Nutritional Implications in Down Syndrome

Kent MacLeod, B.Sc. Phm
Nutri-Chem Research
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Abstract — Every individual requires vitamins, minerals and antioxidants. This fact is recognized by dietary recommendations that describe levels of intake necessary to prevent deficiencies. However, there are certain populations, including those with Down syndrome, where these needs are not being met, or due to underlying metabolic disturbances, the recommended levels are not sufficient. The use of nutrients should be considered in DS to maintain health and prevent disease.

IQ and Nutritional Deficiencies

     It would be wonderful if supplements could make children smarter. However the research on the effect of supplements on IQ in Down syndrome (DS) has been disappointing. A number of studies in the 1980's focused on nutritional supplements and IQ in children with DS (Harrell 1981, Weathers 1983, Smith 1984, Pruess 1989). Most of these studies did not show a beneficial effect.
     Despite a lack of effect of supplementation on IQ in older children, young children may still benefit. A study of 424 premature babies given just 4 weeks of enriched supplements before 2 years of age, had higher verbal IQs than premature infants not given supplements (Lucas 1998). This effect was particularly significant in boys.
     Iron and phosphatidylserine are especially important for brain function. Iron is essential for growing and developing children, and deficiencies of iron are associated with defects in learning (Whitney 1998). In fact, 700,000 toddlers in the U.S. lack sufficient iron, with 1/3 of these severely depleted and anemic (Looker 1997).
     Phosphatidylserine (PS) is a fat that is essential for cell function in all parts of the body, especially in the brain. Dietary sources of PS are limited. Double-blind clinical trials with phosphatidylserine have shown improvements in memory, mood, concentration, and verbal ability (Kidd 1997). Regardless of any effect of supplements on IQ, evidence indicates that deficiencies of vitamins, minerals and antioxidants exist in DS. Supplements should be considered for their ability to maintain health and prevent disease.
     Dietary studies have shown that vitamins A, C, E, thiamin (B1), calcium, iron and zinc may be inadequate in the diet of children with DS (Calvert 1976, Luke 1996). Furthermore, serum measurements of vitamin E, selenium and zinc have been shown to be low in DS (Shah 1989, Neve 1983, Kadrabova 1996, Franceschi 1988, Lockitch 1989). Additional evidence suggests disturbances in folate, vitamin A, and vitamin B6 nutritional states (Peeters 1995a, Peeters 1995b, Palmer 1978, Pueschel 1990, McCoy 1969, Bhagavan 1975, Coleman 1985).
     Individuals with DS may have problems with digestion or absorption of nutrients. Many children with DS suffer from malabsorption, celiac disease and lactose intolerance (Nowak 1983; Simila 1990; Unrah 1994; Van Dyke1995, George 1996). Minor annoyances like constipation, diarrhea, and gas, which are commonplace in children, may be helped with natural products such as fiber, probiotics, flax oil, digestive enzymes, and betaine (Murray 1996, Rolfe 2000).
     Improper or inadequate nutrition, which may lead to nutritional deficiencies, is particularly important in DS where the presence of the third 21st chromosome creates alterations in metabolic pathways. Correcting nutritional inadequacies may impact 3 significant areas in DS: the immune system, the SAM cycle, and oxidative stress.

