Saturday, October 15, 2011

Why supplement and monitor zinc?

Jett just tested low on zinc so I thought I'd do some research. OMG...  Needless to say, we are buying him zinc TOMORROW morning!!! It is absolutely ridiculous that this paper, The Role of Zinc in Down’s Syndrome by Eastland Roxanne, was written 10 years ago and that zinc isn't a mandatory supplement for everyone with DS. 

I just reviewed the (recently revised) Clinical Report on the Health Supervision for Children With Down Syndrome written by the American Academy of Pediatrics to see what they say about zinc. Guess how many times zinc is mentioned? ZERO. I'm going to rewrite the Guidelines for Treatment of DS myself. (Okay, so it's on my to-do list…) You are welcome to listen to the AAP, but I feel that us parents have our children's best interest at heart and seriously wonder about whomever is on the board that created our present guidelines. Of course, I will share my Guidelines with you! (I'm sorry, I am soooooooo angry right now!!) My notes are in italics.

Of course, once I supplement zinc and possibly copper, I have to add l-carnosine to protect his brain. (See Q's post at for an explanation.)

Excerpts from: The Role of Zinc in Down’s Syndrome
Eastland Roxanne 2001
Please find the full article as a pdf here:

...The conclusions have been drawn from a critical review of all the research papers available on the subject of DS and zinc.

It appears that the majority of DS individuals are zinc deficient, and that they exhibit symptoms classically associated with zinc deficiency:

• Thyroid dysfunction
• Immunodeficiency
• Retarded growth
• Faulty DNA repair

Supplementation will raise DS zinc status to normal. Correction of zinc deficiency seems to:

• Improve thyroid function, though it is not clear yet what parameters are being affected
• Raise active thymulin levels and concomitantly lower inactive thymulin
• Possibly increase lymphocyte proliferation
• Possibly restore delayed hypersensitivity
• Improve neutrophil function
• Possibly normalise lymphocyte subset distribution
• Possibly minimise growth retardation
• Regulate DNA repair
• Regulate myeloid cell differentiation and apoptosis

There several possible reasons behind DS zinc deficiency, which are most likely to be working in some combination:

• Over-expression of genes
• Malabsorption
• Dysfunction of transport proteins
• Food choices
...As it is possible for too much zinc to suppress the immune system it would be wise to regularly test an immune parameter, such as lymphocyte proliferation, or to alternate periods of supplementation and periods without. It is possible that zinc therapy could benefit DS babies from birth, but at present it is not possible to recommend this as there is no evidence even as to its safety. It may be that the typical DS diet is low in zinc-rich foods, and it is vital to find ways of preparing such foods so as to appeal to a DS person and to educate individuals to incorporate such food in their diet.
It could also be sagacious to investigate such potential sources of malabsorption as food allergies, hypochlorhydria, and pancreatic insufficiency.

The average adult daily intake of zinc from the diet is 10 mg. Evidence suggests this dietary intake will always be inadequate for patients who are at risk, like those who have Down's syndrome.
Zinc deficiency can result in many health problems and we believe it may be the root cause for the universal brain injury we see in Down's syndrome from a very early age. Medical research is needed to find the best treatment therapy. 25 mg per day of zinc may be needed to prevent zinc deficiency in young people and adults with Down's syndrome. Even higher doses (up to 60 mg per day) has been suggested for adults with DS. Babies and young children would get a much smaller dose rate based on body weight.In the autism community, the dosage is one mg per pound, plus twenty mg. This is the dosage I will go with until Jett's next blood draw. -Andi

For zinc products, please see the DS Day to Day amazon store.

(All of this is my addition. -Andi)

If you purchase from vitacost, be sure to get $10 off your first order.
I'm researching these brands:

Gluten free and contains the amino acid methionine (L-methionine):

Life Extension Optizinc-- 30 mg - 90 Vegetarian Capsules
Vitacost L-OptiZinc® -- 30 mg - 200 Capsules is soy free

Has monomethionine:
Douglas Labs OptiZinc™Uses monomethionine. Other ingredients include cellulose, gelatin (capsule), and vegetable stearate. This product contains no yeast, wheat gluten, soy protein, milk/dairy, corn, sodium, sugar, starch, artificial coloring, preservatives, or flavoring.

