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From the June 3rd, 1996 issue of Smart Drug News [v5n1]. Copyright (c) 1996, 1997, 1998. All rights reserved.
Smart Drugs & Downs Syndrome: Part 3
The previous article of this series (Part 2) discussed genetic overexpression and the antioxidant disturbances associated with the superoxide dismutase (SOD) gene. This article will cover additional metabolic disturbances, and nutritional interventions targeted to ameliorate those disturbances.
Downs syndrome individuals exhibit significant disturbances in methylation pathways (see Figure 1). The over-expression of cystathionine beta-synthase (located on the 21st chromosome) causes homocysteine to be converted into cysteine (reaction 2) at an accelerated rate [Chadefaux, 1985]. This conversion requires serine. One of the signs of increased cystathionine beta-synthase enzyme activity is a systemic depletion of serine reserves. Indeed, the vast majority of untreated Downs individuals show serum serine levels at the low end or below the low end of the normal range.
Serine is also used to fuel the folic acid cycle (Figure 1, cycle B). The shortage of serine impairs the production of methyl tetrahydrofolate (Me-THF), which is required to recycle homocysteine to methionine (reaction 1). With an insufficiency of Me-THF, more homocysteine goes down the cystathionine pathway to be converted into cysteine instead of being recycled into methionine. This undercuts methylation metabolism.
Methionine is required for the production of S-adenosylmethionine (SAM), the active methyl donor that is a vital part of countless metabolic reactions throughout the body. The under-activity of the folate cycle coupled with overactivity of the cystathionine pathway diverts the homocysteine from the SAM cycle (see Figure 2). In other words, the almost-closed cycle is opened and homocysteine drains into the cysteine pool.
Many parents have reported cognitive and behavioral improvements after supplementation with methyl donors (DMAE, choline, DMG and betaine) and methylation catalysts (folic acid and vitamins B-6 and B-12). SAM itself has also been used to treat children with attention-deficit disorders.
Although methylation pathways are usually deficient in Downs syndrome, some degree of moderation is required not to overdrive the folic acid cycle (Figure 1, Cycle B). In Dr. Peters study of folic acid in Downs syndrome, approximately ten percent of the children exhibited excessive hyperactivity and/or irritability when given 20 mg folic acid (50 times the adult RDA). In a recent version of MSB Plus compounded by Nutrichem Pharmacy (which normally includes 45 mg vitamin B6, 45 mcg B12, 1 mg folic acid, 200 mg serine, 75 mg methionine and 75 mg cysteine), an increase of folate to 3 mg (7.5 times RDA) and methionine to 275 mg (approximately the RDA) resulted in a substantial number of children exhibiting extreme irritability and hyperactivity behaviors. The symptoms reversed in days with discontinuation of the additional folate and methionine, but this experience should encourage moderation when supplementing methyl donors and methylation co-factors.
It is not known whether the disturbances in serine, folate and methylation metabolism are fundamentally due to cystathionine beta-synthase overactivity or whether they may also be due to impaired digestion and malabsorption of associated vitamins, minerals and amino acids. An experiment is being designed using trisomy-16 mice to investigate the influence of digestive stimulation on metabolic imbalances that might give us some clues.
Collagen is a major constituent of connective tissue, skin, cartilage, tendon and bone. It comprises approximately 30% of all the protein in the human body. Collagen proteins are fibrous (linear, or branched) and they are responsible for the toughness of tissues. Without collagen, tissue would have the consistency of Jell-O.
Collagen proteins have an unusual amino acid profile. They are 1) devoid of tryptophan and cysteine, and 2) rich in glycine, lysine, proline, hydroxyproline and hydroxylysine. The latter two are rare amino acids.
The collagen connection to Downs syndrome is fairly obvious. Newborn infants and children exhibit extreme joint laxity. In addition, structural defects in the formation of the heart affect roughly half of all Downs syndrome individuals. Of the dozen-plus collagen genes that have been discovered, two of them reside near the tip of the 21st chromosome.
Collagen synthesis is extremely complicated. Collagen is initially made as a preprocollagen, which is transported and converted to procollagen, which is then hydroxylated, glycosylated, wound into a helix and transported again, after which it is clipped into collagen molecules, assembled into collagen fibers, and cross-linked into final form. Each of these steps could be impaired by a host of conditions. For example, the hydroxylation of collagen is dependent on vitamin C, which also serves as an antioxidant. Also, the final cross-linking of collagen depends on the enzyme lysyl oxidase, which uses copper as a cofactor. Copper is also a component of the over-expressed superoxide dismutase. It is not known to what degree collagen mismetabolism may be due to induced deficiencies (e.g., vitamin C), or the direct over-expression of the two collagen genes on the 21st chromosome.