Supplements and the Immune System

     Immune dysfunction is a classic characteristic of DS. Individuals with this condition can have up to a 52 times higher rate of infection than other children. Bronchitis and infections of the respiratory tract and head, including the ears and sinuses, are most common (Lang 1992, Smith 1995, Fabris 1993, Anneren 1992, Burgio 1975). Antibiotics are often prescribed, even though they have been shown to be ineffective for these types of infections (Nyquist 1998).
     Immunoglobulin levels are altered in DS - immunoglobulins are the antibodies used to help fight infections. Some of these immunoglobulins are present in reduced levels (Anneren 1992, Burgio 1975). T cells help regulate the immune response. T cell dysfunction has been shown in DS (Fabris 1993, Franceschi 1988, Bjorksten 1980). Thymulin is a hormone that activates certain white blood cells, and its active form, which requires zinc, is low in DS (Fabris 1993, Franceschi 1988, Brigino 1996).
     When a child is sick, their ability to learn is reduced. Frequent ear infections in infancy are associated with developmental delay and lower IQ scores (Gates 1999). It has been reported that children with DS, who do not have ear infections, do better in language ability than those suffering with ear infections (Whiteman 1986). This clearly demonstrates how illness can affect learning.
     Adults taking vitamin E supplements show dramatic improvements in their immune systems. (Meydani 1997). Improvements in the number of sick days is observed when basic multivitamins are provided to adults at risk of dietary deficiencies (Chandra 1992, Pike 1995). In DS, there is clear evidence that three nutrients can benefit the immune system. These nutrients are zinc, selenium, and vitamin A.
     One of the most important roles of zinc is to help maintain a healthy immune system. Low or deficient zinc levels can decrease the number of T cells, lower thymic hormones and disrupt white blood cell functions. These effects are reversible upon zinc supplementation (Murray 1996).
     Decreased levels of zinc are common in DS and supplementation with zinc can restore serum levels at or above normal (Franceschi 1988, Bjorksten 1980, Lockitch 1989, Kadrabova 1996). Zinc can correct thymulin defects in DS (Fabris 1993, Franceschi 1988). Supplemental zinc can inhibit apoptosis of white blood cells, thus preventing these cells from dying (Antonucci 1997). Administration of zinc has even been shown to lower the number of infectious episodes and the number of days with elevated body temperature, and result in improved school attendance (Fabris 1993).
     Selenium levels are low in DS, and selenium, in supplemental form, can increase immunoglobulins in the blood of children with DS (Neve 1983, Neve 1984, Shah 1989, Anneren 1990).

Annual screening for zinc and selenium deficiencies is now recommended (Pueshel 1999). Why not simply give these minerals in a supplement?

zinc and selenium, at doses found in the literature, are proven safe and effective.

providing a supplement is non-invasive and more cost-effective than testing.

there is no scientific agreement on the best way to assess zinc nutritional status; plasma zinc is commonly used but is problematic because of contamination from other sources. (Wood 2000)

the main therapeutic option for infection in DS (ear, sinus, bronchitis) is antibiotics; they are of limited use (Nyquist 1998)

Children with DS display many symptoms characteristic of vitamin A deficiency (Griffiths 1967, Palmer 1978, Pueschel 1990). Dietary surveys demonstrate inadequate vitamin A consumption (Calvert 1976). An 80% decrease in infection rate was reported in children with DS taking a vitamin A supplement compared to controls. After 5 months, there was no difference in the rate of illness between the two groups (Palmer 1978).
The use of supplemental vitamin A, zinc, and selenium, at doses found in the literature, are proven safe and effective in reducing infection and decreasing the number of sick days in children with DS.

"The era of nutrient supplements to promote health and reduce illness is here to stay..."
(Chandra 1997)

The SAM Cycle, Methylation and Folic Acid

The SAM cycle is involved in a process called 'methylation'. Methylation is essential for the formation of DNA (the genetic material), hormones, carnitine, and numerous other key biochemical compounds. Nutrients essential for the proper functioning of the SAM cycle include vitamins B6 and B12, folic acid, and the amino acids serine, glycine, methionine and choline.
There are several indications that the methylation process is altered in DS:

an enzyme called cystathionine-beta-synthase is found on the 21st chromosome; the increased activity of this enzyme drives the SAM cycle away from normal methylation processes (Chadefaux 1985)
a decrease in the levels of serine, methionine, SAM and homocysteine indicate deviation from normal methylation (Mircher 1997, Chadefaux 1988, James 2000)
patients with DS demonstrate severe methotrexate toxicity at standard doses (methotrexate is a anti-folate drug) (Peeters 1995a)

     The methotrexate toxicity and the overexpression of cystathione-beta-synthase suggests there is a functional folate deficiency in DS. Interestingly, mothers of children with DS are at a higher risk for compromised folate metabolism (James 1999, Hobbs 2000).
     The conversion of dietary folate to a usable form for body tissues, is a complex multi-step process. Folic acid has to be activated before it can be used. Vitamin B12 is needed for this activation (Whitney 1998). Methylcobalamin is a form of vitamin B12, that can bypass some of the complex steps of folate activation.
     Supplemental folates are available in two forms, folic and folinic acids. Folinic acid is converted to a usable form of folate more simply that folic acid. Folinic acid is the most active form of folate, working in circumstances where folic acid has little to no effect (Kelly 1998).
     Folinic acid and methylcobalamin may be useful to correct the functional folate deficiency present in DS.