Source Naturals OptiZinc® has monomethionine and 300 mcgs of copper and is soy free

Solaray-OptiZinc as Zinc Monomethionine and has 20 mgs of B6


Standard Process Zinc Many chiros carry this brand.

Eastland Roxanne 2001:

Zinc and its links with Down's Syndrome
...The importance of zinc is suggested by the many disease states found in DS that have also been observed in subjects with zinc deficiency. These include diabetes mellitus, dwarfism, hypogonadism, atherosclerosis, vitamin A deficiency night blindness, cirrhosis of the liver, myeloid leukaemia (Milunsky, 1970), and hyperthyroidism and hypothyroidism (Napolitano et al, 1990). Fabris et al (1993) cite the importance of zinc in the homeostatic networks found to be altered in DS, namely nervous, neuroendocrine and immune, and their interrelationship, plus a reduced turnover of this mineral, leading to the hypothesis that zinc deficiency could be implicated in at least some of the DS phenotype.
“Zinc forms part of the composition of at least 160 different enzymes. Indeed, zinc is the most widely used mineral in enzymes” (Graham and Odent, 1986).
It is vital for protein, essential fatty acid and carbohydrate metabolism, and for DNA synthesis, and can be used to detoxify lead and mercury (ibid.). The body only has a small pool of biologically available zinc, and a rapid turnover, meaning that deficiency signs appear very quickly (Passwater and Cranton, 1983).

Zinc status in Down's syndrome
It is this author’s opinion that taken as a whole the research to date indicates that it is likely that DS individuals have a low zinc status. Several papers reported normalisation of low zinc levels following zinc supplementation (Björkstén et al, 1980; Franceschi et al, 1988; Lockitch et al, 1989; Napolitano et al, 1990; Stabile et al, 1991; Licastro et al, 1992, 1993, 1994; Brigino et al, 1996; Trubiani et al, 1996; Bucci et al, 1999). This indicates a prevalence of zinc deficiency. If zinc status were already at an optimum level it is unlikely that homeostatic mechanisms would allow supplementation to raise zinc levels...
Importance of the Thyroid
Most investigators have found hypothyroidism in the DS population, with estimates of prevalence as high as 50% (Pueschel, 1990). This means that hypothyroidism is sometimes interpreted as being part of the ‘Down’s Syndrome Gestalt’, and that thyroid function should
be one system that is regularly monitored and treated as appropriate (ibid). ...Pueschel also states that failure to recognise thyroid dysfunction early enough can lead to further disturbances to
the central nervous system.
It should be noted that, although hypothyroidism is by far the most common thyroid dysfunction in DS and the one with which most researchers choose to work, a higher incidence than hyperthyroidism has also been reported (Pozzan et al, 1990). As certain parameters of thyroid function were universally found to be abnormal it is this author’s opinion that both hypo- and hyperthyroidism in DS could very well have the same root cause.
Function of the thyroid and thyroid hormones
The thyroid hormones regulate oxygen use and basal growth rate, cellular metabolism, and growth and development. There are two thyroid hormones under consideration in relation to DS (the third, calcitonin, is unrelated), T3 and T4. T4, also known as thyroxine, is manufactured in the thyroid from a glycoprotein, thyroglobulin, and is the inactive form. T3, triiodothyronine, is the active form and is made from T4. Reverse T3 (rT3) is also made from T4 but is inactive. This may be a mechanism for disposing of excessive amounts of T4.
Thyroid hormones are hydrophobic molecules which usually travel in the blood bound to a protein - specialised alpha globulin or albumin - and are inactive until released. A tiny fraction of the total T3 and T4 is free T3 and T4 (FT3 and FT4), and it is the concentration of free thyroid hormones that determines the effectiveness of these hormones. As they are lipophilic, the thyroid hormones are able to diffuse across plasma membranes and bind to receptors within the cell. This binding increases a receptor’s affinity for specific DNA sequences, controlling the rate of transcription of the appropriate gene. Secretion of T3 and T4 is stimulated by thyroid stimulating hormone (TSH, also known as thyrotropin), the secretion of which is stimulated in turn by thyrotropin releasing hormone (TRH). The release of TRH depends on blood levels of TSH, T3, glucose, and on the body’s metabolic rate.

