Growth Delay
Gene over-expression as a drain on zinc
The best known gene mapped to chromosome 21 is that for copper-zinc superoxide dismutase (SOD-1), and it is estimated that 99% of DS people have three copies of this gene (de Haan et al, 1997). Most researchers found an elevated level of zinc in the erythrocytes (Milunsky et al, 1970; Nève et al, 1983, 1984; Purice et al, 1988) and as there is believed to be a 50% increase in SOD-1 activity in DS subjects (Jeziorowska et al, 1988), it seems “highly probable that the increase of red cell… zinc levels in trisomy 21 is partly attributable to the increased SOD-1 activity” (Nève et al, 1983). Kadrobova et al point out that “adaptations for permanent oxidative stress and changed biochemical functions in DS may lead to the increased requirements of an organism for zinc” (1996). This means that it is highly likely that DS people have an increased need for zinc as they use a larger percentage of that available for manufacturing SOD-1. It also alludes to the effects of increased SOD-1 activity.
The task of SOD-1 is to remove the superoxide radical, but it performs only half of the process of clearing up by transforming the free radical into a much less volatile free radical called hydrogen peroxide. It is glutathione peroxidase (and possibly catalase) which finishes the process by dismantling hydrogen peroxide, otherwise prone to forming the hydroxy radical, the most destructive of the free radicals. While SOD-1 activity is elevated because of gene dosage, glutathione peroxidase and catalase are only present in the normal quantities, quite possibly leading to an accumulation of hydrogen peroxide which could result in considerable oxidative damage.
As well as its role in the formation of SOD-1, zinc has an antioxidant effect in its own right, and stabilises cell membranes (Kadrobova et al, 1996). It is possible that the permanent oxidative stress of excess production of hydroxy radicals uses up a higher proportion of zinc than is used for antioxidant activity in normal people. If oxidative stress were to be a drain on zinc resources it could be expected that exercise would increase this load, as exercise increases oxygen metabolism thus increasing the production of free radicals. Two pieces of research look at the effects of exercise on the plasma and erythrocyte zinc levels. The first, by Laires et al (1994) found that exercise did not change these measurements, but the period of exercise was only twenty minutes rowing. As the paper reports that DS people find such a length of time of concentrated exercise difficult, it is quite possible that many subjects either did not complete twenty minutes, or did so in smaller sections. The second paper, by Monteiro et al (1997), looks instead at the effects of aerobic exercise over the period of time. The subjects’ regime was increased gradually until they were performing 25 minutes of aerobic activity 3 times a week. After 16 weeks their plasma zinc and erythrocyte zinc levels were compared with their starting values, and the plasma zinc was found to be significantly lower. The authors suggest either an activated expression of antioxidant mechanisms or elevated sweat loss as possible reasons. This author considers sweat loss less likely because sweat, as well as having a cooling action, is a mechanism for excreting excess ions. There is no evolutionary advantage to excreting a trace element that is already in short supply. There is of course a possibility that DS people have a faulty sweat mechanism but this author found no mention of this in relation to zinc status in any papers. Thus this author considers this research supportive of the possibility that excess SOD-1 is placing a drain on zinc supplies.
Not all DS subjects express excess SOD-1
It should be added that some researchers have found that it is possible for the clinical features of DS to exist without elevated levels of SOD-1 (Jeziorowska et al, 1988; De La Torre et al, 1996) — a reminder that “among numerous abnormalities reported in DS no finding except for the extra chromosomal material is constant” (Jeziorowska et al). However it is this author’s opinion that excess SOD-1 is likely to be a factor in the majority of DS people.
Over-expression of other proteins
Another known gene on chromosome 21 is that for the protein subunit S100ß. An increase of this could also increase the requirements for zinc (Lejeune, 1990). According to Lejeune it is also possible that there is excessive adenosine formation, mainly produced by a zinc-requiring enzyme, which could be another drain on the available zinc. Trubiani et al (1996) also mention other zinc binding proteins which appear to be over-expressed in DS subjects: polymerase and various kinases which are necessary for cellular metabolism and differentiation.
The possibility of malabsorption
A common explanation for nutritive deficiencies in subjects with a normal diet is that of malabsorption, and several authors consider it a possible reason for low serum zinc in DS (Bruhl et al, 1987; Kanavin et al, 1988; Licastro et al, 1993). Sylvester (1984) considers malabsorption to be a significant reason behind low levels of nutrients. He states that the shortages of some trace metals to which DS people are prone are lifelong, and points out that their absorption from the intestines, measured using the xylose absorption test, has been found to be reduced. Abalan et al (1990) measured the absorption in 4 DS patients by microscopically examining their stools for meat fibres after a measured diet. The meat was minced to negate the effect of insufficient chewing due to poor dentition – DS children are prone to abnormalities of tooth formation, and to periodontal disease (Pueschel, 1990). The finding was a high meat fibre count, strongly supporting the malabsorption hypothesis. As Abalan et al point out, this test does not indicate what the cause of the malabsorption could be, suggesting as possibilities pancreatic insufficiency, reduced intestinal absorptive capacity, or other causes. This author would add hypochlorhydria, and food allergies as possible causes. In the wake of reports of a high incidence of coeliac disease in DS, Strong (1993) performed a study which found all of his ten subjects displayed raised IgE and IgG to one or more of 13 common food allergens. Though only a preliminary study this indicates a possible role of allergies in DS malabsorption. Both of these studies are small-scale, uncontrolled investigations; larger, controlled investigations would provide valuable data regarding DS absorptive status.
