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From the April 15th, 1996 issue of Smart Drug News [v4n10]. Copyright (c) 1996, 1997, 1998. All rights reserved.
Smart Drugs & Downs Syndrome: Part 2
by Steven Wm. Fowkes
Two years ago, we published our first article about smart drugs and Downs syndrome which focused primarily on clinical approaches. This article will begin an extensive discussion of metabolic and biochemical mechanisms underlying Downs syndrome and proposed nutritional interventions which may mitigate these metabolic disturbances.
Unlike most other genetic conditions which are characterized by a deficiency (deletion) or change (mutation) of the genetic material, Downs syndrome is characterized by a duplication of all or part of the 21st chromosome. Normally, each cell in the body is supposed to have two 21st chromosomes (one derived from the mothers egg and the other from the fathers sperm). Every time a cell divides, each of the 46 chromosomes must be duplicated and separated, one copy of each chromosome ending up in each daughter cell. Sometimes the process of pulling apart the duplicated chromosomes malfunctions, and both copies of one of the 21st chromosomes end up in the same daughter cell. In other words, one cell has only one 21st chromosome (which fails to replicate) and the other has three 21st chromosomes. This is why Downs syndrome is referred to as trisomy 21 (tri means three, somy refers to chromosome). This extra genetic material causes overexpression of the duplicated genes. In other words, genes make both enzymes and proteins, and too many genes lead to too many enzymes and proteins. This, in turn, distorts normal metabolism and development.
The key concept underlying nutritional intervention in Downs syndrome is metabolic correction of genetic overexpression. Although the extent of the metabolic disturbances in trisomy 21 is not fully known, several of the more significant disturbances are now becoming well characterized. Effective metabolic management of these disturbances offers the hope of ameliorating the disability typically associated with untreated Downs syndrome. The degree of amelioration must depend on 1) the metabolic effectiveness of the intervention, and 2) the age at which it was begun. Early clinical reports by physicians and anecdotal reports by parents utilizing some of the approaches that will be discussed in this article suggest that functional normalization of growth rate and cognitive development is a reasonable expectation if intervention is begun early in life. This possibility is at complete odds with the orthodox view that Downs syndrome infants are born retarded and that treatment is fundamentally futile.
Several of the major metabolic pathways known to be disturbed in trisomy 21 are directly attributable to genetic overexpression. Perhaps the most important example of this is destabilization of the antioxidant defense system by over-expression of the enzyme superoxide dismutase (SOD), which is located on the 21st chromosome. Overexpression of the enzyme cystathionine beta-synthase seems to be significantly responsible for the metabolic disruption of active methylation pathways (the SAM cycle). And connective-tissue problems appear to be directly attributable to overexpression of collagen genes on the 21st chromosome.
Other metabolic disturbances have not been tied to specific genes. As examples, tryptophan deficiency and ammonia accumulation are common features of Downs syndrome. Fortunately, these metabolic disturbances are just as amenable to nutritional intervention as those tied to genes. The remainder of this article will be devoted to discussing the antioxidant disturbances associated with overexpression of SOD.
Superoxide dismutase (SOD) is a vital free-radical scavenger. Its job is to mop up stray superoxide ion radicals (O2-) and convert them to hydrogen peroxide (see Figure 1). Hydrogen peroxide is then detoxified by other enzymes (catalase and glutathione peroxidase). Normally, SOD is in balance with catalase and glutathione peroxidase. But in Down's syndrome, there are three copies of the SOD gene instead of the normal two. 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 (see Figure 2) causing increased oxidative stress, free-radical proliferation and accelerated aging.
When endogenous (internally manufactured) antioxidant enzymes (catalase and glutathione peroxidase) are overwhelmed with hydrogen peroxide, exogenous (dietary) antioxidants are forced to take up the slack. This greater-than-normal burden on exogenous antioxidants is evidenced by depleted levels of vitamins A, E and/or C, zinc, selenium, and/or glutathione in untreated Down's syndrome individuals.
Glutathione (GSH) is a central player in the antioxidant defense system (see Figure 3). It is a tripeptide (3-amino-acid protein) made from glutamate, cysteine and glycine. The active site on the glutathione molecule is the sulfhydryl (SH) group on the cysteine part of the glutathione (which is where the SH comes from in the GSH abbreviation for glutathione). The sulfhydryl group (sometimes called a thiol group) interacts with a free radical to form a glutathione radical, which dimerizes (pairs up with another glutathione radical) to form oxidized glutathione (GSSG) (see Figure 3). Oxidized glutathione is then recycled (reduced) back to glutathione for reuse.
