Robert J. Thiel, Ph.D., N.M.D.

8th Annual Scientific Program of the Orthomolecular Health-Medicine Society March 1, 2002. San Francisco, CA Reprinted with the permission of the author

INTRODUCTION
Trisomy 21, more commonly referred to as Down syndrome, is a genetic disorder which is present in approximately 1 out of every 700 live births. It results in three number 21 chromosomes, as opposed to the normal two [1]. "The diagnostic clinical features of this condition are usually readily evident, even at birth. The flat facial profile, oblique palpebral fissures...Down syndrome is a leading cause of mental retardation. The mental retardation is severe...Virtually all patients with trisomy 21 older than 40 years of age develop neuropathologic changes characteristic of Alzheimer's disease, a degenerative disorder of the brain. Patients with Down syndrome have abnormal immune responses that predispose them to serious infections, particularly of the lungs, and to thyroid autoimmunity" [1]. Down's patients tend to be short since at age 18 the median average female with Down Syndrome grows to approximately 4'9½", and the average male grows to approximately 5'½" [2]. "These patients also have immune defects and an increased susceptibility to leukemia...Essentially nothing is known about how one extra chromosome 21 could have such profound effects" [3].

While there is no effective medical intervention for trisomy 21, there are treatments for complications such as cardiovascular disorders, hypothyroidism, and infections. Though some recommend nutrition as part of a program for those with trisomy disorders, the prevalent medical opinion appears to be that orthomolecular medicine is ineffective [4,5].

In 1940, Dr. Henry Turkel (M.D.) began experimenting with orthomolecular medicine for Down syndrome [4]. Due to problems with the US FDA, he ended up basically being confined to practicing only in Michigan (as well as Japan). In the mid 1970s, Dr. F. Jack Warner (M.D.) began to communicate with Turkel. In a meeting in California in 1984, Turkel asked Warner to take over his work. Since that time, Warner began to specialize in seeing patients with trisomy 21. Warner has probably seen more people with Down syndrome than any doctor currently living. The mother of one of his patients, Dixie Lawrence, did additional research and developed another formula, originally similar to that which Warner uses, but without iron and L-glutamine, but including certain amino acids. Dr. Lawrence Leichtman (M.D.), with others (including Lawrence), has been working to modify/expand Lawrence's formula. This researcher (Thiel) has made modifications to previous approaches by attempting to better individualize orthomolecular medicine for those with Down syndrome, advocating more natural vitamins/minerals, supporting suspected hypothyroidism nutritionally, and correlating some of the orthomolecular connections between Down syndrome and epilepsy [6,7]. This paper discusses some nutrients used in orthomolecular therapy and some of the results that Warner has attained.

SELECTED NUTRIENTS OF INTEREST
There are any number of nutrients which could be looked into; those shown below are some of those thought to be of more interest for this paper.

Vitamin A

Based on a review of several published studies, Baer et al concluded, "Serum vitamin A levels have been reported to be lower in individuals with Down syndrome...possibly due to malabsorption...However other workers have failed to confirm these findings" [8]; it appears that beta-carotene levels may be high [8]. It has been speculated that the alteration of the conjunctival epithelium in patients with Down syndrome may be due to altered metabolism of vitamin A [9]. A five month study involving 23 children with Down syndrome tested supplementation with vitamin A and concluded that it significantly reduced the incidence of infection and improved plasma vitamin A levels [10].

Vitamin B1 (Thiamin)

A blood study of 90 children up to 16 years old with Down syndrome found that marginal thiamin deficiency seemed to exist in this population at higher rates than the general public [11]. A smaller study found that non-institutionalized children with Down syndrome tended to consume thiamin below the recommended daily allowance [12].

Vitamin B6

It appears that vitamin B6 metabolism may be abnormal in those with Down syndrome [13-14]. A three year double-blind placebo controlled longitudinal study involving those with Down syndrome found that vitamin B6 supplementation helped normalize brain function by reducing elevated cortical auditory evoked potentials to a more normal level [15].

Folate (once known as vitamin B8)

Children with Down syndrome often have below normal levels of folate [16-18]. Erythrocyte macrocytotis is more common in children and adults with Down syndrome and may be due to an alteration of the folate remethylation pathway [16]. As those with Down syndrome age, further declines in folate levels seem to occur [19].

Vitamin B12

Some reports suggest that serum vitamin B12 levels are reduced for those with Down syndrome [20] while others have not found that [16].

Vitamin C

One study found that many children with Down syndrome had a deficiency of vitamin C according to serum tests which correlated to dietary intakes [21]. A case report [22] found the same result, yet a small study [12] found that institutionalized children with Down syndrome tended to consume more vitamin C than the recommended daily allowance.

