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Homocysteine, factor VII and antithrombin III in subjects with different gene dosage for cystathionine beta-synthase
L Brattström1, B Israelsson, L Tengborn
1Department of Neurology, University Hospital, Lund, Sweden.
Insights
Cystathionine beta-synthase deficiency impacts homocysteine levels and cardiovascular health. Down syndrome individuals show an unexpected lack of gene dosage effect on homocysteine metabolism, potentially explaining their lower arteriosclerosis risk.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia, leading to premature arteriosclerosis and thromboembolism.
- CBS deficiency is associated with reduced antithrombin III activity and Factor VII levels.
- Heterozygotes may show increased arteriosclerosis, while Down syndrome (DS) individuals, with increased CBS gene dosage, exhibit reduced arteriosclerosis.
Purpose of the Study:
- To investigate plasma homocysteine levels, antithrombin III activity, and Factor VII antigen in individuals with CBS deficiency (homozygotes and heterozygotes) and in subjects with Down syndrome.
- To determine if Down syndrome individuals exhibit an expected gene dosage effect on homocysteine metabolism.
- To explore potential correlations between homocysteine levels, antithrombin III activity, and Factor VII antigen in these groups.
Main Methods:
- Measurement of total plasma homocysteine levels in homozygotes, heterozygotes, and Down syndrome subjects compared to controls.
- Assessment of plasma homocysteine response after methionine loading in heterozygotes and Down syndrome subjects.
- Quantification of antithrombin III activity and Factor VII antigen levels in all study groups.
Main Results:
- Total plasma homocysteine was elevated in CBS homozygotes and heterozygotes. Down syndrome subjects did not show reduced homocysteine levels as expected.
- Methionine loading revealed pathologically high homocysteine increases in most heterozygotes but not in Down syndrome subjects.
- Antithrombin III activity was reduced in Down syndrome subjects, while Factor VII antigen was normal. No significant correlations were found between homocysteine, antithrombin III, and Factor VII.
Conclusions:
- Down syndrome individuals do not display the anticipated gene dosage effect on homocysteine metabolism, which may contribute to their reduced susceptibility to arteriosclerosis.
- Antithrombin III activity and Factor VII antigen levels do not appear to be directly related to homocysteine metabolism in the context of CBS deficiency or Down syndrome.
Abstract:
Cystathionine beta-synthase deficiency results in severe homocysteinaemia, precocious arteriosclerosis and frequent thromboembolism. In addition, antithrombin III activity and factor VII are low. Arteriosclerosis seems to be increased in heterozygotes as well (cystathionine beta-synthase gene dosage 50%) but rare in Down syndrome (cystathionine beta-synthase gene dosage 150%). In the present study total plasma homocysteine was high in three homozygotes, slightly increased in 20 obligate heterozygotes but not reduced in nine subjects with Down syndrome when compared to controls. After methionine loading, increases of homocysteine were pathologically high in 14 of 20 heterozygotes but was not, as expected, low in subjects with Down syndrome. Antithrombin III activity and factor VII antigen tended to be low in homozygotes but were normal in heterozygotes. In Down syndrome antithrombin III activity was reduced and factor VII antigen normal. There were no correlations between levels of homocysteine, antithrombin III activity and factor VII antigen. Thus, subjects with Down syndrome seem not to exhibit the expected gene dosage effect on homocysteine metabolism which could explain their reduced proneness to develop arteriosclerosis, nor do antithrombin III activity or factor VII antigen seem to be related to homocysteine metabolism.
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