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Nutritionalsupplementation inDown syndrome:theoreticalconsiderations andcurrent status Cornelius Ani* MBBS MSc DCH, Research Fellow;Sally Grantham-McGregor MBBS MD, Professor of ChildHealth and Nutrition, Centre for International Child Health;David Muller PhD, Reader in Biochemistry, BiochemistryUnit, Institute of Child Health, University College London,London, UK. *Correspondence to first author at Centre for InternationalChild Health, Institute of Child Health, University CollegeLondon, 30 Guilford Street, London WC1N IEH, UK.
E-mail: cani@ich.ucl.ac.uk Down syndrome (DS) is the most common inherited cause activity may alter the normal steady state equilibrium of reac- of learning disability1, and affected individuals are more tive oxygen species leading to oxidative injury in DS4,5. prone to infections, leukaemia, congenital heart disease and SOD catalyses the dismutation of superoxide radicals to other anomalies, thyroid dysfunction, early senescence and hydrogen peroxide which is further metabolised to water by Alzheimer’s disease2. These complications create a heavy glutathione peroxidase (GSH-Px) or catalase3. In DS, the burden for carers of individuals with DS and the social and SOD:GSH-Px ratio is increased and this imbalance may lead health services. Consequently, any intervention that amelio- to the accumulation of unmetabolised hydrogen peroxide rates some of these complications will have a significant which may then react with transition metals like iron (Fenton impact on the quality of life of individuals with DS and their reaction)3 to form the hydroxyl radical6 (Fig. 1). The latter is carers. However, before investing resources in interventions, the most reactive oxygen radical known and can, for exam- it is important to ascertain their scientific validity.
ple, readily initiate lipid peroxidation resulting in damage to The Internet and the lay press make many claims that cer- cell membranes3. Because the brain is rich in highly polyun- tain expensive nutritional supplements improve the out- saturated fatty acids which are particularly susceptible to come in DS. These claims have left some health professionals lipid peroxidation, it is potentially vulnerable to this type of confused and parents of children with DS vulnerable to pres- damage7. Therefore, it is hypothesised that an overexpres- sures to spend large amounts of money on nutritional sup- sion of SOD causes free radical mediated damage and that plements whose benefits have not been proved. This review this may contribute to the learning disability and early onset was undertaken firstly, to determine whether there is a theo- of Alzheimer’s disease which are typical of DS. The following, retical basis to expect that nutritional supplements may which will be considered in turn, support the above hypoth- improve the pathology of DS, and secondly, to critically esis: (1) there is an increase in SOD activity, (2) there is evi- examine published trials of nutritional supplements in DS to dence of increased lipid peroxidation, (3) there is a determine whether the existing evidence supports claims compensatory increase in the activities of GSH-Px and the that nutritional supplements improve the outcome in DS.
Increased superoxide dismutase (SOD) activity The presence of an extra chromosome 21 in DS results in Oxidative stress is defined as an imbalance between produc- overexpression of genes residing on that chromosome. The tion of oxygen-derived free radicals and their removal by resulting ‘gene dose effect’ is thought to account for most of antioxidants3. The activity of superoxide dismutase (SOD) – the pathophysiology of DS1. One of these genes codes for the a key enzyme in the metabolism of oxygen-derived free radi- enzyme SOD6. As expected from the gene dose effect, many cals – is increased in DS (see below). This increase in SOD studies have found an increase in SOD activity of 50% or Developmental Medicine & Child Neurology 2000, 42: 207–213 more in various tissues of individuals with DS8–16.
control fetuses. These authors also showed that cells with a Similarly, many animal studies have shown 50% or more high SOD:GSH-Px ratio are more likely to undergo apoptosis overexpression of SOD in transgenic mouse models of when challenged with hydrogen peroxide, which supports the findings of Busciglio and Yankner24 cited earlier.