Vitamin D

Disorders of vitamin D metabolism have also been speculated for Down's patients [4,23]. Not only have poor dietary intakes of vitamin D been found in those with Down syndrome [24], low levels have been found even in cases of high exposure to sunlight [23].

Vitamin E

A recent study found that children with Down syndrome have significantly less vitamin E levels than those without it [25]. Down syndrome patients with dementia appear to have lower plasma levels of vitamin E than those that do not [26].

Calcium

Turkel & Nusbaum speculated that those with Down syndrome often have disorders of calcium metabolism [4]. A small study found that children with Down syndrome tended to consume more calcium than the recommended daily allowance [12]. Decreased intracellular calcium levels have been found in those with Down syndrome [27]. Decreased hair levels of calcium have also been noted in the Down syndrome population [28].

Copper

Down syndrome patients have often been found to have elevated levels of copper. These elevations have been found in erythrocytes, neutrophils, platelets, and serum [26,29-31]. Interestingly, one study found normal copper levels in those with Down syndrome who had poor dietary intakes of copper [24], which may suggest that some metabolic disturbance increases copper retention in this population.

Iron

Anneren et al found that median levels of iron in erythrocytes and neutrophils were significantly lower in those with Down syndrome than in controls without it [31]. A small study found that children with Down syndrome tended to consume less iron than the recommended daily allowance [12].

Magnesium

One study found that magnesium levels in erythrocytes and thrombocytes, but not neutrophils were lower in children with Down syndrome [31]. Another found lower red blood cell levels of magnesium lower in the Down's group as compared to the non-Down's group [32].

Manganese

One study found that manganese levels in erythrocytes and thrombocytes were lower in children with Down's [31]. Another study found that hair levels of manganese seems to be lower in those with Down syndrome [33].

Selenium

Down's patients may have below normal plasma levels of selenium (31,32,34,35). As selenium does affect thyroid metabolism by helping convert T4 to T3 [36], it is possible that supplementing with it would have some benefit. Hamilton reports that one study found that supplementation with selenium reduced (by 50%) elevated mononuclear cell copper content in Down syndrome [35].

Zinc

Several reports suggest that Down's patients have below normal plasma levels of zinc [29,30,34,35,37]. Stabile et al. found that supplementation with zinc has been shown to increase DNA synthesis in Down's patients with low zinc levels [38]. A study by Bucci et al found that zinc reduced TSH by 34% for hypothyroid Down syndrome patients [39]. In addition, it has been found that children with Down syndrome become deficient in a zinc-containing insulin-like growth factor type 1 (IGF-1) after one year of age [40]. Even though zinc is a constituent in cytoplasmic superoxide dismutase, zinc supplementation was reported by Abdalla & Samman to reduce superoxide dismutase levels in non-Down's female subjects [41].

Carnitine

Deficient blood levels of carnitine are much more common in children with Down syndrome than in children without it [26].

Carnosine

No studies on carnosine levels have been found for this population.

Choline

Down syndrome is associated with a presynaptic cortical cholinergic deficit involving an extensive loss of choline acetyltransferase [42]. A case report showed that the EEG pattern of a 2½ year with DS improved after phosphatidyl choline supplementation [43].

Cysteine

People with Down syndrome have been found to have abnormally high levels of cysteine [44]. As an attempt to compensate, this may be why abnormally high levels of cathepsin S (a lysosomal cysteine protease) have been found, post-mortum, in those with Down's and Alzheimer's [45].

Dimethylglycine/Trimethylglycine

Dimethylglycine (DMG) is a precursor of glycine, which is a neuroinhibitory amino acid [46]. "Children with Down syndrome usually have particular difficulties with, and delays in, language development" [47]. Warner believes that DMG can improve speech and affect behavior for Down syndrome patients [48]. Leichtman, however, told this researcher that he prefers trimethylglycine (TMG) to DMG for those with Down syndrome. Rimland told this researcher that although TMG has certain theoretical advantages over DMG, that he felt that it seemed that, to date, DMG was still better clinically.

Inositol

People with Down syndrome tend to have abnormally high levels of myo-inositol [49-51]. This has also been confirmed in animal models [52].

Omega-6 Fatty Acids

Hamilton reported that long-chain omega-6 polyunsaturated fatty acid concentrations appear to be higher in Down syndrome patients [53].

Phenylalanine

Excess phenylalanine is often present in those with Down's [54]. There seems to be a difficulty in converting phenylalanine into tyrosine in Down's, probably because the activity of phenylalanine hydroxylase is impaired in the liver of those with Down syndrome [55].

