SEVERE AND MILD MUTATIONS IN CIS FOR THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE, AND DESCRIPTION OF 5 NOVEL MUTATIONS IN MTHFR

Methyltnetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocys teine to methionine. Patients with severe MTHFR deficiency have hyperh omocysteinemia, hypomethioninemia, and a range of neurological and vas cular findings with a variable age at onset. We have previously descri bed nine mutations in patients with severe MTHFR deficiency. A mild fo rm of MTHFR deficiency, associated with a thermolabile enzyme, has bee n proposed as a genetic risk factor for cardiovascular disease and for neural tube defects, We have shown that a common missense mutation (a n alanine-to-valine substitution) encodes this thermolabile variant. W e now report an additional five mutations causing severe MTHFR deficie ncy and an analysis of genotype (alanine/valine status) and enzyme the rmolability in 22 patients with this inborn error of metabolism. Six o f these patients have four mutations in the MTHFR gene-two rare mutati ons causing severe deficiency and two mutations for the common alanine -to-valine mutation that results in thermolability. Even in severe MTH FR deficiency, the thermolabile variant is frequently observed, and th ere is a strong relationship between the presence of this variant and increased enzyme thermolability.