Thyroid dysfunction in Down’s Syndrome
Research into thyroid function and zinc therapy in DS is still in its infancy and a clear picture has yet to form. The patterns that have emerged so far are that DS subjects exhibit:
• Elevated levels of TSH (Napolitano et al, 1990; Pozzan et al, 1990; Licastro et al,
1992, 1993; Sustrová and Strbák, 1994; Bucci et al, 1999)
• Reduced levels of rT3 (Lejeune, 1990; Licastro et al, 1992, 1993a)
• Normal levels of total T3 and total T4 (Franceschi et al, 1988; Napolitano et al, 1990;
Pozzan et al, 1990; Licastro et al, 1992, 1993a)
• Only a small percentage of disfunctional thyroids explained by antithyroid autoantibodies (Napolitano et al, 1990; Pozzan et al, 1990; Bucci et al, 1999)
The causes of these unusual ratios of hormones are as yet unknown. However, several authors make similar suggestions as to why TSH would be raised and T3 and T4 levels normal - i.e. why the thyroid has not been stimulated to release excess thyroid hormones. It is possible that there is some kind of dysfunction of communication between the hormone and its receptor.
Napolitano et al mention some kind of resistance syndrome, Pozzan et al posit the possibility of a less active TSH, and Sustrová and Strbák also put forward the idea, amongst others, of a hormone resistance. Licastro et al (1992) have a different approach, suggesting that there may be an increased rate of T4 degradation in the periphery, and that the body needs to secrete increased amounts of T4 to maintain a homeostasis.
Licastro et al (1992) put forward two possible reasons for the lowered amounts of rT3 found
in DS subjects: a decrease in formation T4 due to most of the T5 transforming into T3; or an increased conversion of rT3 into T2 (one of the precursors of T3 and T4). The latter is interesting as Lejeune states that excess SOD1 (discussed later) experimentally increases the transformation of rT3 into (inactive form) T2.
Sustrová’s and Strbák’s paper adds an interesting dimension to this picture as they separated their subjects by age into 3 groups: DS1 = 1-6 years, DS 2 = 6-15 years, and DS3 = 15-35 years. They found that all three groups had high TSH levels, high thyroxine binding globulin (TBH) levels, and low FT3 and FT4 levels. However, the T3 and T4 results told a more complicated story. DS1 had high levels of T3 and T4, DS 2 had high T3 and low T4, and DS 3 had T4 and T3 which were in lower concentration than the controls. Were the other researchers finding ‘normal’ levels of thyroid hormones because they were combining the high levels of the youngest subjects with the low measurements of the oldest? This could be true of Napolitano et al and Bucci et al whose DS subjects spanned the Sustrová’s and Strbák’s groups, though Bucci did find a significant inverse correlation between age and both T3 and FT3 levels. Licastro et al (1993a) fail to give the ages of the “children” in their 1993 paper - they could be as old as 17 or 18- but in their 1992 paper their DS subjects are 6-15 years old. Though this is the same age as the DS 2 group, Licastro et al (1993a) found normal T3 and T4 levels, thus contradicting Sustrová and Strbák. However, the idea that thyroid hormone production declines with age in DS people is worth further investigation and if true would beg many questions. Does TSH effectiveness decline? Does the ability of the thyroid to manufacture its hormones decline?
How could thyroid dysfunction be associated with the pathology of Down’s syndrome?
The thyroid hormones, along with insulin and human growth hormone, are responsible for accelerating body growth. It has been found that low rT3 levels could impair growth hormone stimulation (Lejeune), and that all DS children with elevated TSH exhibit more severe growth delay (Bucci et al). Increased weight gain often becomes apparent in many individuals with DS (Pueschel), a common symptom of hypothyroidism as the thyroid controls basal metabolic weight. Indeed Pueschel states that one cause of weight gain in DS is a decreased intracellular metabolic rate. Thyroid dysfunction interferes with the hypothalamic-pituitary-thyroid axis which modulates thymic activity, thus affecting immunity (Napolitano et al) and DS subjects are characterised by an unbalanced immune control including poor performance by the thymus (Serra and Neri, 1990). Both thyroid hormone deficiency (Barnes and Galton) and DS (Lejeune) are associated with mental retardation. Lejeune discusses the role of the thyroid in directing tubulin organisation, and points out that only three conditions exhibit neurofibrillary tangles: Alzheimer’s disease, hypothyroidism, and DS. It is interesting that many of the physical characteristics of cretinism (extreme thyroid deficiency during foetal or early life) correspond with those of DS such as enlarged tongue, open mouth, broad face and flat nose.
What role does zinc play?
Altered zinc levels have been observed in both DS subjects and in hypothyroid patients when compared to controls (Napolitano et al; Bucci et al), though the roles zinc plays are only beginning to be teased out.
Thyroid hormone receptors require zinc ions (Licastro et al, 1992; Sustrová and Strbák) which facilitate folding into their active shape (Bucci et al). Zinc is also required for binding thyroid hormone receptors to the target DNAs, called thyroid response elements (Licastro, 1992; Bucci et al). A zinc deficiency may require more of a hormone to be secreted in order that enough is taken up. Sustrová and Strbák suggest that if the pituitary receptors were affected, normal thyroid hormone concentrations would not inhibit TSH secretion. This author wonders whether TSH receptors are rendered less active by zinc deficiency, meaning more TSH must be secreted to maintain a normal level of T3 and T4.
Zinc is required by thyroid hormone deiodinase, which modulates the deiodination activity vital for the homeostasis of the thyroid hormones. Thyroid hormone deiodinase converts T4 to T3, and removes the iodine ions from excess T1 and T2 (thyroid hormone precursors) to be reused in the synthesis of more T3 and T4. Perhaps a zinc deficiency would affect the rate of conversion of T4 to rT3 via the deiodinising enzyme? It is impossible to ignore the connection between the function of the thyroid and of the thymus, especially when discussing the importance of zinc. There is a close correlation between zinc, the thymic hormone and the pituitary-thyroid axis. Thymulin - the thymic hormone - is associated with an improvement in thyroid function (Bucci et al) and each thymulin molecule contains a zinc ion (thymic function is discussed in more detail further on). Zinc may affect the action of the binding proteins that carry thyroid hormones, and this could interfere with the pituitary-thyroid axis (Napolitano et al). Zinc deficiency appears to affect the utilisation of thyroid hormones in the peripheral tissues (Licastro et al, 1992).