Serine

One study found a significant plasma deficit of serine for those with Down syndrome compared those with non-Down's mental retardation [44].

Superoxide Dismutase

It is well recognized that superoxide dismutase levels are abnormally high in those with Down syndrome [8,32,41,56]. Tryptophan "There appears to be an abnormality of tryptophan metabolism in Down's syndrome" [14,26]. Infants with Down syndrome have been shown to improve muscle tone by taking tryptophan supplementation [57].

RESULTS
This researcher conducted an investigation of a randomly-selected sample of Warner's Down syndrome patient files. Height, weight, facial swelling, nose bridge development, and epicanthal eye fold was examined. The brief results are shown in the tables below (study details are part of two papers [58-59]):

Table 1 Height

Gender	N	Attibute	Initial Mean	Final Mean
			as Percentile on Down's Grid
Female	36	Height	63.1%	73.6%
Male	48	Height	63.6%	77.8%
Total	84	Height	63.4%	76.0%

Table 2 Weight

Gender	N	Attibute	Initial Mean	Final Mean
			as Percentile on Down's Grid
Female	40	Weight	60.9%	59.3%
Male	50	Weight	45.2%	53.7%
Total	90	Weight	52.2%	56.2%

For facial appearance, a comparison was made of before and after photographs in Warner's files. A ten point scale was developed with zero signifying normal for children without Down syndrome and to a maximum of ten signifying an appearance consistent with the more pronounced presentation of this feature. For example, a lack of any noticeable (or completely flat) nose bridge would receive a score of 10, whereas a completely normal appearing nose bridge would receive a score of zero. Some data was excluded if it was unclear from the photographs.

Table 3 Facial Swelling (excessive = 10)

Gender	N	Attibute	Initial Mean	Final Mean	Percent  Improvement
			on 10 Point Scale
Female	39	Facial Swelling	5.9	4.2	28.8%
Male	46	Facial Swelling	6.6	2.8	57.6%
Total	85	Facial Swelling	6.3	3.4	46.0%

Table 4 Nose Bridge (lack of =10)

Gender	N	Attibute	Initial Mean	Final Mean	Percent  Improvement
			on 10 Point Scale
Female	37	Nose Bridge	7.8	5.1	34.6%
Male	45	Nose Bridge	7.5	5.2	30.7%
Total	82	Nose Bridge	7.6	5.1	32.9%

Table 5 Epicanthal Fold (highly discernible =10)

Gender	N	Attibute	Initial Mean	Final Mean	Percent  Improvement
			on 10 Point Scale
Female	38	Epicanthal Fold	5.4	3.8	29.6%
Male	43	Epicanthal Fold	6.1	4.0	34.4%
Total	81	Epicanthal Fold	5.8	3.9	32.8%

DISCUSSION
In spite of apparent nutritional differences and clinical results, the use of orthomolecular medicine for persons with Down syndrome has been repeatedly challenged [5,60,61]. However, even some mainstream researchers have recommended vitamin and mineral supplementation for those with Down syndrome [62,63]. Early work, done by Turkel [4] as well as a study by Harrell et al [64] concluded that nutritional intervention did raise intelligence of persons with Down syndrome. Others, including the American Academy of Pediatrics, have criticized these researchers and have concluded that nutritional interventions are not effective [5,59,65]. Yet, Dr. Bernard Rimland (Ph.D.) investigated the work of some of the critics and found that they do not in fact properly duplicate with the Turkel or Harrell work; furthermore Rimland has written that the position of the American Academy of Pediatrics is "inaccurate, biased, and inept" [66]. Turkel, Warner, and others have shown before and after photographs to demonstrate that orthomolecular medicine can improve the appearance of those with Down syndrome [4,48]. This researcher, as shown above, has found that height, as well as facial features, appear to respond to orthomolecular medicine, specifically the Warner protocol [58,59]. Napolitano et al found that zinc supplementation increased growth in 15 of 22 children with Down syndrome [40].

Why might orthomolecular medicine play a role? Aside from the obvious nutritional differences previously mentioned in this paper, there are several possible reasons.

Down syndrome patients have increased incident of thyroid disorders [1,67,68]. Most orthomolecular interventions for it contain iodine which has been shown to be helpful for some thyroid problems [69] as well as the amino acid tyrosine (the primary thyroid hormone is composed of iodine and tyrosine [70]) and the minerals zinc and selenium. Bucci speculated that zinc deficiency may be one cause of subclinical hypothyroidism in children with Down syndrome [39], while a study by Kanavan et al found that thyroid hypofunction in Down syndrome appeared to be partially related to low selenium levels [71].