The maintenance of reduced glutathione appears to be especially critical for overall health maintenance; Down's syndrome children appear to be more susceptible to infection when glutathione levels are low, even when other deficiencies are milder than expected [MacLeod, 1996]. Down's syndrome children with high glutathione levels appear to be more healthy, even if they are suffering from additional deficiencies that are more severe than usual.
Although glutathione levels do tend to increase when other antioxidant deficiencies are corrected, they generally do not fully normalize. We do not know why. Given that cysteine is a component of glutathione, it is somewhat paradoxical that Down's syndrome is characterized by abundant cysteine and deficient glutathione. The dynamics of this relationship are not yet fully understood, but it may be wholly or partly the direct result of oxidative stress.
Glutathione peroxidase (GSHpx) is a endogenous antioxidant enzyme that detoxifies hydrogen peroxide (HOOH) and fatty acid hydroperoxides (fatty-OOH). It is constructed from four identical subunits, each of which contains one atom of selenium (Se). Glutathione peroxidase uses reduced glutathione to detoxify peroxides, releasing oxidized glutathione in the process. Oxidized glutathione is recycled by glutathione reductase back to reduced glutathione (see Figure 3) using riboflavin (vitamin B2) as a cofactor and NADPH as a reducing agent (an anti-oxidizing substance).
The central role of selenium in glutathione peroxidase activity provides a possible focus for intervention. Selenium supplementation may be able to up-regulate glutathione peroxidase activity to restore some degree of balance with the overexpressed SOD. In areas of the world where selenium deficiency is severe (i.e., New Zealand and China), selenium supplementation has been found to readily reverse selenium-deficiency diseases in animals (e.g., white-muscle disease in sheep) and man (Keshan's disease).
Food sources of selenium can be problematic. Selenium is not an essential nutrient in plants as it is in animals. Wheat grown in selenium-rich soil (i.e., South Dakota) contains respectable levels of selenium, but wheat grown in selenium-poor soil (i.e., Oregon) does not. Does anybody really know where their wheat was grown?
In one trial of Down's syndrome individuals, selenium supplementation was found to increase the levels of glutathione peroxidase. Thus, selenium supplementation appears to be a viable strategy for compensating for SOD overexpression.
The control of free radicals and oxidizing agents is central to the life process. While the atmosphere is dominated by oxygen (20%) and free radicals (billions per cubic foot), the chemical environment within our cells is reduced (the opposite of oxidized). A good way to think of oxidation and reduction (redox for short) is in terms of electrons. The atmosphere and oxidizing agents are poor in electrons, and the reduced chemicals of cellular metabolism (fatty acids, carbohydrates and amino acids) are rich in electrons. We tap into the electron tug-of-war between oxidants and reductants to drive our biochemical machinery, much like how a battery drives an electric motor. By carefully transporting oxygen (safely bound to hemoglobin) to the cells where it can be combined with carbohydrate (acetate) under enzymatically controlled conditions, a host of electron-rich chemicals essential to life can be generated (NADH, NADPH, FADH2, and ATP).
The fundamental antagonism between the oxidized atmosphere and reduced living systems makes control of oxidation (and oxidizing free radicals) essential. The gasoline-air explosion in a car engine or a raging forest fire are graphic examples of the power of oxidation in action. By comparison, the bio-oxidation of fats and carbohydrates is a severely constrained process. Even so, significant quantities of oxidizing free radicals (a few percent of the total energy flux) escape from biological control. The antioxidant defense system is necessary to mop up these stray free radicals to maintain the reduced conditions necessary for life.
Loss of control of oxidation and free radicals has been implicated in such diverse conditions as bruising, cataracts, sunburn, radiation poisoning, cancer, heart disease, and sudden infant death syndrome.
Part 3 of this series will continue in the next issue with discussion of disturbances in methylation metabolism, collagen synthesis, tryptophan metabolism and ammonia detoxification.
Daumer-Haus C, Schuffenhaurer S, Walther JU, Schipper RD, Porstmann T and Korenberg JR. Tetrasomy 21 pter>of q21.1 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.
MacLeod K. Personal communication, Down's Syndrome Conference, Los Angeles, 24 February 1996.