What effect does zinc supplementation have on thyroid function?
Every piece of research this author found which measured the effects of zinc supplementation on DS thyroid function found significant changes. However these changes were different in almost every case, and sometimes contradictory. Each piece of research supplemented the subjects by os, that is 1mg of supplement per kg body weight per day. Though most stated the use of zinc sulphate, some, such as Licastro (1992), did not make clear whether the measurement was of elemental zinc or a zinc compound. This would affect the amount of elemental zinc the children were receiving. This could be one of the reasons behind variations in results. 1mg per kg per body weight is a high dose when compared with the governmental Estimated Average Requirement for the normal population. Using growth charts for children with DS (Cronk et al, 1988) to estimate bodyweight a 1-3 year old would be given 12.5mg while the EAR is 3.8mg per day, and a 15 year old would be supplemented with 55mg instead of the EAR 7.3mg. In both their 1992 and 1993 papers, Licastro et al found that TSH levels returned to normal with zinc supplementation. Bucci et al note that it was the hypozincaemic DS subjects which exhibited high TSH and that they experienced a significant decrease after supplementation. Conversely, Napolitano et al found that TSH remained the same after 6 months supplementation and Sustrová and Strbák found that after a year of alternating three months with supplementation with three months off, ending on three months off, the TSH levels were found to rise. The only papers to measure rT3, both by Licastro et al, found a rise to normal levels after supplementation. These papers also found T3 and T4 remained the same while Napolitano et al found a rise in T3, and Sustrová and Strbák found a drop in T4. Napolitano et al found a drop in FT3 after zinc treatment, and Bucci et al found that FT4 levels reduced significantly, also reducing the FT4/FT3 ratio.