Phenylketonuria, which can also cause mental retardation, is caused by a deficiency of hepatic phenylalanine hydroxylase and reduces the conversion of phenylalanine into tyrosine, and is often controlled by reducing consumption of high phenylalanine foods [72]; there is a case report where a improvements were noted in a Down's patient who went on a low phenylalanine diet [73]. Since those with Down's tend to have a problem converting phenylalanine into tyrosine [55], it is possible that DYRK (dual-specificity tyrosine-regulated kinase) may have some involvement. DYRK1A, which is located in the Down syndrome critical region of chromosome 21, catalyzes tyrosine directed autophosphorylation as well as the phosphorylation of serine residues--it is suspected that DYRK1A may be involved in causing mental retardation in Down syndrome [74,75]. It should be added that DYRK1A only affects certain tyrosine forms [76]. DYRK1A may not have anything to do directly with the development of hypothyroidism or any other specific tyrosine abnormality currently recognized as being part of Down syndrome, but its impact does show that there are metabolic differences in Down syndrome that affect nutrients somewhat differently than occur in the non-Down's population.

Oxygen radical-induced damage appears to be important in Down's, Alzheimer's, and other illnesses with a neuropsychiatric components [56,77]. Biomarkers of oxidative stress have been found to be significantly elevated in patients with Down syndrome [78,79]. Warner has clinical findings which support his position that ingestion of antioxidant nutrients have the effect of lowering the body's levels of superoxide dismutase [79]--others involved with natural health have suggested that antioxidant nutrients such as vitamin C, beta carotene, flavonoids, zinc, selenium, and vitamin E may reduce free radical damage and possibly slow the accelerated aging associated with Down's [77,80]. Some believe that the impaired viability of Down syndrome neurons can be amended by antioxidants, such as vitamin E [78].

Carnosine is an efficient chelating agent for copper [81] which is of interest as many with DS have abnormally high copper levels [26,29,30]. Carnosine and related compounds such as homocarnosine have been found to have protective effects against hydrogen peroxide-mediated Cu,Zn-superoxide dismutase fragmentation [82] and Cu,Zn-superoxide mutants [83]. Accelerated brain glycation (and the resulting brain damage) occurs early in the life of those with Down syndrome [84]and carnosine is also an antiglycation agent [85,86]. Since selenium rich yeast has been shown to have 123 times the antiglycation effect as sodium selenite for diabetics [87], it may be the preferred form to use when Down syndrome is present.

Supplementation with acetyl-l-carnitine has been shown to improve memory and attention in patients with Down syndrome [88]. N,n-dimethylglycine (DMG), an amino acid derivative, is naturally found in the human body and supports transmethylation processes [89]. There is a report of a Korean study which used DMG for autistic children which found that it improved verbal communications and behavior, while a report of a Taiwanese study suggests that DMG reduced lethargy in autistic children, but did not improve speech [90]--Warner has found that it does improve speech in those with Down syndrome [48]. Down children are especially prone to bacterial respiratory infections [1]. One study found that supplementation with selenium rich yeast tablets significantly stimulated serum concentrations of IgG2 and IgG4 antibodies (which are frequently low in Down syndrome patients) [34]. IgG2 is known to be directed against the bacterial polysaccharide antigens of encapsulated bacteria such as streptococcus pneumoniae and hemophilus influenza [34]. An Italian study, however, found that low levels of vitamin C consumption was correlated with increased infection rates for children with Down syndrome [21]. Warner reports a reduced incidence of infections for those undergoing his treatment [48].

Dietary restrictions may also be advisable. A study involving Dutch children with Down syndrome concluded that those children were more prone to have celiac disease than other Dutch children, but not more likely to have a cow's milk intolerance [91]. Celiac disease seems to increase IgA and IgG in Down's patients [92,93]. A German study concluded that children with Down syndrome had higher bovine serum albumin antibody levels than others [94]. Thiel, Warner, and Leichtman often advise against the consumption of cow's milk for those with Down syndrome, but Turkel did not.

CONCLUSION
Whether or not specifically due to the presence of a third 21^st chromosome, metabolic disturbances are involved with Down syndrome. The nutritional profiles of the Down syndrome population do in certain significant ways, differ from those of the general public. Various signs and symptoms associated with Down syndrome have been reported to improve when certain nutritional protocols have been tried (and there is no accepted medical treatment currently in existence for Down syndrome). Orthomolecular medicine has safely been treating people with Down syndrome for over sixty years. Orthomolecular medicine is a logical therapy to consider when Down syndrome is present.

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