"The function of folate ... is especially important during the early development of the brain, and for the maintenance of normal brain function."
(Weir 2000)

Antioxidants, Free Radicals & Oxidative Stress

A free radical is a highly reactive molecule that can damage DNA, protein or fat. Antioxidants stop free radicals from doing damage (Ames 1993). Among the better known dietary antioxidants are vitamin C, vitamin E, beta-carotene, and coenzyme Q10 (Briviba 1994).
Oxidative stress results when there is an excess of free radicals in the body and there are insufficient defense mechanisms, like antioxidants, to destroy them. Oxidative stress has been implicated in aging and a variety of diseases including DS, cancer, heart disease, AIDS, diabetes, Alzheimer's disease, Parkinson's disease, and cataracts (Kehrer 1994). In DS, there is significant evidence of oxidative stress:

elevation of superoxide dismutase activity (Feaster 1977, Sinet 1975, Sinet 1976, Sinet 1982)
plaques and lesions in the brain similar to that observed in Alzheimer's disease by age 35 (Wisniewski and Rabe 1985, Kolata 1985, Rabe 1990)
premature aging of the brain (Kolata 1985, Sinet 1982, Roth 1996)
decreased levels of several antioxidants (Shah 1989)
antioxidants prevent cultured fetal neurons, from the brain of individuals with DS, from dying (Busciglio 1995)

In 1998 we showed the first direct evidence of oxidative damage in Down syndrome:

damaged DNA and lipids are increased in children with DS (Jovanovic 1998)

     Individuals with DS may be limited in their ability to repair damaged DNA (Druzhyna 1998). Oxidative stress may further complicate immune function in DS. Mice that overexpress superoxide dismutase have damaged immune cells and reduced immune function (Mirochnitchenko 1996).
     Supplemental antioxidants are being used to fight free radical damage. Vitamin E slows the mental deterioration of Alzheimer's disease (Sano 1997) - this research prompted the American Psychiatric Association to recommend the use of vitamin E for patients with Alzheimer's (Am Psy Assoc1997). The Institute of Medicine, which sets the recommended daily requirement for nutrients, revised and increased the required dietary level of vitamin E and C in the year 2000. Even doctors believe in the value of antioxidants — 45% of American cardiologists surveyed admit to taking antioxidants (Mehta 1997).
     In vitro studies demonstrate that the use of multiple antioxidants gives better protection from free radical damage that single antioxidants (Knudsen 1996). This has been shown very well by research on beta-carotene. For many years, it was believed that the health benefits obtained from eating fruit and vegetables was due to the presence of beta-carotene. Science has now learned that other carotenoids, in addition to betacarotene, are antioxidants and have specific roles in disease prevention. Some of these carotenoids include cryptoxanthin, lutein, zeaxanthin, alpha-carotene and lycopene.
     To combat oxidative stress in DS, using multiple antioxidants is important because antioxidants interact: selenium is required for glutathione peroxidase function (an antioxidant enzyme) and selenium helps maintain vitamin E levels; lipoic acid can recycle vitamin C, E and glutathione; antioxidants like vitamin C and beta-carotene can help recycle oxidized vitamin E (Health Canada 1990, Packer 1995).

"The evidence that antioxidant vitamins ... may play an important role in promoting health and reducing the risk of several chronic diseases has been accumulating for >20 years"
(Blumberg 1995)

Nutritional Synergism

Nutrients, unlike drugs, do not act in isolation. Many nutrients have synergistic relationships and require other vitamins or minerals for optimal function. For example, vitamin E and zinc are required for proper vitamin A metabolism; riboflavin (vitamin B2) helps convert vitamin B6 into other metabolic forms; vitamin D increases calcium absorption (Whitney 1998).
With nutritional synergism in mind, a multi-nutrient supplement (vitamins, minerals, antioxidants, and amino acids) was formulated and provided to children with DS. After six months, the incidence of infection was reduced by 50% (Peeters and MacLeod, 1999).

"If anything is well established in biochemistry, it is that nutrients interact with one another...Probably, no single agent exists that is completely sufficient; rather, nutrients act optimally in conjunction with numerous other agents."
(Block 1995)

Conclusions

Oxidative stress, methylation disruptions and immune dysfunction are present in DS.
All 3 of these features can be influenced by nutritional supplements.
Common sense dictates that 'multi'-nutrients be used to preserve nutritional synergism.

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