Immunodeficiency - The Thymus
“Patients with Down’s syndrome suffer from frequent infections and have an increased
mortality in infectious diseases compared to a normal population. Several laboratory studies
have demonstrated abnormalities of cell-mediated and humoral immune capacity and of
phagocyte function.” (Björkstén et al, 1980). As zinc is vital for the functioning of the
immune system (Meek, 1996) it makes sense to consider the role of zinc when questioning
why the DS immune system is weak, and how it can be supported. It has been found that
young animals and humans, when receiving insufficient zinc, exhibit:
• Rapid thymic atrophy
• Decreased production of thymic hormones
• Impaired lymphocyte proliferation after phytomitogen stimulation
• a) decreased number of, and dysfunction of, T-lymphocytes b) abnormal T-
helper and/or suppressor cell function
• Deficiency of natural killer cells
• Significantly reduced antibody and cell-mediated responses
• Delayed hypersensitivity reaction
• Decreased spleen and lymph nodes
• Generalised defective development of lymph tissue
(Franceschi et al, 1988; Stabile et al, 1991; Brigino et al, 1996)
The significance of the thymus
“The majority of immune alterations observed in DS subjects seem to depend on defective
thymic function.” (Fabris et al, 1993). This would include low levels of thymulin; a reduction
in and/or disruption to the subset division of, T-lymphocytes; a reduction in B-lymphocytes
(the proliferation of which is controlled by the T helper cells) and diminished delayed
hypersensitivity — all part of what is known as the adaptive immune system. Napolitano et al
(1990) claim that low zinc levels are responsible for the early atrophy of the thymus. One
obvious link between the thymus and low zinc status is that zinc is required to transport
vitamin A from the liver, and vitamin A is necessary for the growth hormone which
maintains the thymus (Meek, 1996).

The importance of functional assays
Before the effects of zinc supplementation on these parameters is considered, a ground-
breaking piece of research by Fabris et al in 1984 must be considered. Having realised that
plasma concentrations of thymic factors are not necessarily a reliable index of the functional
activity of the gland, the investigators measured the levels of active thymulin and the levels
of thymulin inhibitory activity in young DS subjects and in healthy controls. They then added
zinc sulphate in vitro and assayed again. The finding was that the DS individuals and the
normal subjects over 50 years old had an inverse correlation between plasma active thymulin
and thymulin-inhibitory activity. In normal people up to 20 years old thymulin levels were
highest of all those measured and thymulin-inhibitory activity was not detected in healthy
subjects until they reached 30. Conversely thymulin-inhibitory activity was high even in the
youngest DS children. In both the elderly people and DS subjects plasma zinc was below the
normal range for healthy adults. Once zinc sulphate was added to the plasma samples from
both these groups the active thymulin levels become the same as those found in healthy
young adults and the thymulin-inhibitory activity completely disappeared. These inhibitory
factors have not yet been identified, though some experiments suggest an anti-thymulin anti-
body is involved. However, as Fabris et al point out, this is highly unlikely in their work, as
there is a strict inverse correlation between the thymulin and the thymulin inhibitory activity,
which is reversed by the addition of zinc sulphate. Their interpretation is that the inhibitory
substance is in fact biologically inactive thymulin, which is still able to bind to thymulin
receptor sites, and that the thymulin is activated by zinc. This is a very neat assumption,
which accords with other research. Interestingly, though the DS active/inactive thymulin ratio
was completely corrected by the addition of zinc sulphate, in the normal subjects this was
only partial, suggesting that in physiological ageing other factors interfere with thymulin
turnover. The overall picture is that DS people’s thymuses do produce sufficient thymulin,
that insufficient zinc is available to activate it, and, importantly, simply measuring levels of
thymulin in the plasma was not telling the whole story. This paper plainly shows that
measuring levels and counting numbers is not the same as assaying what is biologically
available. In deed Lockitch et al acknowledge in their paper that “lymphocyte number and
subset distribution are relatively static indexes of immune system capability and that
functional assays such as in vitro antibody or interleukin production may be more sensitive
indicators for future studies.”