Further evidence of increased oxidative stress in DS was provided by Sinet and coworkers7 who demonstrated a 15% A number of animal studies have shown that an increase in increase in HMPS activity in the red blood cells of individu- SOD is associated with increased rates of lipid peroxidation als with DS compared with individuals without DS. Because HMPS is involved in the metabolic pathway that sustains the A 36% increase in lipid peroxidation was also demonstrat- activity of GSH-Px, its increased activity in individuals with ed in the cerebral cortex of fetuses with DS who were incu- DS is further evidence for the presence of oxidative stress7.
bated in vitro with iron and ascorbate compared with infants An increase in HMPS activity has also been reported in mice without DS12. In addition, Busciglio and Yankner24 showed that cultured cortical neurons from fetuses with DS hadapproximately four times more intracellular free radicals and OXIDATIVE STRESS AND OTHER FEATURES OF DS an increased level of lipid peroxidation compared with neu- rons from individuals without DS. The neurons of fetuses It has been hypothesised that abnormal metabolism of reac- with DS were also more likely to undergo apoptotic degener- tive oxygen species may also contribute to the defective ation which was prevented by the addition of antioxidants.
immunity and increased susceptibility to infections typically Significantly higher levels of the products of lipid peroxi- seen in individuals with DS. The formation of oxygen radicals dation have also been reported in the blood or urine of indi- is one of the key mechanisms by which phagocytic leuko- viduals with DS than in individuals without DS13,25–27.
cytes kill pathogens36. The serious consequence of failure inthis system is clearly seen in the dramatic increase in severe Compensatory increase in the activity of glutathione infections of patients with chronic granulomatous disease37 peroxidase and the hexose monophosphate shunt whose leukocytes cannot form the superoxide radical In addition to increased SOD activity, many studies have because of a deficiency of nicotinamide adenine dinu- reported increased activity of GSH-Px in various tissues of individuals with DS6,7,11,13,16,28–33, as well as in animal There are at least two possible mechanisms by which an models18. Because Wijnen and colleagues34 have localised increase in SOD activity can reduce immunity in DS. Firstly, a the gene for GSH-Px on chromosome 3, its increase in indi- hyperactive SOD system is likely to result in a decrease in the viduals with DS is not a gene dose effect. Therefore, it is likely concentration of superoxide radicals, which may in turn to be a physiological/protective response to cope with the cause a reduction in the microbicidal activity of leuko- excess hydrogen peroxide produced by the hyperactive SOD cytes23,36. Secondly, an increase in SOD activity may lead to system6. However, the 50% increase in activity of SOD is much an excess of hydrogen peroxide which may damage immune higher than the percentage increase usually reported in activ- cells and impair normal signal transduction processes ity of GSH-Px6,7,16,32,33. De Haan and colleagues35 reported a two-fold elevation in the SOD:GSH-Px ratio measured in a In support of these hypotheses, it has been shown that number of organs of aborted fetuses with DS compared with neutrophils from individuals with DS produce less superox-ide radicals than individuals without DS36,39. Similarly,Mirochnitchenko and Inouye23 found that a two-fold over-production of SOD by intraperitoneal macrophages from transgenic mice, resulted in an inhibition of extracellularrelease of superoxide radicals, increased intracellular pro-duction of hydrogen peroxide, and a reduction in microbici- Peled-Kamar and colleagues5 have shown that the activity of SOD in the thymus of transgenic mice is increased by two-to five-fold, and that the thymus is more susceptible to lipopolysaccharide-induced apoptotic cell death. The increased SOD activity was also associated with an increased production of hydrogen peroxide and lipid peroxidation.
When cultured under stressed conditions (e.g. addition oftumour necrosis factor), the bone marrow cells from the transgenic mice produced two to three times fewer granulo-cyte and macrophage colonies than control mice. It was sug-gested that these defects resulted from increased oxidativedamage5 although the authors did not investigate whetherthe addition of antioxidants corrected the immune defects.
