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Homocysteine metabolism in children with Down syndrome: in vitro modulation
M Pogribna1, S Melnyk, I Pogribny
1Division of Biochemical Toxicology, Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Insights
Children with Down syndrome (DS) exhibit altered homocysteine metabolism due to cystathionine beta-synthase (CBS) gene overexpression. Nutrient supplementation in vitro improved metabolic profiles, suggesting a potential therapeutic approach for DS-related metabolic imbalances.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- The cystathionine beta-synthase (CBS) gene on chromosome 21 is overexpressed in Down syndrome (DS).
- Overexpression of CBS impacts homocysteine metabolism and DNA methylation.
- Down syndrome is associated with oxidative stress, potentially linked to superoxide dismutase gene overexpression.
Purpose of the Study:
- To evaluate the impact of CBS gene overexpression on homocysteine metabolism in children with DS.
- To determine if nutrient supplementation can correct metabolic imbalances in trisomy 21 lymphoblasts in vitro.
Main Methods:
- Collected plasma samples from 42 children with trisomy 21 and 36 controls.
- Measured homocysteine metabolism metabolites and lymphocyte DNA methylation status.
- Supplemented cultured trisomy 21 lymphoblastoid cells with methionine, folinic acid, methyl-B12, thymidine, or dimethylglycine.
Main Results:
- Children with DS showed decreased plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine.
- Increased plasma cystathionine and cysteine levels indicated elevated CBS activity.
- Lymphocyte DNA was hypermethylated, and plasma glutathione levels were reduced in children with DS.
- In vitro nutrient supplementation improved the metabolic profile of trisomy 21 lymphoblasts.
Conclusions:
- CBS overexpression in DS significantly alters homocysteine metabolism, compromising methionine resynthesis and leading to a functional folate deficiency.
- This metabolic imbalance may contribute to the pathology of Down syndrome.
- Nutrient supplementation shows promise in ameliorating these metabolic alterations in DS.
Abstract:
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.