Does zinc improve the functioning of the immune system in Down’s syndrome?
Franceschi et al found that zinc significantly raised active thymulin and lowered inactive
thymulin, echoing Fabris’s findings, but Brigino found no increase in thymulin levels despite
normalised cellular zinc levels. These findings can not really be compared as Brigino used
only 5 subjects, all of whom presented with recurrent infections such as pneumonias and
chronic otitis media. It is quite possible that such conditions, which did improve with
supplementation, were utilising the extra available zinc. Franceschi et al used 18 subjects and
Fabris et al used 72, all off whom were basically healthy.
Zinc supplementation appears to increase lymphocyte proliferation (Stabile et al, Licastro et
al, Brigino et al), which may be because zinc is essential for cell division. This is because
DNA polymerase is the enzyme central to DNA replication, and cannot function without zinc.
The aforementioned three papers also all found a reduced incidence of recurrent infections.
Lockitch et al however, found no improvement in the frequency of infections. It is this
author’s opinion that the methods of assessing frequency of infectious episodes prior to and
after zinc supplementation were far too inexact to be useful. For example Licastro et al asked
parents to remember the number and type of infections their child had had the previous year
and Stabile et al give no indication how they collected the information. The parents in
Lockitch’s investigation were instructed in detail how to fill in an infection log, which lends
more credence to this research, but still relied on parental judgement on what would be
considered normal. Possibly more objective means of assessing day-to-day infectious status,
such as a daily temperature chart, should be investigated.
Other papers found improvements such as increased T-lymphocytes (Franceschi et al),
improved skin responsiveness (Björkstén), or improved utilisation of interleukin 2 (IL-2)
(Licastro et al), but until these tests are repeated it is not possible for this author to
confidently comment on their validity. Lockitch et al found no improvement in any of the
parameters they measured, and indeed found that lymphocyte proliferation decreased even
further. The researchers themselves suggest that “although low doses raise serum zinc values,
a much higher intake is needed to correct cellular deficiencies,” but Licastro et al propose the
possibility that “the zinc supplementation was given for a longer period (6 months in the
[Lockitch] study). Prolonged zinc administration (6 months versus [Licastro’s] 4 months)
might suppress immune functions. An excessive zinc intake has indeed been shown to
impair... lymphocyte [proliferation] in humans, polymorphonuclear migration response to the
chemotactic factors and granulocyte phagocytosis of opsonized bacteria.”


Immunodeficiency - Leukocyte Function
It has been found that the chemotaxis, phagocytosis, and other anti-foreign microorganism
actions of leukocytes are reduced (Fabris et al, 1993). Licastro et al (1993b, 1994)
investigated the ability of DS neutrophils to produce chemically active molecules, such as the
superoxide anion, when stimulated. They observed that chemical activity was low before
supplementation but after zinc therapy neutrophil reaction to a stimulus was normalised. The
authors point out that protein kinase C is believed to play an important role in the activation
of human neutrophils, including superoxide generation, and that the activity of protein kinase
C is regulated by zinc ions. Possibly the actual fault is an impaired activation of protein
kinase C because of a poor supply of zinc ion. Rates of infection amongst the subjects were
found to decrease with supplementation, but the same problems with this data apply as
previously discussed, especially the compilation of a record of each child’s infection history
for the year preceding the experiment from what the parents recalled.
Neutrophil chemotaxis was also found to be reduced in DS patients by about 30%, but
normalised after zinc therapy (Björkstén et al, 1980). Björkstén et al relate zinc enhancement
of neutrophil activity to possible membrane phenomena and also mention intracellular
activity, as leukocyte locomotion is very complex. Licastro et al (1993) also followed up their
subjects a year after ceasing zinc therapy and found that neutrophil activity had dropped
again, supporting their assumption that zinc had improved their functioning. Unfortunately
Björkstén did not follow up his subjects so a similar comparison is not available.
That zinc supplementation may improve neutrophil deadliness is very important in attempting
to understand how to reduce the incidence of infection in DS people. Further investigation to
expand understanding in this area could prove very fruitful, including investigation into the
role of protein kinase C and its relationship with zinc.