Figure 1: Hypothesised pathway for increase in SOD There is now evidence linking increased oxidative stress with leading to increased oxidative stress in DS. increased DNA damage in DS27,40. Jovanovic and coworkers27 Developmental Medicine & Child Neurology 2000, 42: 207–213 compared the levels of 8-hydroxy-2-deoxyguanosine (a bio- an extra demand for antioxidant nutrients like vitamins C marker of oxidative damage to DNA) in 166 matched pairs of and E, β-carotene, and selenium (cofactor for GSH-Px). Thus individuals with DS and their siblings, and found a significant- even normal serum concentrations of these nutrients could ly increased concentration of 8-hydroxy-2-deoxyguanosine in be functionally deficient in the face of excess demand. This the urine of individuals with DS. Pincheira and colleagues40 opens the possibility that antioxidant nutrient supplementa- found an increase in chromosomal damage in lymphocytes of tion might help to ameliorate the pathology of DS. We individuals with DS compared with individuals without DS, would, therefore, hypothesise that supplementation with which could be reduced by more than 50% by the addition of increased amounts of antioxidant nutrients could benefit vitamin E to the cell culture. As vitamin E is a powerful antiox- individuals with DS. The following section reviews trials of idant, it was hypothesised that the increased chromosomal nutritional supplementation and a selection of other non- damage in DS resulted from increased oxidative stress. These nutritional/pharmacological interventions which have been studies, therefore, not only provide further direct evidence for increased oxidative stress in DS but also suggest a possibleexplanation for the increased malignant potential associated We found many published trials of supplementation withnutrients and pharmacological agents in individuals with DS, including zinc, selenium, megavitamin/mineral prepara- There is some evidence of an association between mental tions, vitamin A, vitamin B6 and its precursors, ‘targeted development in DS and oxidative stress. Sinet and nutritional intervention (TNI) supplements’, vasopressin, colleagues7 found a highly significant positive correlation and ‘U series’ (see below). The results have been varied and between GSH-Px activity and IQ in 22 individuals with DS and will now be briefly reviewed. Unfortunately, only a few of the concluded that GSH-Px may play an important role in pre- studies were randomised trials and although, as indicated serving the cerebral status of individuals with DS. As GSH-Px above, there is a theoretical rationale for antioxidant supple- is an endogenous antioxidant, it is possible that supplement- mentation, none of the trials was specifically designed to ing individuals with DS with exogenous antioxidants may offer similar protection to their cerebral status. This is sup-ported by the protective effect of antioxidants on DS neurons in culture, referred to earlier24. A randomised controlled trial Zinc is part of the cytosolic copper-zinc-SOD enzyme6. Zinc of vitamin E in Alzheimer’s disease41 found significant benefi- supplementation trials have been justified mainly because of cial effects. Because individuals with DS almost invariably reports of relatively low serum zinc in DS. Of 16 studies develop Alzheimer’s disease, this trial suggests a role for which have compared serum levels of zinc in individuals with oxidative damage in the pathology of both conditions.
DS and individuals without DS, 13 showed significantlyreduced zinc concentrations in individuals with DS42–54, while three found no significant difference55–57.
De Haan and colleagues35 have carried out several studies We found only one randomised controlled trial of zinc in suggesting that increased oxidative stress could be implicat- DS58. These investigators assigned 64 individuals with DS ed in ageing. They found (1) a significant increase in the aged 1 to 19 years to receive 25 to 50 mg of zinc/day (depend- SOD:GSH-Px ratio (p<0.005) and susceptibility to lipid per- ing on age) or placebo for 6 months with a crossover for oxidation (p<0.005) in normal mouse brain during ageing, another 6 months. Outcome criteria consisted of laboratory (2) that cultured murine cells which have been transfected to measures of immune competence and an infection log which have an increased SOD:GSH-Px ratio showed the characteris- included respiratory symptoms such as coughing. They tic features of senescence, (3) that normal mouse cells found no significant changes in lymphocyte function, com- exposed to hydrogen peroxide in culture also showed fea- plement levels, or number of infections. However, the trend tures of senescence, and (4) that cells derived from children was in favour of the zinc-treated group (p=0.07) for days with DS showed features of senescence which were not seen coughed and they had significantly (p=0.03) fewer episodes in cells from age-matched control children.
of cough. Also, among children less than 10 years old, thezinc-treated group had significantly fewer cough days CONCLUSIONS AND SOME IMPLICATIONS OF INCREASED OXIDATIVE (p=0.01) than placebo controls.