A cautious note is struck by Licastro et al who point out that some elements, such as copper and magnesium, are found in the normal range in DS, an argument against malabsorption as an explanation for low zinc levels.
Zinc ions need to be bound to a carrier to travel in the bloodstream. Another possible explanation for decreased plasma zinc status is “a perturbation of the plasma zinc transport due to a defect in its transport protein (Purice et al, 1988). Usually, approximately 80% is associated with albumin, 15-19% is associated with alpha-2-macroglobulin and much smaller amounts (less than 1%) are associated with amino acids or metalloenzymes. It has been suggested that alpha-2-macroglobulin is a transport protein for zinc and that, as DS adults have been found to have abnormal levels of this protein, this may explain the low levels of zinc found in their plasma (Halstead and Smith, 1970; Purice et al, 1988). The problem with this suggestion is that the research that found these low levels of alpha-2-globulins was performed in the 1950’s and 1960’s, using institutionalised patients. Liver disease amongst such patients occurred frequently and this could well have affected the formation of alpha-2-globulins (Milunsky et al, 1970). Research into the relationship between zinc status and transport proteins is surprisingly patchy, especially since the 1970’s, considering how important it could be. Milunsky et al found that plasma zinc was low in DS children, all living at home, and that their alpha-1 and alpha-2-globulin levels were normal. Annerén and Gebre-Medhin (1987) assayed plasma zinc, alpha-2-macroglobulin, albumin, and other serum proteins in home-residing DS children, using their siblings and other healthy children as controls. It was found that the DS children had significantly higher alpha-2-macroglobulin concentrations than their siblings, but similar albumin concentrations. The authors could find no correlation between the amounts of circulating zinc and alpha-2-macroglobulin, a state they believe points to a ‘true’ zinc deficiency. The suggestion is that there is a high concentration of alpha-2-macroglobulin because of subclinical infections. However the activity of the alpha-2-macroglobulins has not been measured. Could the alpha-2-globulin be failing to transport zinc satisfactorily? Could the presence of a fault in the protein being produced mean that a negative feedback loop is not being completed and the liver continues to make more? There were found to be normal concentrations of albumin, but it is possible that albumin is not working efficiently. It is also possible that carriers are transporting the wrong ions; the concentrations of heavy metals is beyond the remit of this paper, but it is known that cadmium, aluminium, and copper are zinc antagonists and can replace zinc ions. This author believes that problems with transport proteins could play a role in DS low zinc status, and the way forward is to measure the activity of all the proteins known to be involved.
One possible reason behind low zinc status in DS subjects which has been not just completely, but deliberately, over looked is that of food choices and eating habits. Most papers do not mention this aspect at all, but those that do dismiss it in one sentence. Two typical examples are:
Bruhl et al, working with institutionalised subjects: “A diet prepared to Recommended Dietary Allowance standards was offered to all” (1987)
- Annerén et al, working with children living at home: “No systematic investigation of the dietary intake was performed, but an interview did not reveal any obvious deviations in dietary habits, pica phenomena or food preferences” (1985)
As Pipes (1992) points out, just because food is offered to institutionalised patients it does not mean it is consumed. Patients can choose what to eat, probably unobserved, when there are other retarded patients who also require assistance. And asking parents whether they regard their children’s diet as normal is not very illuminating. Mention has already been made of the poor dentition from which most DS people suffer, and it would not be unreasonable to presume that food choices would be amongst those foods easy to chew. DS children develop more slowly than normal children, and spend longer in developmental stages (Cunningham, 1988), meaning that weaning could be a problematic, drawn out process for parents. Children are drawn to sweet foods, and as taste develops will often reject other foods the first time they are tried before accepting them on reintroduction (Bennett, 1988). If meal times are hard work for a parent it is easy to see that they could begin to rely on the foods first accepted instead of continually trying to reintroduce other foods, especially once the DS child is of an age when a normal child would be feeding itself. Once food habits are formed it is very unlikely they will change to much degree (ibid.).
It is worth noting that almost all foods known to be good sources of zinc require thorough chewing, including meat (though the antagonistic effect of iron may negate meat’s usefulness), wholegrains, canned fish (with accompanying problematic small bones), nuts and seeds, and shellfish. Only eggs can be prepared in a way that is easy to masticate. “Clinical experiences of the author have indicated that low blood levels of zinc… in preschool children with DS have resulted from inadequate dietary intake” (Pipes, 1992). Amongst older children and young adults with some responsibility for food choice and preparation, mental retardation could mean it is difficult for them to understand the concept of a balanced diet. “Individual observations indicate that many convenience and already-prepared foods are used. An abundance of sweet foods of high calorific density are consumed and little support is given in helping the individuals in selecting an adequate diet” (ibid.). A diet high in sugar will affect zinc status not just due to sugary foods taking the place of zinc-rich foods in the diet, but because sugar increases the excretion of zinc, as the zinc-containing hormone insulin is required to rebalance blood sugar. There is the possibility that DS affects the taste buds, which would also have an effect on food choices. In all the literature this author read, only Pipes even mentioned food choices and eating habits in DS, and she found them to often be disturbed or inadequate. It is vital that this area is investigated, and in this author’s opinion should be a priority, when considering reasons for zinc deficiency in DS.