Maturation of blood cells
Differentiation is the process by which subsets of a family of cells are formed from parent, or
‘stem’ cells by the acquisition of specific functions. It is of particular importance in
haemopoiesis, the process by which blood cells are formed, and the consequent development
of T-lymphocytes. Differentiation is a gradual process with cells passing through various
stages before achieving maturity, and is stimulated by various growth factors. Apoptosis is a
mechanism of programmed cell death, which occurs as a response to an external factor or the
withdrawal of a growth factor. It is an important part of cell differentiation for both the
immune system and haemopoiesis as it culls excess cells to maintain a suitable subset balance. The enzymes concerned in breaking apart DNA fragmentation during apoptosis are

Inefficient cell maturation

DS individuals have been found to have an unusual presence of immature myeloid cells
(found in the earliest stages of haemopoiesis) in peripheral blood circulation associated with
low levels of zinc plasma (Trubiani et al, 1996a, 1996b). Both pieces of research found that
six months of zinc therapy induced the disappearance of the immature myeloid cells, but the
authors offer different possible explanations:
• That zinc is required for the process of programmed cell suicide: “ The results here show that zinc therapy in Down’s patients induces cell death of undifferentiated and ineffective myeloid cells, recovering a mechanism related to cellular differentiation of the haemopoietic system”  (1996a)
• That zinc is required for normal cell differentiation: “Since leukocytes contain high
levels of zinc and this level varies with cell maturity, being lowest in the most
immature cells, we suggest that low plasma zinc levels in DS subjects could be
responsible for a reduced rate of myeloid differentiation resulting in accumulation and
in escape from the bone marrow of immature cells reaching the peripheral blood”
• These reasons are not mutually exclusive and most likely zinc supplementation is
supporting both processes (Trubiani et al, 1996a).

Inappropriate apoptosis

A paper was published the following year, by essentially the same researchers (Antonucci et al, 1997), which evaluated the presence of apoptosis in the peripheral blood cells in DS subjects before and after six months of zinc supplementation. It was found that there were signs of programmed cell death before the zinc treatment, which decreased in all the patients following supplementation. The authors state that endonucleases are inhibited by normal plasma zinc concentrations and suggest that in DS individuals low levels of plasma zinc activate the endonucleases. Zinc therapy would therefore inhibit the apoptotic process leading to a decrease in the number of apoptotic cells.

Meanings of these results
It would appear that programmed cell suicide is happening at an inappropriately high rate in
mature DS peripheral blood cells. This author believes that when combined with the
weakened cell maturation process discussed above these findings represent a serious decrease
in the numbers of healthy, efficient blood cells in circulation, and the apparent success in
treating this deficiency with zinc has important implications for supporting DS people’s
health. Murphy et al (1995) found that DS spleens are markedly missing T cells “suggesting
the inefficient release of mature T cells from the DS thymus to the DS spleen”. Could this
lack of mature T cells be related to a poor rate of stem cell maturation? Or to a rapid
destruction of healthy, mature cells by a high rate of apoptosis? Or both? How does this
confusion of the cell differentiation process relate to the 10 to 20 times higher risk DS people
have of developing myeloid leukaemia (Milunsky et al, 1970)? The question must also be
asked as to why these scientists found that zinc deficiency appears to reduce programmed cell death in immature cells and promote it in mature cells. It is unfortunate that at present one
group of investigators has done all the research and it is hoped that in the future other
scientists will pick up the baton.