These two mechanisms may not be easily separable. The competitive effects between overactive and underactive collagen pathways may induce secondary proline or vitamin C deficiencies. In other words, the overactive collagen pathways may squander scarce resources leaving the underactive pathways starved for raw materials.
It is this latter observation that led Dixie Tafoya to try feeding the collagen pathways as a nutritional intervention strategy for her daughter. When she added vitamin C, bioflavonoids, alpha-ketoglutarate and proline, her daughters connective tissue and ligaments improved markedly. This strategy appears to be universally successful.
Downs syndrome individuals frequently show low serum tryptophan levels. Whether this deficiency is primary (poor tryptophan absorption) or secondary (increased tryptophan catabolism) is not known. Regardless of the cause, low tryptophan levels impair protein synthesis (tryptophan is usually a rate-limiting amino acid) and decrease serotonin levels (tryptophan is the precursor to serotonin). Serotonin is the brain neurotransmitter that not only regulates emotional control and sleep quality, but helps influence carbohydrate feeding behavior. People with low serotonin levels tend to have carbohydrate cravings.
Serotonin is also the precursor for melatonin, an important neurohormone that plays a role in the synchronization of circadian (daily) biorhythms, the regulation of aspects of immune function, and protection from hydroxyl radicals (an especially dangerous kind of free radical that can be easily produced from hydrogen peroxide). Although newborn infants produce minimal melatonin, production dramatically increases during the first two years of life. Melatonin peaks in early childhood, and begins a steep decline just before puberty.
One of the key ammonia-carrying molecules in the brain is glutamine, an amino acid which tends to accumulate in Downs syndrome. Glutamine is made from glutamate (glutamic acid) by the addition of one ammonia molecule, and from alpha-ketoglutarate by the addition of two ammonia molecules. Due to the general overabundance of ammonia in Downs syndrome, alpha-ketoglutarate is the ideal precursor to supplement the glutamate/glutamine pathways without increasing the ammonia burden.
The primary urea-carrying molecule in the body is the amino acid arginine. When arginine reaches the kidneys, it is split into urea and ornithine by the enzyme arginase. The urea is dumped in the urine and ornithine is recycled to pick up more urea. Due to the over-abundance of ammonia, ornithine is the preferred supplement to increase urea-carrying capacity in Downs syndrome.
Arginine and ornithine are also used clinically to increase the release of growth hormone. Typically, relatively large doses are required to produce this effect. However, there might be some degree of growth-hormone effect from smaller doses in children who are slower growing and/or metabolically challenged in varying ways. More research will be needed to determine whether this effect is significant in Downs syndrome.
Although antioxidant disturbances, and serine and tryptophan deficiencies, are almost universal concomitants of Downs syndrome, there are other metabolic problems that commonly show up. Zinc deficiency, for example, may have serious manifestations in Downs syndrome infants. Zinc is not only a component of superoxide dismutase, it is required for proper growth, healing and immune function. Perhaps more importantly, zinc is required to produce insulin-like growth factor type 1 (IGF-1), which is specifically deficient in Downs syndrome children after about one year of age. Zinc supplementation has been shown to significantly increases IGF-1 levels in non-Downs syndrome children. In an earlier Downs syndrome study, 15 of 22 individuals receiving zinc sulfate experienced increased growth [Napolitano et al., 1990]. This suggests that zinc deficiency may be a common problem in Downs syndrome.
Another problem that has been reported to be somewhat common is hypothyroidism, which is usually treated with thyroid supplements. Although overexpression of SOD may be directly responsible for the diminished levels of rT3 [Lejeune, 1990], this hormone has minimal biological activity and this mechanism cannot account for lowered T3 or T4. Some other nutritional factors may directly influence thyroid hormone regulation. Iodine is necessary for the production of thyroxine (T4), and selenium is a component of the enzyme that converts T4 into T3, the most potent and active form of thyroid hormone.
Some doctors suggest that thyroid should be in the top half of the normal range for best health, but many doctors unfamiliar with hypothyroidism and Downs syndrome de-emphasize thyroid medications because of a widespread professional prejudice against supplementing thyroid when blood tests indicate that thyroid hormones are in the low-normal range.
In the last decade, several new testing technologies have been developed for assessing nutritional requirements. The use of these testing systems offers the potential of identifying the specific nutritional deficiencies of each individualwhether they have Downs syndrome or not. Red-blood-cell mineral analysis is good for determining nutritional trace mineral deficiencies (and excesses) for less than $200. Hair mineral analysis of trace minerals is also a valuable nutritional assessment, but it is especially valuable for testing heavy metals (lead, mercury, cadmium, bismuth, arsenic, etc.). Although it may be more difficult to interpret, it costs only about $50.