There have been seven uncontrolled zinc trials with pre- In summary, the evidence for increased oxidative stress in DS and posttreatment measurements with a total of 168 individ- is reasonably strong and includes: gene dose overexpression uals with DS aged 2 to 22 years43,45,47,49–51,53. All the studies of SOD, increased lipid peroxidation in human individuals consistently reported mainly laboratory evidence for benefi- with DS and transgenic mice models, compensatory increas- cial effects of zinc supplementation on the immune function es in GSH-Px and HMPS activities, increased products of of individuals with DS. However, as these studies had no oxidative DNA damage, increased chromosomal damage placebo treated controls or blind assessment of outcome, reduced by 50% in vitro by the addition of vitamin E, and most importantly there are increased intracellular free radi- We found two in vitro studies with zinc in DS. Fabris and cals and enhanced apoptosis in neurons of fetuses with DS colleagues44 reported that adding zinc to the serum of indi- which can be prevented by addition of antioxidants.
viduals with DS increased their serum thymic factor (FTS) to Therefore, there is good evidence that increased oxidative levels normally seen in individuals without DS and also stress may play a role in the complications of DS. This means reduced the concentration of FTS inhibitory factor. Chiricolo that an excess of oxygen-derived free radicals could result in and coworkers59 showed that individuals with DS who were supplemented for 4 months with 1 mg of zinc/kg/day had an enced significantly more frequent infections than their sib- increase in the in vitro incorporation of thymidine into their lings (p<0.01). However, during follow-up, the difference in phytohaemagglutinin (PHA) stimulated lymphocytes similar frequency of infections between the vitamin A treated partici- to individuals without DS. In addition, following gamma pants with DS and their siblings gradually reduced, becoming radiation induced damage to DS cells, zinc supplementation insignificant (p>0.05) by the fifth month of the study. In con- reduced the abnormally high DNA repair rate (which predis- trast, the difference remained significant (p<0.01) between poses to mutations and increases malignant potential) in DS the untreated participants with DS and their siblings through- cells to normal levels59. However, as these studies were con- out the study. However, the analyses were difficult to inter- ducted in vitro their in vivo significance remains uncertain.
pret because the treated and control groups were not In summary, although there are encouraging results from statistically compared and the frequency of infections of indi- uncontrolled studies and in vitro experiments suggesting vidual children were summed. Also, it was not clear if the that zinc supplementation may enhance immunity and assessment of infections was performed ‘blind’. This trial was reduce malignant potential in individuals with DS, there is conducted on the basis of reports of poor absorption and no rigorous or consistent evidence from clinical trials to reduced serum vitamin A concentration in DS25,56,69.
However, this rationale is weak as impaired absorption of vit-amin A was not reported in a larger study70 and others have not found reduced serum vitamin A concentrations14,70–73.
Selenium is a component of GSH-Px which is part of thebody’s endogenous antioxidant system6. In a study by VITAMIN B6 / 5-HYDROXYTRYPTAMINE (5-HTP) SUPPLEMENTATION Anneren and coworkers60, 10 µg of selenium/kg/day was Individuals with DS have been treated with vitamin B6 or 5- administered to 48 individuals with DS aged 1 to 16 years for HTP in order to increase their serotonin level74, which is fre- 6 months, and concentrations of immunoglobulin G2 and quently reported to be reduced75–77. Despite two G4 increased by up to 33% and 75% respectively. The partici- uncontrolled studies76,78 which reported improvements in pants also reported fewer infections during the study.
the muscle tone of 23 babies and children with DS treated However, as this study was uncontrolled and almost half of with 5-HTP, two randomised controlled trials74,79 failed to the sample was lost during follow-up, the result is impossible find any significant clinical improvements in a total of 108 to interpret. In another study, Antila and coworkers61 gave 15 babies with DS treated with vitamin B6 or 5-HTP for 3 years.
to 25 µg of selenium/kg/day to seven individuals with DSaged 1 to 54 years for a period of 0.3 to 1.5 years and TARGETED NUTRITIONAL INTERVENTION (TNI) SUPPLEMENTATION reported a 25% increase in the activity of GSH-Px and a 24% Supplementation with TNI is probably the most popular nutri- reduction in the SOD:GSH-Px ratio compared with 10 tional therapy currently advocated for individuals with DS judging by its extensive coverage on the Internet and in laypublications. Its proponents claim to have identified the bio- chemical abnormalities in DS and have formulated a supple- In 1981, Harrell and colleagues62 randomised 22 children ment to ‘target’ these abnormalities. A typical TNI supplement aged 5 to 15 years with learning disability (five of whom had contains about 56 nutrients including vitamins, minerals, DS) to receive either a megavitamin/mineral preparation or enzymes, amino acids, electrolytes etc. Unfortunately, we placebo for 4 months initially. After the first phase, all the par- found no published trial on the safety or efficacy of this sup- ticipants received the megavitamin/mineral supplement for plement. In addition, we found that a typical TNI preparation another 4 months. The supplement consisted of 11 vitamins contains 1000 mg of vitamin C which may be unsafe in chil- and eight minerals in high doses and included two antioxi- dren, given that a daily intake of 500 mg of vitamin C has been dants: vitamin C, 1500 mg; and vitamin E, 600 IU, daily. The shown to have pro-oxidant effects in adults80.
investigators reported dramatic improvements in IQ,growth, physical appearance, language, educational attain- ment, and general health of the treated participants. This In addition to the nutritional supplements discussed above, study had significant problems in that the loss of participants individuals with DS have also been treated with various phar- reduced the already small sample from 22 to 16 and only four macological agents and two of these will now be briefly of these had DS. However, the findings stimulated several more trials of megavitamin/mineral supplementation. Following reports that vasopressin enhances learning in Six randomised controlled trials63–68 attempted to repli- animals81, Eisenberg and colleagues82 treated nine individu- cate the findings of Harrell and coworkers62 using similar vit- als with DS, aged 10 to 42 years, with vasopressin or placebo amin/mineral supplements. These studies consisted of a for 10 days using a double-blind randomised crossover total of 161 individuals with DS aged between 6 months and design. They found no significant improvements in tests of 40 years and none of the studies showed any improvement in IQ, physical appearance, or general health.
Bumbalo and coworkers83 conducted a double-blind ran- domised controlled trial of a preparation called the ‘U series of drugs’ on 24 children with DS aged 3 months to 11 years We found only one small trial of vitamin A (retinol) in DS.
and reported no significant treatment effects after 1 year. The Palmer69 paired 23 individuals with DS aged 3 to 15 years with ‘U series of drugs’ was developed by Henry Turkel84 and has their own siblings and randomly assigned each pair to receive been a popular therapy for DS in many countries. The supple- either 1000 IU/kg/day of vitamin A or placebo for 6 months. At ment contained 48 items which, in addition to vitamins and baseline, the participants with DS in both groups experi- minerals, included substances such as rutin, naphazoline Developmental Medicine & Child Neurology 2000, 42: 207–213 hydrochloride, propyl paraben, and pentylene tetrazole. No References1. Epstein CJ. (1995) Down syndrome (trisomy 21). In: Scriver CR, theoretical rationale was given for most of the items included Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease Volume 1. New York:McGraw Hill. p 749–94.
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from The Friends of the Cheyne Centre for Children with Cerebral Palsy, Tadworth Court, Tadworth, Surrey KT20 5RU,priced £5, plus 55p postage.

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