DNA Repair
Premature ageing is a universal problem for DS people, including a far higher risk of
developing Alzheimer’s disease (Opitz and Gilbert-Barness, 1990). This observation suggests
a fault in the integrity of the DNA repair system. Chiricolo et al (1993) investigated whether
zinc supplementation affected the maintenance of DNA integrity by damaging lymphocyte
DNA with radiation in vitro, before and after four months of zinc supplementation, and
observing the rates of repair. The finding was that before supplementation the DNA damage
(which was normal) was repaired extraordinarily rapidly when compared with the cells from
normal children. The authors suggest that persistent oxidative stress may mean that DNA
repair enzymes are activated in higher numbers in DS, a possible explanation for the
increased rate of repair. It may even be that zinc deficiency contributes to this oxidative
stress. They also suggest that the high speed of repair is likely to mean more mistakes are
made and that “it could contribute to neurodegeneration and precocious ageing which are
both hall-marks of the system.” (Chiricolo et al). After the period of zinc therapy the damage
received by the DS lymphocytes was the same as before, but the rate of DNA repair was
significantly reduced, back down to a normal, and presumably more accurate, speed.
Thus the paper shows that zinc does not appear to have a protective effect against DNA
damage - at least not radiation damage - but rather modulates the speed of repair and so
probably its accuracy. The authors speculate that this is because four months of zinc therapy
was enough time to reduce the oxidative stress, but this author believes it is also possible that
zinc is a requirement for one or more enzymes which regulate DNA repair. Possibly this
could be investigated in vitro, without zinc supplementation in vivo, to observe the effect of
immediate availability of zinc ions rather than a slow build up of effects associated with a
gradual rise of zinc status to normal. Though this is only one paper it appears to be the first
that demonstrates a nutritional intervention apparently affecting DNA repair, and so is a
ground-breaking paper.

Growth Delay
“Growth retardation is a cardinal characteristic of Down syndrome” (Annerén et al, 1990). It
is not known what the underlying mechanism is responsible for the retardation of growth. DS
children have normal levels of human growth hormone (hGH) and low levels of
somatomedin C — also called insulin-like growth factor (IGF-1). IGF-1 is regulated by hGH
postnatally, and it appears that in DS there is a delayed, possibly incomplete, transfer from
foetal IGF-1 to the hGH regulated IGF-1 (Annerén et al, 1990). Growth is mainly restricted
between the ages of 6 months (when hGH starts to regulate growth) and 3 years. Some, but
not all, researchers have found that growth after this age is near to normal, just starting from a
smaller stature (Annerén et al, 1993). Napolitano et al (1990) found that the level of IGF-1
rose after zinc supplementation, especially in children over 7. Zinc levels diminish with age
in DS people, as with normal people, though this happens earlier in DS, so it is conceivable
that the results were more pronounced with older children as they had a greater need for extra
zinc. The effect of zinc supplementation
Strangely, despite the well documented link between zinc deficiency and growth delay
(Passwater and Cranton, 1983), this author found only one paper investigating the effects of
zinc supplementation on growth in DS children. Napolitano et al studied 22 DS children
whose growth velocity was calculated for the six months before the period of
supplementation and during the six months of therapy. They were supplemented by os, and
their rate of growth compared with special growth charts for DS children (Cronk et al, 1988).
It was found that 15 of the subjects moved into a higher centile in their growth charts and,
interestingly, that the children older than 7 years showed a greater differential in growth
velocities before and during supplementation than the children aged 4-7 years. This
particularly noteworthy when compared to the finding that suppressed growth occurs earlier.
Unfortunately, no children under 3.8 years were included. The results for children under 4
years, and over 10 years (girls) or12 years (boys) were considered separately to avoid
interference by first childhood and pubertal growth spurts.
This author considers that there could be huge potential for zinc therapy to minimise growth
retardation. Zinc is essential for DNA and RNA polymerase and thus for cell proliferation; it
is necessary for protein metabolism; and as it is essential for the functioning of hormone
receptors (such as protein kinase C) zinc is possibly required for hGH and/or any of the hGH
regulated growth factors to function efficiently. The results of Napolitano et al’s work are
encouraging, but need to be repeated with measurements of the foetal variant form of IGF-1,
and assays into numbers and activity of hGH binding sites in DS would be useful.  Further
research using younger children would be extremely valuable in illuminating the role of zinc
in hGH functioning, transfer to hGH regulated IGF-1, and growth delay. Napolitano et al
suggest the possibility that thymus hormones may have a role in regulating the secretion of
hGH in DS children. Considering the importance of the thymus and thymic factors already
discussed, this link raises many more possibilities.

Gene over-expression as a drain on zinc
Extra SOD-1 gene

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 function of SOD-1
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.

Zinc as an antioxidant
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

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.
... 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

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