caa a22 4500 47578698X CHVBK 20180406123701.0 cr unu---uuuuu 170329e20001201xx s 000 0 eng 10.1007/PL00014405 doi (NATIONALLICENCE)springer-10.1007/PL00014405 Blom Henk J. Laboratory of Paediatrics and Neurology, Department of Paediatrics, University Hospital Nijmegen, PO Box 9101, 6500HB Nijmegen, The Netherlands e-mail: h.blom@ckslkn.azn.nl Tel.: +31-24-3613469; Fax: +31-24-3618900, NL aut Genetic determinants of hyperhomocysteinaemia: the roles of cystathionine β-synthase and 5,10-methylenetetrahydrofolate reductase [Elektronische Daten] [Henk J. Blom] Over the last decade mild hyperhomocysteinaemia has widely been recognised as a new risk factor for arteriosclerosis and thrombosis. Main regulating enzymes of homocysteine (Hcy) metabolism are cystathionine β-synthase (CBS), methionine synthase and methylenetetrahydrofolate reductase (MTHFR). Early studies on patients with vascular disease described elevated Hcy concentrations after methionine loading and decreased CBS activity, resembling heterozygotes for CBS deficiency. Therefore, heterozygosity for CBS deficiency was proposed as the main cause of mild hyperhomocysteinaemia. However, more recent enzymatic and molecular genetic studies have demonstrated that heterozygosity for CBS deficiency is not or only a very minor cause of mild hyperhomocysteinaemia in vascular disease. We discovered two common genetic causes of mild hyperhomocysteinaemia, the 677C > T and the 1298A > C mutations in the coding region of MTHFR. The 677C > T mutation causes reduced enzyme activity with thermolabile protein properties, elevated Hcy and low-normal or decreased plasma folate levels. The 1298A > C mutation relates also to decreased enzyme activity, but not to thermolabile protein, and Hcy and folate levels are not influenced. However, compound heterozygosity for these two mutations, i.e. individuals with the 677CT/1298AC genotype, have elevated Hcy and decreased plasma folate levels. Gene-enviroment interactions between 677C > T and folate is demonstrated in individuals with the 677TT genotype. Those with low-normal folate have elevated Hcy, whereas those with high-normal folate have normal Hcy concentrations. The elevated Hcy levels due to these mutations can be normalised by administration of folate, but whether folate reduces the risk of cardiovascular disease remains to be established. Conclusion Heterozygosity for cystathionine β-synthase deficiency is a minor cause of hyperhomocysteinaemia. The current data on mutations in the methylenetetrahydrofolate reductase gene do not tell us whether elevated plasma homocysteine plays a causal role in vascular disease. Low cellular vitamin status may be a possible cause and homocysteine may just be a marker for this situation. Springer-Verlag Berlin Heidelberg, 2000 Key words Cardiovascular disease nationallicence Cystathionine β-synthase nationallicence Genetics nationallicence Methylenetetrahydrofolate reductase nationallicence Mild hyperhomocysteinaemia nationallicence https://doi.org/10.1007/PL00014405 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/PL00014405 text/html Onlinezugriff via DOI NATIONALLICENCE 100 1- Blom Henk J. Laboratory of Paediatrics and Neurology, Department of Paediatrics, University Hospital Nijmegen, PO Box 9101, 6500HB Nijmegen, The Netherlands e-mail: h.blom@ckslkn.azn.nl Tel.: +31-24-3613469; Fax: +31-24-3618900, NL aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer