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Hultdin J. Downs syndrome - should we increase homocysteine [debate]? Rondel 2001; 9. URL: http://www.rondellen.net

Down syndrome – should we increase homocysteine?

Elevated levels of homocysteine are usually regarded as a risk marker for disease. Reducing the homocysteine levels as much as possible is considered beneficial. Considering Down syndrome this might be a slightly simplified point of view. In recent years there have been a number of reports linking folate deficiency and low homocysteine levels to Down syndrome.

The risk of giving birth to a child with trisomy 21 is highest in older mothers but most of the children with Down syndrome are born by mothers younger than 30 years of age (1). All trisomies are caused by non-disjunction at the meiosis. The frequency of trisomies has been found to be around 80 % in embryos older than nine weeks with neural tube disease (NTD) (2,3). NTD is associated with folate deficiency. This is also the case for functional deficiency, caused by common polymorphisms in the enzyme methylene tetrahydrofolate reductase (MTHFR). At least 10 % of the population are homozygotes for the 677C® T polymorphism. The enzyme activity is reduced and folate deficiency occurs at serum folate levels below 15 nmol/L. This is reflected by increased homocysteine due toe the formation of insufficient amounts of 5-methyl-tetrahydrofolate (Fig).

The effect of the MTHFR 677C® T polymorphism on the risk of giving birth to a child with trisomy 21 was reported in 1999 (4). Mothers with the polymorphism had an odds ratio of 2,6 compared to those without the T-allele. The mechanism for this is not known but the functional folate deficiency that may occur causes a reduced remethylation of homocysteine to methionine. This leads to deficiency of S-adenosyl-metionine (SAM), which is the most important methyl donor. DNA may be hypomethylated due to methyl group deficiency, causing non-disjunction of the chromosomes at the meiosis. Well known for preventing NTD, folate supplementation during pregnancy has been proposed as a means of preventing Down syndrome. This hypothesis has not been tested in clinical trials.

Some changes/disturbances in homocysteine metabolism occur in trisomy 21. The gene for the vitamin B₆-dependent enzyme cystathione-b -synthase (CBS) is located on chromosome 21. CBS is important for the transsulphuration of homocysteine to cysteine. In trisomy 21 the enzyme activity is approximately 157 %. The homocystein levels are lower compared to other individuals. Recently a study was published comparing 42 children with trisomy 21 and 36 normal siblings (5). As expected lower levels of homocysteine was found in trisomy 21. The levels of methionine and SAM were decreased as well, methionine levels were only 50 % compared to siblings. This situation mimics what may occur if vitamin B6 is supplemented when the availability of folate and B₁₂ is insufficient (6,7). Homocysteine is cleared from the system by the high CBS activity with methionine deficiency as a result, thus causing a methyl group deficiency (SAM). A sort of "folate trap" is formed and methyl groups are lost in the transulphuration. Generally, it is not possible to compensate this by the methionine in food. In B₁₂ deficiency the "folate trap" is responsible for the methyl group deficiency that is considered to cause polyneuropathy and cognitive dysfunction. The methylation is crucial for the function of myelin sheaths and for synthesis of neurotransmittors. This might be important for the development of children with trisomy 21 after birth. Individuals with Down syndrome have an increased sensibility for methotrexate (8).

Experiments with lymphoblastoid cells with trisomy 21 were also performed in the recent study (5) By giving folinic acid or B₁₂ levels of methionine and SAM could be increased. Homocysteine increased as well. It might seem like a contradiction to find an increase of homocysteine after supplementation with B₁₂/folate. In this case it reflects a normalization of the metabolism in the cells. The authors present the hypothesis that folate supplementation might improve methylation in trisomy 21 and maybe prevent some of the neurological features of Down syndrome.

Prospective studies are needed to determine the value of folate supplementation for preventing Down syndrome and other trisomies. The folate enrichment of flour in the US has reduced the incidence of NTD but there have been no reports on the frequency of Down syndrome. Prospective studies are also needed to establish if supplementation might be beneficial for the development of individuals with trisomy 21. The lesson from Down syndrome is that some individuals might have too low levels of homocysteine. However, this is not the case for the majority of the population, as long as one considers the delicate balance of intake for B₁₂, B₆ and folate needed for optimal function and well being.

 References

1. Rosenblatt DS. Folate and homocysteine metabolism and gene polymorphisms in the etiology of Down syndrome. Am.J.Clin.Nutr. 1999;70(4):429-30.

2. McFadden DE, Kalousek DK. Survey of neural tube defects in spontaneously aborted embryos. Am.J.Med.Genet. 1989;32(3):356-8.

3. Seller MJ. Recent developments in the understanding of the aetiology of neural tube defects. Clin.Dysmorphol. 1995;4(2):93-104.

4. James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am.J.Clin.Nutr. 1999;70(4):495-501.

5. Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ. Homocysteine metabolism in children with Down syndrome: in vitro modulation. Am.J.Hum.Genet. 2001;69(1):88-95.

6. Naurath HJ, Riezler R, Putter S, Ubbink JB. Does a single vitamin B-supplementation induce functional vitamin B-deficiency? Clin.Chem.Lab Med. 2001;39(8):768-71.

7. Hultdin J. Vitamin B₆ and polyneuropathy. The Rondel vol 4, July-Aug 2000 (www.rondellen.net).

8. Ueland PM, Refsum H, Christensen B. Methotrexate sensitivity in Down's syndrome: a hypothesis. Cancer Chemother.Pharmacol. 1990;25(5):384-6.

Published January 6, 2002