia and their children had died. Fortunately, two of the children were able to be resuscitated. There was not a dry eye as the Jones family told of the loss of the darling son Bryan. The family called for more research in this area. These families also wanted to know why their anesthesiologist and their doctors did not know that individuals with DS were sensitive to certain anesthesia (atropine and scoplomine) and why the national DS organizations does not inform doctors and parents about this topic. (Locally, a 3-year-old DS went in for tonsils, tubes and adenoids. The mother reports the child was hospitalized for 2 days because she would not "wake up". The mother further states that her daughter regressed, lost many vital skills and it took almost 2 months for her to "be herself".
Dr. Charles Thomas and Steven Fowkes presented on the genetic over expression of SOD and the damage it causes. Kent MacLeod presentation covered many of the metabolic disturbances he has seen in amino acid profiles (see metabolic disturbance). Some of these disturbance have been noted in other scientific studies. Dr. Thomas presented oxidative stress test results on over 100 individuals with DS. Across the board testing showed them to be deficient in most antioxidant vitamins and minerals (see SOD article).
Since oxidative damage created by SOD is so profound, discussion covered whether it should be considered medically negligent in not treating DS with antioxidants. There are many medical precedents of treating inborn errors of metabolism, such as Phenyiketonuria (PKU). Phenyiketonuria, is caused by an enzyme deficiency (hepatic phenylalanine hydroxilase) which prevents phenylalanine from being converted into the amino acids tyrosine. Treatment involves dietary restriction of phenylalanine. If untreated, PKU result in severe mental retardation and an I.Q. of around 20.
Many of the parents were very enthused about this opportunity for their children. One parent, a medical doctor, was so pleased with the changes she has seen in her child with DS that she is leaving private practice and taking a research position so she can facilitate additional nutritional research.
While at the convention I had the opportunity to see pictures of children who had started targeted nutritional supplementation when they were just months old. These children looked very, very good and parents report they have improved skills and cognition over their untreated DS peers. All DS children should have this same opportunity!
Thank you Dixie and all the presenters. If you would like a video of the medical conference you may contact MOM, Juliee Bramson at 310-472-8778. In addition the LA Times covered the conference did a very balanced job reporting the conference.
Many of the Metabolic test results have ended up at Nutri-Chem. The results have been analyzed by Kent MacLeod and Dr. Lin, Ph.D. Some of the metabolic trends and abnormalities are listed below. This information was presented at the L.A. symposium.

By: Kent MacLeod, Nutri-Chem
  1. Impaired conversion of beta-carotene to vitamin A.
    • 70% results show vitamin A deficiency.
  2. Deficiency of the anti-oxidant enzyme glutathione.
  3. Impairment of fatty acid transfer into mitochondria.
    • 70% acetyl-l-carnitine.
    • 70% CoQ1O.
  4. Impaired methyladon which results in many defective enzymes.
    • Folic acid deficiencies.
    • Excess ethanolamine which results in low acetylcholine levels.
    • Digestive enzyme deficiencies.
    • Enhanced requirement of methionine.
    • Sensitivity to atropine and methotrexate.
  5. Disturbance in sulfur metabolism.
    • Molybdenum deficiency.
    • Sensitivity to sulfur antibiotics.
    • Sensitivity to anesthetics.
    • Sensitivity to sulfites and nitrites.
    • Possible behavior disturbances from sulfur sensitivities.
    • Skin rash.
    • Higher incidence of autistic and ADHD behavior.
  6. Amino acid disturbances with tryptophan deficiency. - Tryptophan necessary to break down protein.
  7. B vitamin and urine organic acid disturbances. - 100% of test showed vitamin B6 deficiency.
  8. Mineral deficiencies.
    • Magnesium.
    • Zinc.
    • Molybdenum.
  9. Heavy Metal toxicities.
    • Aluminum.
    • Titanium.
    • Others barium, lead, vanadium.
  10. Superoxide dismutase impairs the conversion of thyroid hormones T4 to T3 and results in high levels of inactive T2.

I have a new book. (Don't I always have a new book.) This one is called Growth Hormone by Harvey Scanes and Daughaday, published by CRC Press, 1995. While reading this book one comes to realize how important growth hormone is to our metabolic processes and how a deficiency can have such a profound effect. The book has many highly technical portions. (For some reason I no longer find Danielle Steel novels very challenging reading material).

So many of the symptoms and pathologies discussed in the book would be identical to symptoms and pathologies seen in DS.

CERI (Cognitive Enhancement Research Institute) has been following the evolving research and targeted nutritional therapy for individuals with DS. The April issue has an outstanding article, "Antioxidant Intervention in Down's Syndrome". I recommend every one order a copy at (415) 321-2374. The article presents a persuasive review of the metabolic disturbances and how new testing technologies are helpful in assessing antioxidant status and guiding nutritional intervention strategies.

Did you know that one of the key people who help start the National Down Syndrome Congress was a fellow by the name of George Johnson. One of the many original goals of the NDSC was to research Dr. Turkel's vitamin treatment of DS. Mr. Johnson stills runs a newsletter.

George Johnson
1409 N. First St.
Aberdeen, SD 57401
Following is a chart supporting the use of growth hormone treatment in Down syndrome.


Deficit in head circumference.   " is now well established that GH stimulates neuronal and glial proliferation and increases brain and cranial size in young animals" pg. 443.

Delayed brain development and myelination of cerebral pathways.   "A neurotrophic role for GH is also indicated by the severe deficits in brain development and RNA/DNA synthesis, and impaired proliferation and myelination of neural and glial cell that occur in GH-deficient states." pg. 443

Slow learning and memory problems.   "GH may influence memory by affecting cholinergic transmission ...or by generally enhancing brain development." pg. 445.

Decreased height and shortened limbs.   "GH stimulates the cartilage and bone growth by increasing circulating concentrations of IGF-1." pg. 391.

Hypotonia   "Collagen synthesis is stimulated after only 14 days of GH treatment." pg. 490.

Low immune response.   "Growth hormone is necessary to maintain lymphatic tissue populated with lymphocytes since the removal of ...GH... results in the atrophy of the thymus gland." pg. 407.

Abnormal thyroid function.   "GH administration to hGH deficient children is followed by increased circulating concentration of T3 but decreased concentration of T4." pg. 424.

High amounts of body fat and poor digestion.   "...effects of GH on protein and carbohydrate metabolism.." and "..excess body fat is significantly reduced by GH treatment." pgs 486,485.

Excerpts from "Growth Hormone" by Harvey, Scanes and Daughaday.



Next newsletter in September, 1996

This newsletter has been provided as a courtesy of The MAGIC Foundation. It is for informational purposes only. The MAGIC Foundation does not assume any liability for its content. Consult your physician for diagnosis and treatment.

  Revised: May 27, 1999.