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Homocysteine metabolism in children
with Down syndrome: in vitro modulation.
• Pogribna M,
• Melnyk S,
• Pogribny I,
• Chango A,
• Yi P,
• James SJ.
Division of Biochemical Toxicology, Food and Drug Administration,
National Center for Toxicological Research, Jefferson, AR
72079, USA.
The gene for cystathionine beta-synthase (CBS) is located
on chromosome 21 and is overexpressed in children with Down
syndrome (DS), or trisomy 21. The dual purpose of the present
study was to evaluate the impact of overexpression of the
CBS gene on homocysteine metabolism in children with DS and
to determine whether the supplementation of trisomy 21 lymphoblasts
in vitro with selected nutrients would shift the genetically
induced metabolic imbalance. Plasma samples were obtained
from 42 children with karyotypically confirmed full trisomy
21 and from 36 normal siblings (mean age 7.4 years). Metabolites
involved in homocysteine metabolism were measured and compared
to those of normal siblings used as controls. Lymphocyte DNA
methylation status was determined as a functional endpoint.
The results indicated that plasma levels of homocysteine,
methionine, S-adenosylhomocysteine, and S-adenosylmethionine
were all significantly decreased in children with DS and that
their lymphocyte DNA was hypermethylated relative to that
in normal siblings. Plasma levels of cystathionine and cysteine
were significantly increased, consistent with an increase
in CBS activity. Plasma glutathione levels were significantly
reduced in the children with DS and may reflect an increase
in oxidative stress due to the overexpression of the superoxide
dismutase gene, also located on chromosome 21. The addition
of methionine, folinic acid, methyl-B(12), thymidine, or dimethylglycine
to the cultured trisomy 21 lymphoblastoid cells improved the
metabolic profile in vitro. The increased activity of CBS
in children with DS significantly alters homocysteine metabolism
such that the folate-dependent resynthesis of methionine is
compromised. The decreased availability of homocysteine promotes
the well-established "folate trap," creating a functional
folate deficiency that may contribute to the metabolic pathology
of this complex genetic disorder.
PMID: 11391481 [PubMed - indexed for MEDLINE]
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