Two different kinds of antioxidant tests are now available. An antioxidant profile measures the levels of specific antioxidants (ascorbate, carotenoids, tocopherols, bilirubin, ubiquinone, urate, etc.) and oxidants (iron, TIBC, ferritin, etc.). This is probably one of the most useful tests for nutritional assessment in Downs syndrome. The oxidant stress test measures the ability of living cells to resist oxidative stress in an ex vivo assay. The latter test is an exciting new development.
Organic acid testing measures the many chemicals that are found in urine. This test may be one of the most useful tests for fine-tuning a nutritional program. By quantifying the waste acids in urine, signs of overactive or underactive enzyme systems can be identified.
Although all these tests require considerable sophistication for meaningful interpretation, they are powerful tools for identifying metabolic problems and guiding nutritional (and pharmacological) intervention. These tests are in no way limited to individuals with Downs syndrome. They can be used to identify nutritional deficiencies in anybody and everybody. We will describe these testing systems in more detail in future articles.
Anneren G and Edman B, Down syndromea gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide type-1 (SOD-1) gene. AMPIS Suppl 40: 71-9, 1993.
Antila E, Norberg U-R, Syvaoja E-L and Wetermarck T. Selenium therapy in Downs Syndrome (DS): a theory and a clinical trial. In: Antioxidants in Therapy and Preventative Medicine, pp. 183-86, Plenum Press, New York, 1990.
Chadefaux B, Rethor MO, Raoul O, Ceballos I, Poissonnier M, Gilgenkrantx S and Allard D. Cystathionine beta synthase: Gene dosage effect in trisomy 21. Biochem Biophys Res Commun 128: 1-10, 1985.
Daumer-Haas C, Schuffenhauer S, Walther JU, Schipper RD, Porstmann T and Korenberg JR. Tetrasomy of 21 pterq22.1 and Down syndrome: molecular definition of the region. Amer J Med Genetics Supplement 53(4): 359-65, 1 December 1994.
Epstein CJ. Models for Downs syndrome: Chromosome 21-specific genes in mice. Prog Clin Biol Res 360: 215-32, 1990.
Licastro F, Mocchegiani E, Zannotti M, Arena G and Masi M. Zinc affects the metabolism of thyroid hormones in children with Downs syndrome: normalization of thyroid stimulating hormone and of reversal triiodothyronine plasmic levels by dietary zinc supplementation. International Journal of Neuroscience 65(1-4): 259-68, Jul-Aug 1992. Before zinc supplementation, plasmic levels of zinc and thymulin, a zinc dependent thymic hormone, were significantly decreased in DS children. After four months of dietary supplementation with zinc sulphate, a normalization of plasma zinc, thymulin and TSH levels was observed. Plasmic levels of rT3 significantly increased, and after zinc treatment no difference was detectable between DS children and normal children. Clinical evaluation of the health status of DS children showed that zinc supplementation decreased the incidence of infectious diseases and improved school attendance.
Murphy M, Insoft RM, Pike-Nobile L, Derbin KS, Epstein LB. Overexpression of LFA-1 and ICAM-1 in Down syndrome thymus. Implications for abnormal thymocyte maturation. Journal of Immunology 150(12): 5696-703, 15 June 1993. Given our recent observation that DS thymuses overexpress mRNA for IFN-gamma and TNF... TNF induces indoleamine-2,3-dioxygenase (IDO), the peripheral enzyme which catabolizes tryptophan in response to immune activation.
Napolitano G, Palka G, Grimaldi S, Giuliani C, Laglia G, Calabreese G, Satta MA, Neri G and Monaco F. Growth delay in Downs syndrome and zinc sulphate supplementation. Amer J Med Genetics Supplement 7: 63, 1990.
Stabile A, Pesaresi MA, Stabile AM, Pastore M, Sopo SM, Ricci R, Celestini E and Segni G. Immunodeficiency and plasma zinc levels in children with Downs syndrome: a long-term follow-up of oral zinc supplementation. Clinical Immunology & Immunopathology 58(2): 207-16, February 1991. 63.2% of DS children had plasma Zn levels below 0.7 mcg/dl DS children showed significantly lower proliferative response to phytohemagglutinin A significant increase in DNA synthesis was obtained after oral administration of zinc sulfate (20 mg/kg/day), for 2 months) The lumphocyte response to PHA appeared to be normal in all patients up to six months after the end of zinc supplementation and it became low in half of the patients 22 months after therapy.